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Entry
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- *113705 - BRCA1 DNA REPAIR-ASSOCIATED PROTEIN; BRCA1
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- OMIM
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<p>
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<span class="h4">*113705</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#evolution">Evolution</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/113705">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=672" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=113705" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001407571,NM_001407581,NM_001407582,NM_001407583,NM_001407585,NM_001407587,NM_001407590,NM_001407591,NM_001407593,NM_001407594,NM_001407596,NM_001407597,NM_001407598,NM_001407602,NM_001407603,NM_001407605,NM_001407610,NM_001407611,NM_001407612,NM_001407613,NM_001407614,NM_001407615,NM_001407616,NM_001407617,NM_001407618,NM_001407619,NM_001407620,NM_001407621,NM_001407622,NM_001407623,NM_001407624,NM_001407625,NM_001407626,NM_001407627,NM_001407628,NM_001407629,NM_001407630,NM_001407631,NM_001407632,NM_001407633,NM_001407634,NM_001407635,NM_001407636,NM_001407637,NM_001407638,NM_001407639,NM_001407640,NM_001407641,NM_001407642,NM_001407644,NM_001407645,NM_001407646,NM_001407647,NM_001407648,NM_001407649,NM_001407652,NM_001407653,NM_001407654,NM_001407655,NM_001407656,NM_001407657,NM_001407658,NM_001407659,NM_001407660,NM_001407661,NM_001407662,NM_001407663,NM_001407664,NM_001407665,NM_001407666,NM_001407667,NM_001407668,NM_001407669,NM_001407670,NM_001407671,NM_001407672,NM_001407673,NM_001407674,NM_001407675,NM_001407676,NM_001407677,NM_001407678,NM_001407679,NM_001407680,NM_001407681,NM_001407682,NM_001407683,NM_001407684,NM_001407685,NM_001407686,NM_001407687,NM_001407688,NM_001407689,NM_001407690,NM_001407691,NM_001407692,NM_001407694,NM_001407695,NM_001407696,NM_001407697,NM_001407698,NM_001407724,NM_001407725,NM_001407726,NM_001407727,NM_001407728,NM_001407729,NM_001407730,NM_001407731,NM_001407732,NM_001407733,NM_001407734,NM_001407735,NM_001407736,NM_001407737,NM_001407738,NM_001407739,NM_001407740,NM_001407741,NM_001407742,NM_001407743,NM_001407744,NM_001407745,NM_001407746,NM_001407747,NM_001407748,NM_001407749,NM_001407750,NM_001407751,NM_001407752,NM_001407838,NM_001407839,NM_001407841,NM_001407842,NM_001407843,NM_001407844,NM_001407845,NM_001407846,NM_001407847,NM_001407848,NM_001407849,NM_001407850,NM_001407851,NM_001407852,NM_001407853,NM_001407854,NM_001407858,NM_001407859,NM_001407860,NM_001407861,NM_001407862,NM_001407863,NM_001407874,NM_001407875,NM_001407879,NM_001407881,NM_001407882,NM_001407884,NM_001407885,NM_001407886,NM_001407887,NM_001407889,NM_001407894,NM_001407895,NM_001407896,NM_001407897,NM_001407898,NM_001407899,NM_001407900,NM_001407902,NM_001407904,NM_001407906,NM_001407907,NM_001407908,NM_001407909,NM_001407910,NM_001407915,NM_001407916,NM_001407917,NM_001407918,NM_001407919,NM_001407920,NM_001407921,NM_001407922,NM_001407923,NM_001407924,NM_001407925,NM_001407926,NM_001407927,NM_001407928,NM_001407929,NM_001407930,NM_001407931,NM_001407932,NM_001407933,NM_001407934,NM_001407935,NM_001407936,NM_001407937,NM_001407938,NM_001407939,NM_001407940,NM_001407941,NM_001407942,NM_001407943,NM_001407944,NM_001407945,NM_001407946,NM_001407947,NM_001407948,NM_001407949,NM_001407950,NM_001407951,NM_001407952,NM_001407953,NM_001407954,NM_001407955,NM_001407956,NM_001407957,NM_001407958,NM_001407959,NM_001407960,NM_001407962,NM_001407963,NM_001407964,NM_001407965,NM_001407966,NM_001407967,NM_001407968,NM_001407969,NM_001407970,NM_001407971,NM_001407972,NM_001407973,NM_001407974,NM_001407975,NM_001407976,NM_001407977,NM_001407978,NM_001407979,NM_001407980,NM_001407981,NM_001407982,NM_001407983,NM_001407984,NM_001407985,NM_001407986,NM_001407990,NM_001407991,NM_001407992,NM_001407993,NM_001408392,NM_001408396,NM_001408397,NM_001408398,NM_001408399,NM_001408400,NM_001408401,NM_001408402,NM_001408403,NM_001408404,NM_001408406,NM_001408407,NM_001408408,NM_001408409,NM_001408410,NM_001408411,NM_001408412,NM_001408413,NM_001408414,NM_001408415,NM_001408416,NM_001408418,NM_001408419,NM_001408420,NM_001408421,NM_001408422,NM_001408423,NM_001408424,NM_001408425,NM_001408426,NM_001408427,NM_001408428,NM_001408429,NM_001408430,NM_001408431,NM_001408432,NM_001408433,NM_001408434,NM_001408435,NM_001408436,NM_001408437,NM_001408438,NM_001408439,NM_001408440,NM_001408441,NM_001408442,NM_001408443,NM_001408444,NM_001408445,NM_001408446,NM_001408447,NM_001408448,NM_001408450,NM_001408451,NM_001408452,NM_001408453,NM_001408454,NM_001408455,NM_001408456,NM_001408457,NM_001408458,NM_001408459,NM_001408460,NM_001408461,NM_001408462,NM_001408463,NM_001408464,NM_001408465,NM_001408466,NM_001408467,NM_001408468,NM_001408469,NM_001408470,NM_001408472,NM_001408473,NM_001408474,NM_001408475,NM_001408476,NM_001408478,NM_001408479,NM_001408480,NM_001408481,NM_001408482,NM_001408483,NM_001408484,NM_001408485,NM_001408489,NM_001408490,NM_001408491,NM_001408492,NM_001408493,NM_001408494,NM_001408495,NM_001408496,NM_001408497,NM_001408498,NM_001408499,NM_001408500,NM_001408501,NM_001408502,NM_001408503,NM_001408504,NM_001408505,NM_001408506,NM_001408507,NM_001408508,NM_001408509,NM_001408510,NM_001408511,NM_001408512,NM_001408513,NM_001408514,NM_007294,NM_007297,NM_007298,NM_007299,NM_007300" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_007294" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=113705" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=00218&isoform_id=00218_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/BRCA1" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/555932,728984,1000569,1498737,1546074,1698399,1841427,2218154,6552299,9739179,23266700,24430095,24430097,24430099,24430101,24430104,24430106,24430108,24430110,24430112,24431185,24431187,24431189,25140446,30039659,32140995,37537746,38382815,47939870,52001522,52001524,52001526,53794093,55250220,70611296,70959462,73665398,73665400,73665402,73665404,73665406,75874527,75874617,75874675,75874794,75874871,75874961,75875069,75875129,78070589,78070810,82623248,82623250,82623252,82623254,82623256,82623258,82623262,82623271,82623276,82623285,82623287,82623289,82623291,82623293,82623295,82623297,82623299,82623301,82623303,82623305,82623307,82623309,82623311,82623313,82623315,82623317,82623319,84626582,84626584,86279115,92096024,94315232,116283824,119581326,119581327,119581328,119581329,119581330,119581331,119581332,119581333,119581334,119581335,119581336,119581337,119581338,119581339,119581340,119581341,119581342,119581343,119581344,119581345,119581346,221045788,237681119,237681121,237681123,237681125,237930356,344179065,350540199,350540201,350540203,350540205,350540207,350540209,350540211,353441749,408773036,408773038,408773040,408773042,408773044,408773046,408773048,408773050,655204045,655204048,655204051,655204056,655204086,655204131,655204145,655204176,655204185,655204200,655204214,655204234,655204246,655204252,655204270,655204290,655204304,655204315,655204331,655204348,655204685,655204701,655204741,655204766,655204773,655204781,655204824,655204872,655204873,655204916,655204955,655205017,725825441,815932479,815932481,815932483,815932485,815932487,815932489,815932491,815932493,819326628,819327290,819327325,819327355,819327357,827494114,827514371,891070991,891071011,891071029,896689375,896689377,925719367,929982561,952951593,952951595,952951597,974031366,974031368,1003107961,1003107963,1003107965,1003107967,1003107969,1003107971,1003107973,1003107975,1003107977,1003107979,1060746688,1246291365,1367361247,1378096911,1378096913,1378096915,1378096917,1378096919,1378096921,1378096923,1378096925,1378096927,1378096929,1378096931,1378096933,1378096935,1378096937,1378096939,1435082957,1435082959,1435082961,1435082963,1435082965,1435082967,1435082969,1435082971,1483525253,1483525255,1483525257,1483525259,1483525260,1483525262,1483525264,1483525275,1483525277,1483525282,1483525284,1483525286,1483525288,1483525290,1483525292,1483525294,1483525296,1483525298,1483525300,1483525302,1483525304,1483525306,1483525308,1483525310,1483525312,1483525314,1483525316,1483525318,1483525320,1483525322,1483525324,1483525326,1483976470,1483976472,1483976474,1534889324,1534889326,1534889328,1534889330,1534889332,1534889334,1534889336,1534889338,1534889340,1534889342,1534889344,1534889346,1534889348,1534889350,1534889352,1534889354,1534889356,1534889358,1534889360,1534889362,1534889364,1534889366,1534889368,1534889370,1534889372,1534889374,1534889376,1534889378,1534889380,1534889382,1534889384,1534889386,1534889388,1534889390,1534889392,1534889394,1534889396,1534889398,1534889400,1534889402,1534889404,1534889406,1534889408,1534889410,1534889412,1534889414,1534889416,1534889418,1534889420,1534889422,1534889424,1534889426,1534889428,1534889430,1534889432,1534889434,1534889436,1534889438,1534889440,1534889442,1534889445,1591645911,1591645913,1591645915,1591645917,1591645919,1591645921,1591645923,1591645925,1591645927,1591645929,1591645931,1591645933,1591645935,1591645937,1591645939,1591645941,1591645943,1591645945,1591645947,1591645949,1591645951,1591645953,1591645955,1591645957,1591645959,1591645961,1591645963,1591645965,1591645967,1591645969,1591645971,1591645973,1591645975,1591645977,1591645979,1591645981,1591645983,1591645985,1591645987,1591645989,1591645991,1591645993,1591645995,1591645997,1591645999,1591646001,1591646003,1591646005,1591646007,1591646009,1591646011,1591646013,1591646015,1591646017,1591646019,1591646021,1591646023,1591646025,1591646027,1591646029,1591646031,1591646033,1591646035,1591646037,1591646039,1591646041,1591646043,1591646045,1591646047,1591646049,1591646051,1591646053,1591646055,1591646057,1591646059,1591646061,1591646063,1591646065,1591646067,1591646069,1591646071,1591646073,1591646075,1591646077,1591646079,1591646081,1591646083,1591646085,1591646087,1591646089,1591646091,1591646093,1591646095,1591646097,1591646101,1591646107,1591646111,1591646113,1591646115,1591646119,1591646121,1591646123,1591646125,1591646129,1591646131,1591646133,1591646135,1591646137,1591646139,1591646141,1591646143,1591646145,1591646147,1591646149,1591646151,1591646153,1591646155,1591646157,1591646159,1591646161,1591646163,1591646165,1591646167,1591646169,1591646171,1591646173,1591646175,1591646177,1591646179,1591646181,1591646183,1591646185,1591646187,1591646189,1591646191,1591646193,1591646195,1591646197,1591646199,1591646201,1591646203,1591646205,1591646207,1591646209,1591646211,1591646213,1591646215,1591646217,1591646219,1591646221,1591646223,1591646225,1591646227,1591646229,1591646231,1591646233,1591646235,1591646237,1591646239,1591646241,1591646245,1591646247,1591646249,1591646251,1591646253,1591646255,1591646257,1591646259,1591646261,1591646263,1591646265,1591646269,1591646271,1591646273,1591646277,1591646279,1591646285,1591646289,1591646291,1591646293,1591646295,1591646297,1591646299,1591646301,1591646303,1591646305,1591646307,1591646309,1591646311,1591646313,1591646315,1591646317,1591646319,1591646321,1591646323,1591646325,1591646327,1591646331,1591646337,1591646339,1591646341,1591646343,1591646345,1591646347,1591646349,1591646351,1591646353,1591646355,1591646357,1591646359,1591646361,1591646363,1591646365,1591646367,1591646369,1591646373,1591646375,1591646377,1591646379,1591646381,1591646383,1591646385,1591646387,1591646389,1591646391,1591646393,1591646395,1591646397,1591646399,1591646401,1591646403,1591646405,1591646407,1591646409,1591646411,1591646413,1591646415,1591646417,1591646419,1591646421,1591646423,1591646425,1591646427,1591646429,1591646431,1591646433,1591646435,1591646437,1591646439,1591646441,1591646443,1591646445,1591646447,1591646449,1591646451,1633439648,1633439650,1633439661,1775113870,1775113872,1811001076,1821655611,1821655613,1821655615,1821655621,1896049792,1896049794,1896049796,1931625759,2001549011,2029084593,2029084595,2029084597,2029084599,2043420397,2043420465,2043420467,2043420469,2043420471,2043420538,2043420540,2043420542,2043420544,2054258294,2054258296,2094552264,2094552272,2095878425,2164862743,2164862749,2164862751,2164862757,2164862765,2164862781,2164862783,2164862785,2164862787,2164862789,2164862791,2164862793,2164862795,2164862797,2164862799,2164862801,2164862803,2178104996,2178104998,2178105000,2178105002,2178105203,2178105575,2179160378,2214793706,2218468102,2218468124,2218469276,2218469280,2218469282,2218469284,2248537882,2249006927,2249006935,2249006949,2249006951,2249006953,2249006955,2249006961,2249006973,2249006975,2249006977,2249006989,2249006991,2249006993,2249006998,2249007000,2249007002,2249007004,2249007008,2249007012,2249007021,2249007023,2249007027,2249007031,2249007033,2249007035,2249007039,2249007045,2249007047,2249007051,2249007058,2249007060,2249007068,2249007070,2249007072,2249007074,2249007076,2249007078,2249007080,2249007091,2249007093,2249007106,2249007124,2249007127,2249007129,2249007131,2249007133,2249007138,2249007144,2249007146,2249007149,2249007153,2249007155,2249007158,2249218165,2249629730,2249629735,2249629737,2249629741,2249629743,2249629754,2249629756,2249629758,2249629760,2249629762,2249629769,2249629771,2249629773,2249629775,2249629777,2249629787,2249629789,2249629791,2249629793,2249629799,2249629801,2249629803,2249629805,2249629807,2249629809,2249629813,2249629819,2249629821,2249629823,2249629825,2249629829,2249629833,2249629840,2249629844,2249629848,2249629852,2249629854,2249629862,2249629864,2249629870,2249629872,2249629876,2249629879,2249629885,2249629887,2249629889,2249629891,2249629895,2249629897,2249629909,2249629917,2249629919,2249629929,2249629931,2249629937,2249629945,2249629950,2249629952,2249629954,2249629958,2249629960,2249629962,2249629966,2249629975,2249629977,2249629981,2249629983,2249629987,2249629989,2249629991,2249629993,2249629997,2249629999,2249630003,2249630011,2250017139,2250017141,2250017151,2250017165,2250017167,2250017187,2250017189,2250017197,2250017202,2250017206,2250017224,2250017250,2250017256,2250017260,2250017272,2250017274,2250017276,2250017278,2250017282,2250017290,2250017298,2250017304,2250017306,2250017308,2250017329,2250017337,2250017339,2250017345,2250017347,2250017349,2250017351,2250017353,2250017355,2250017362,2250017366,2250017368,2250017381,2250017383,2250017389,2250017393,2250017405,2250017411,2250017413,2250017417,2250017419,2250232291,2250232293,2250232295,2250232302,2250232314,2250232316,2250232320,2250232322,2250232324,2250232332,2250232334,2250232336,2250232340,2250232342,2250232345,2250232347,2250232349,2250232355,2250232357,2250232366,2250232368,2250232372,2250232374,2250232378,2250232380,2250232388,2250232394,2250232400,2250232408,2250232410,2250232412,2250232414,2250232416,2250232418,2250232426,2250232432,2250232434,2250232441,2250232444,2250232448,2250232453,2250232458,2250232460,2250232462,2250232467,2250232472,2250232476,2250232480,2250232482,2250232484,2250232489,2250232491,2250232496,2250232498,2250232502,2250232504,2250232508,2250232510,2250232512,2250232520,2250232527,2250232529,2250232531,2250232536,2250232539,2250232541,2250232547,2250232551,2250232553,2250232555,2250232557,2250232559,2250232562,2250232575,2250232577,2250232581,2255444081,2255444083,2255444085,2255444087,2255444091,2255444093,2255444095,2255444097,2255444101,2255444107,2255444112,2255444118,2255444122,2255444126,2255444135,2255444139,2255444145,2255444147,2255444151,2255444153,2255444157,2255444159,2255444163,2255444167,2255444169,2255444174,2255444176,2255444178,2255444180,2255444184,2255444192,2255444194,2255444196,2255444200,2255444202,2255444204,2255444206,2255444208,2255444212,2255444216,2255444218,2255444220,2255444222,2255444224,2255444228,2255444232,2255444241,2255444249,2255444251,2255444253,2255444257,2255444259,2255444261,2255444263,2255444265,2255444267,2255444275,2255444282,2255444288,2255444306,2255444308,2255444312,2255444318,2255444320,2255444324,2255444344,2255444346,2255444573,2255444941,2255445265,2255445399,2255445557,2255446218,2255446601,2255446638,2255446641,2255446662,2255446667,2255446697,2255446717,2255447520,2255447721,2255447825,2255448079,2255448093,2255448600,2255448770,2255449024,2255449180,2255449844,2255450433,2255450585,2255450762,2255451067,2255451245,2255451431,2255451928,2255452079,2255452260,2255452523,2255452864,2255453230,2255453587,2255453951,2255454031,2255454272,2255454491,2255454693,2255455096,2255455874,2255456066,2255456860,2389772339,2389772341,2389772343,2389772345,2389772347,2389772349,2389772351,2396616248,2396616250,2396616252,2396616370,2430144117,2430144119,2430144121,2430144123,2430144125,2430144127,2430144129,2430144131,2430144133,2430144135,2450748324,2450748325,2450748326,2450748327,2450748328,2468371728,2468371792,2468371861,2468371888,2468371927,2468371966,2468372051,2468372089,2468372140,2468372185,2468372302,2468372349,2468372391,2468372427,2468372461,2468372497,2468372629,2468372656,2468372732,2468372756,2468372816,2468372848,2468372873,2468372900,2468372952,2468372976,2468373004,2468373025,2468373061,2468373086,2468373110,2468373155,2468373213,2468373236,2468373259,2468373377,2468373407,2557734826,2557734828,2557734830,2557734832,2557734834,2557734836,2607637241,2607637243,2607637245,2607637247,2616260797,2616260799,2616260801,2616260803,2616260805,2701656703,2703623452,2703623454,2703623456,2703623458,2909903171,2909903173" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P38398" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=672" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000012048;t=ENST00000357654" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=BRCA1" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=BRCA1" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+672" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/BRCA1" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:672" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/672" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr17&hgg_gene=ENST00000357654.9&hgg_start=43044295&hgg_end=43170327&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:1100" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:1100" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/brca1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=113705[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=113705[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/BRCA1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000012048" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=BRCA1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=BRCA1" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=BRCA1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://chromium.liacs.nl/LOVD2/cancer/home.php?select_db=BRCA1" title="LOVD - BReast CAncer 1 - literature unclassified variants (BRCA1)" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">LOVD - BReast CAncer 1 - l…</a></div><div style="margin-left: 0.5em;"><a href="http://databases.lovd.nl/genomed/home.php?select_db=BRCA1" title="Zhejiang University-Adinovo Center BRCA1 Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Zhejiang University-Adinov…</a></div><div style="margin-left: 0.5em;"><a href="http://research.nhgri.nih.gov/bic/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Breast Cancer</a></div><div style="margin-left: 0.5em;"><a href="http://www.umd.be/BRCA1/" title="The UMD BRCA1 mutations database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">The UMD BRCA1 mutations da…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=BRCA1&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA25411" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:1100" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:104537" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/BRCA1#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:104537" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/672/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=672" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000264;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:113705" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:672" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=BRCA1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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113705
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
|
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BRCA1 DNA REPAIR-ASSOCIATED PROTEIN; BRCA1
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
BREAST CANCER 1 GENE
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=BRCA1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BRCA1</a></em></strong>
|
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/17/610?start=-3&limit=10&highlight=610">17q21.31</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:43044295-43170327&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">17:43,044,295-43,170,327</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=604370,614320,617883" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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</th>
|
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
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<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/17/610?start=-3&limit=10&highlight=610">
|
|
17q21.31
|
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</a>
|
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</span>
|
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</td>
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|
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<td>
|
|
<span class="mim-font">
|
|
{Breast-ovarian cancer, familial, 1}
|
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</span>
|
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</td>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>BRCA1 plays critical roles in DNA repair, cell cycle checkpoint control, and maintenance of genomic stability. BRCA1 forms several distinct complexes through association with different adaptor proteins, and each complex forms in a mutually exclusive manner (<a href="#165" class="mim-tip-reference" title="Wang, B., Hurov, K., Hofmann, K., Elledge, S. J. <strong>NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control.</strong> Genes Dev. 23: 729-739, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19261749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19261749</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19261749[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.1770309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19261749">Wang et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19261749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#101" class="mim-tip-reference" title="Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P. A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L. M., Ding, W., Bell, R., Rosenthal, J., and 33 others. <strong>A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.</strong> Science 266: 66-71, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7545954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7545954</a>] [<a href="https://doi.org/10.1126/science.7545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7545954">Miki et al. (1994)</a> identified cDNA sequences corresponding to the BRCA1 gene by positional cloning of the region on 17q21 implicated in familial breast-ovarian cancer syndrome (<a href="/entry/604370">604370</a>). The deduced 1,863-residue protein with zinc finger domains near the N terminus. A 7.8-kb mRNA transcript was identified in testes, thymus, breast and ovary. There appeared to be a complex pattern of alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Bennett, L. M., Haugen-Strano, A., Cochran, C., Brownlee, H. A., Fiedorek, F. T., Jr., Wiseman, R. W. <strong>Isolation of the mouse homologue of BRCA1 and genetic mapping to mouse chromosome 11.</strong> Genomics 29: 576-581, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575748</a>] [<a href="https://doi.org/10.1006/geno.1995.9963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575748">Bennett et al. (1995)</a> found that the mouse Brca1 gene shares 75% identity of the coding region with the human sequence at the nucleotide level, whereas the predicted amino acid identity was only 58%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8575748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#80" class="mim-tip-reference" title="Jensen, R. A., Thompson, M. E., Jetton, T. L., Szabo, C. I., van der Meer, R., Helou, B., Tronick, S. R., Page, D. L., King, M.-C., Holt, J. T. <strong>BRCA1 is secreted and exhibits properties of a granin.</strong> Nature Genet. 12: 303-308, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589722</a>] [<a href="https://doi.org/10.1038/ng0396-303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589722">Jensen et al. (1996)</a> demonstrated that BRCA1 encodes a 190-kD protein with sequence homology and biochemical analogy to members of the granin protein family, including chromogranin A (<a href="/entry/118910">118910</a>), chromogranin B (<a href="/entry/118920">118920</a>), and secretogranin II, also known as chromogranin C (<a href="/entry/118930">118930</a>). They noted that BRCA2 (<a href="/entry/600185">600185</a>) also includes a motif similar to the granin consensus at the C terminus of the protein. Both BRCA1 and the granins localize to secretory vesicles, are secreted by a regulated pathway, are posttranslationally glycosylated, and are responsive to hormones. The authors stated that as a regulated secretory protein, BRCA1 appears to function by a mechanism not previously described for tumor suppressor products. As reviewed by <a href="#147" class="mim-tip-reference" title="Steeg, P. S. <strong>Granin expectations in breast cancer?</strong> Nature Genet. 12: 223-225, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589705</a>] [<a href="https://doi.org/10.1038/ng0396-223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589705">Steeg (1996)</a>, granins are a family of acidic proteins that bind calcium and aggregate in its presence. Known members of the granin family have been solely neuroendocrine or endocrine in origin; if BRCA1 is a granin it will necessarily expand the protein family boundaries. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8589705+8589722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="ElShamy, W. M., Livingston, D. M. <strong>Identification of BRCA1-IRIS, a BRCA1 locus product.</strong> Nature Cell Biol. 6: 954-967, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15448696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15448696</a>] [<a href="https://doi.org/10.1038/ncb1171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15448696">ElShamy and Livingston (2004)</a> identified a splice variant of BRCA1 that incorporates a unique 40-nucleotide first exon, exon 1c, that is located 24 Mb upstream of BRCA1 exons 1a and 1b. The 3-prime end of this cDNA extends 335 nucleotides into intron 11, prompting <a href="#42" class="mim-tip-reference" title="ElShamy, W. M., Livingston, D. M. <strong>Identification of BRCA1-IRIS, a BRCA1 locus product.</strong> Nature Cell Biol. 6: 954-967, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15448696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15448696</a>] [<a href="https://doi.org/10.1038/ncb1171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15448696">ElShamy and Livingston (2004)</a> to designate it IRIS for 'in-frame reading of BRCA1 intron 11 splice variant.' The deduced BRCA1-IRIS protein contains 1,399 amino acids. In vitro transcription-translation resulted in a protein with an apparent molecular mass of about 150 kD. Northern blot analysis of fibroblast mRNA detected BRCA1-IRIS at about 4.5 kb. Semiquantitative PCR detected variable and developmentally regulated expression of BRCA1-IRIS and full-length BRCA1 in several adult and fetal human tissues. Unlike full-length BRCA1, BRCA1-IRIS was exclusively chromatin associated, failed to interact with BARD1 in vivo or in vitro, exhibited unique nuclear immunostaining, and coimmunoprecipitated with core DNA replication initiation sites and with replication initiation proteins. Suppression of BRCA1-IRIS hindered DNA replication, whereas overexpression stimulated DNA replication. <a href="#42" class="mim-tip-reference" title="ElShamy, W. M., Livingston, D. M. <strong>Identification of BRCA1-IRIS, a BRCA1 locus product.</strong> Nature Cell Biol. 6: 954-967, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15448696/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15448696</a>] [<a href="https://doi.org/10.1038/ncb1171" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15448696">ElShamy and Livingston (2004)</a> concluded that endogenous BRCA1-IRIS positively influences the DNA replication initiation machinery. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15448696" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#101" class="mim-tip-reference" title="Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P. A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L. M., Ding, W., Bell, R., Rosenthal, J., and 33 others. <strong>A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.</strong> Science 266: 66-71, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7545954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7545954</a>] [<a href="https://doi.org/10.1126/science.7545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7545954">Miki et al. (1994)</a> determined that the BRCA1 gene contains 22 exons spanning about 110 kb of DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Brown, M. A., Xu, C.-F., Nicolai, H., Griffiths, B., Chambers, J. A., Black, D., Solomon, E. <strong>The 5-prime end of the BRCA1 gene lies within a duplicated region of human chromosome 17q21.</strong> Oncogene 12: 2507-2513, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8700509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8700509</a>]" pmid="8700509">Brown et al. (1996)</a> determined the detailed structure of the BRCA1 genomic region. They showed that this region of chromosome 17 contains a tandem duplication of approximately 30 kb which results in 2 copies of BRCA1 exons 1 and 2, of exons 1 and 3 of the adjacent gene that <a href="#19" class="mim-tip-reference" title="Brown, M. A., Nicolai, H., Xu, C.-F., Griffiths, B. L., Jones, K. A., Solomon, E., Hosking, L., Trowsdale, J., Black, D. M., McFarlane, R. <strong>Regulation of BRCA1. (Letter)</strong> Nature 372: 733 only, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7997258/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7997258</a>] [<a href="https://doi.org/10.1038/372733a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7997258">Brown et al. (1994)</a> designated 1A1-3B (M17S2; <a href="/entry/166945">166945</a>), and of a previously reported 295-bp intergenic region. Sequence analysis of the duplicated exons of BRCA1, 1A1-3B, and flanking genomic DNA revealed to <a href="#20" class="mim-tip-reference" title="Brown, M. A., Xu, C.-F., Nicolai, H., Griffiths, B., Chambers, J. A., Black, D., Solomon, E. <strong>The 5-prime end of the BRCA1 gene lies within a duplicated region of human chromosome 17q21.</strong> Oncogene 12: 2507-2513, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8700509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8700509</a>]" pmid="8700509">Brown et al. (1996)</a> that there was maintenance of exon/intron structure and a high degree of nucleotide sequence identity, which suggested that these duplicated exons are nonprocessed pseudogenes. They noted that these findings could not only confound BRCA1 mutation analysis but have implications for the normal and abnormal regulation of BRCA1 transcription, translation, and function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8700509+7997258" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#144" class="mim-tip-reference" title="Smith, T. M., Lee, M. K., Szabo, C. I., Jerome, N., McEuen, M., Taylor, M., Hood, L., King, M.-C. <strong>Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1.</strong> Genome Res. 6: 1029-1049, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8938427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8938427</a>] [<a href="https://doi.org/10.1101/gr.6.11.1029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8938427">Smith et al. (1996)</a> sequenced 117,143 bp from human chromosome 17 encompassing BRCA1. The 24 exons of BRCA1 spanned an 81-kb region that had an unusually high density of Alu repetitive DNA (41.5%), but a relatively low density (4.8%) of other repetitive sequences. BRCA1 intron lengths ranged in size from 403 bp to 9.2 kb and contained 3 intragenic microsatellite markers located in introns 12, 19, and 20. In addition to BRCA1, the contig contained 2 complete genes which they called RHO7 (<a href="/entry/601555">601555</a>) and VAT1. RHO7 is a member of the RHO family of GTP binding proteins and VAT1 is an abundant membrane protein of cholinergic synaptic vesicles. The order of genes on the chromosome was found to be: centromere-IFP35 (<a href="/entry/600735">600735</a>)-VAT1-RHO7-BRCA1-M17S2-telomere. <a href="#144" class="mim-tip-reference" title="Smith, T. M., Lee, M. K., Szabo, C. I., Jerome, N., McEuen, M., Taylor, M., Hood, L., King, M.-C. <strong>Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1.</strong> Genome Res. 6: 1029-1049, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8938427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8938427</a>] [<a href="https://doi.org/10.1101/gr.6.11.1029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8938427">Smith et al. (1996)</a> suggested that these features may contribute to chromosomal instability or changes in transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8938427" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The BRCA1 gene maps to human chromosome 17q21 (<a href="#101" class="mim-tip-reference" title="Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P. A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L. M., Ding, W., Bell, R., Rosenthal, J., and 33 others. <strong>A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.</strong> Science 266: 66-71, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7545954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7545954</a>] [<a href="https://doi.org/10.1126/science.7545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7545954">Miki et al., 1994</a>). <a href="#5" class="mim-tip-reference" title="Albertsen, H., Plaetke, R., Ballard, L., Fujimoto, E., Connolly, J., Lawrence, E., Rodriguez, P., Robertson, M., Bradley, P., Milner, B., Fuhrman, D., Marks, A., Sargent, R., Cartwright, P., Matsunami, N., White, R. <strong>Genetic mapping of the BRCA1 region on chromosome 17q21.</strong> Am. J. Hum. Genet. 54: 516-525, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8116621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8116621</a>]" pmid="8116621">Albertsen et al. (1994)</a> used simple sequence repeat (SSR) markers to construct a high-resolution genetic map of a 40-cM region around 17q21. For 5 of the markers, genotypes were 'captured' by using an ABI sequencing instrument and stored in a locally developed database as a step toward automated genotyping. In a second report, <a href="#5" class="mim-tip-reference" title="Albertsen, H., Plaetke, R., Ballard, L., Fujimoto, E., Connolly, J., Lawrence, E., Rodriguez, P., Robertson, M., Bradley, P., Milner, B., Fuhrman, D., Marks, A., Sargent, R., Cartwright, P., Matsunami, N., White, R. <strong>Genetic mapping of the BRCA1 region on chromosome 17q21.</strong> Am. J. Hum. Genet. 54: 516-525, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8116621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8116621</a>]" pmid="8116621">Albertsen et al. (1994)</a> described construction of a physical map of a 4-cM region containing the BRCA1 gene. The map comprised a contig of 137 overlapping YACs and P1 clones, onto which they had placed 112 PCR markers. They localized more than 20 genes on the map, 10 of which had not been mapped to the region previously, and isolated 30 cDNA clones representing partial sequences of as yet unidentified genes. They failed to find any deleterious mutations on sequencing of 2 genes that lie within a narrow region defined by meiotic breakpoints in BRCA1 patients. <a href="#111" class="mim-tip-reference" title="O'Connell, P., Albertsen, H., Matsunami, N., Taylor, T., Hundley, J. E., Johnson-Pais, T. L., Reus, B., Lawrence, E., Ballard, L., White, R., Leach, R. J. <strong>A radiation hybrid map of the BRCA1 region.</strong> Am. J. Hum. Genet. 54: 526-534, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8116622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8116622</a>]" pmid="8116622">O'Connell et al. (1994)</a> developed a radiation hybrid map of the BRCA1 region as the basis of YAC cloning and pulsed field gel electrophoretic mapping of the candidate region for the BRCA1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7545954+8116622+8116621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#177" class="mim-tip-reference" title="Xu, C.-F., Brown, M. A., Nicolai, H., Chambers, J. A., Griffiths, B. L., Solomon, E. <strong>Isolation and characterisation of the NBR2 gene which lies head to head with the human BRCA1 gene.</strong> Hum. Molec. Genet. 6: 1057-1062, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9215675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9215675</a>] [<a href="https://doi.org/10.1093/hmg/6.7.1057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9215675">Xu et al. (1997)</a> determined that the NBR2 gene (<a href="/entry/618708">618708</a>) is located between the BRCA1 gene and the pseudo-BRCA1 genes and is aligned in a head-to-head orientation with BRCA1. The transcriptional start sites of NBR2 and BRCA1 are separated by 218 bp. <a href="#151" class="mim-tip-reference" title="Suen, T.-C., Tang, M., Goss, P. E. <strong>Model of transcriptional regulation of the BRCA1-NBR2 bi-directional transcriptional unit.</strong> Biochim. Biophys. Acta 1728: 126-134, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15777733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15777733</a>] [<a href="https://doi.org/10.1016/j.bbaexp.2005.01.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15777733">Suen et al. (2005)</a> reported that the NBR2 and BRCA1 genes share a 56-bp segment between them as a bidirectional promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15777733+9215675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By an intersubspecific backcross using a DNA sequence variant in the Brca1 locus, <a href="#13" class="mim-tip-reference" title="Bennett, L. M., Haugen-Strano, A., Cochran, C., Brownlee, H. A., Fiedorek, F. T., Jr., Wiseman, R. W. <strong>Isolation of the mouse homologue of BRCA1 and genetic mapping to mouse chromosome 11.</strong> Genomics 29: 576-581, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8575748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8575748</a>] [<a href="https://doi.org/10.1006/geno.1995.9963" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8575748">Bennett et al. (1995)</a> mapped the Brca1 gene to distal mouse chromosome 11 in a region of extensive homology of synteny to human chromosome 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8575748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#133" class="mim-tip-reference" title="Schrock, E., Badger, P., Larson, D., Erdos, M., Wynshaw-Boris, A., Ried, T., Brody, L. <strong>The murine homolog of the human breast and ovarian cancer susceptibility gene Brca1 maps to mouse chromosome 11D.</strong> Hum. Genet. 97: 256-259, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8566965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8566965</a>] [<a href="https://doi.org/10.1007/BF02265277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8566965">Schrock et al. (1996)</a> mapped the Brca1 gene to mouse chromosome 11, specifically 11D. <a href="#33" class="mim-tip-reference" title="DeGregorio, L., Harshman, K., Rosenthal, J., Dragani, T. A., Pierotti, M. A. <strong>Genetic mapping of the Brca1 gene on mouse chromosome 11.</strong> Mammalian Genome 7: 242, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8833256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8833256</a>] [<a href="https://doi.org/10.1007/s003359900070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8833256">DeGregorio et al. (1996)</a> mapped the gene to mouse chromosome 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8833256+8566965" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pseudogene</em></strong></p><p>
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The 5-prime end of the BRCA1 gene lies within a duplicated region on chromosome 17q21. This region contains BRCA1 exons 1A, 1B, and 2 and their surrounding introns; as a result, a BRCA1 pseudogene lies upstream of BRCA1. <a href="#122" class="mim-tip-reference" title="Puget, N., Gad, S., Perrin-Vidoz, L., Sinilnikova, O. M., Stoppa-Lyonnet, D., Lenoir, G. M., Mazoyer, S. <strong>Distinct BRCA1 rearrangements involving the BRCA1 pseudogene suggest the existence of a recombination hot spot.</strong> Am. J. Hum. Genet. 70: 858-865, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11880951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11880951</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11880951[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/339434" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11880951">Puget et al. (2002)</a> found extensive homology between the tandemly situated BRCA1 and its pseudogene. Exon 1A of BRCA1 and of the pseudogene were 44.5 kb apart. Distinct homologous recombination events had occurred between intron 2 of BRCA1 and intron 2 of the BRCA1 pseudogene, leading to 37-kb deletions. These breakpoint junctions were found to be located at close but distinct sites within segments that are 98% identical. The mutant alleles lack the BRCA1 promoter and harbor a chimeric gene consisting of pseudogene exons 1A, 1B, and 2, which lacks the initiation codon, fused to BRCA1 exons 3-24. This represented a new mutational mechanism for the BRCA1 gene. The presence of a large region homologous to BRCA1 on the same chromosome appeared to constitute a hotspot for recombination. <a href="#18" class="mim-tip-reference" title="Brown, M. A., Lo, L.-J., Catteau, A., Xu, C.-F., Lindeman, G. J., Hodgson, S., Solomon, E. <strong>Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients: identification of a novel deletion consistent with BRCA1:psi-BRCA1 recombination.</strong> Hum. Mutat. 19: 435-442, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11933198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11933198</a>] [<a href="https://doi.org/10.1002/humu.10055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11933198">Brown et al. (2002)</a> likewise identified a deletion consistent with recombination between BRCA1 and the BRCA1 pseudogene. In germline BRCA1, a promoter deletion was found in 1 of 60 familial breast cancer patients from the Australian population. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11880951+11933198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#157" class="mim-tip-reference" title="Thompson, M. E., Jensen, R. A., Obermiller, P. S., Page, D. L., Holt, J. T. <strong>Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression.</strong> Nature Genet. 9: 444-450, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795653</a>] [<a href="https://doi.org/10.1038/ng0495-444" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7795653">Thompson et al. (1995)</a> found that BRCA1 mRNA levels were markedly decreased during the transition from carcinoma in situ to invasive cancer in sporadic breast cancer. Experimental inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells but had no effect on nonmammary epithelial cells. The results suggested that BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth and that this function is compromised in breast cancer either by direct mutation or by alterations in gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7795653" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Chen, Y., Chen, C.-F., Riley, D. J., Allred, D. C., Chen, P.-L., Von Hoff, D., Osborne, C. K., Lee, W.-H. <strong>Aberrant subcellular localization of BRCA1 in breast cancer.</strong> Science 270: 789-791, 1995. Note: Erratum: Science 270: 1424 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7481765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7481765</a>] [<a href="https://doi.org/10.1126/science.270.5237.789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7481765">Chen et al. (1995)</a> identified the BRCA1 gene product as a 220-kD nuclear phosphoprotein in normal cells, including breast ductal epithelial cells, and in 18 of 20 tumor cell lines derived from tissues other than breast and ovary. However, in 16 of 17 breast and ovarian cancer lines and in 17 of 17 samples of cells obtained from malignant effusions, BRCA1 localized mainly in the cytoplasm. Absence of BRCA1 or aberrant subcellular location was also observed to a variable extent in histologic sections of many breast cancer biopsies. The findings suggested to the authors that BRCA1 abnormalities may be involved in the pathogenesis of many breast cancers, sporadic as well as familial. <a href="#136" class="mim-tip-reference" title="Scully, R., Ganesan, S., Brown, M., De Caprio, J. A., Cannistra, S. A., Feunteun, J., Schnitt, S., Livingston, D. M. <strong>Location of BRCA1 in human breast and ovarian cancer cells.</strong> Science 272: 123-125, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8600523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8600523</a>] [<a href="https://doi.org/10.1126/science.272.5258.123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8600523">Scully et al. (1996)</a>, however, reported results that did not support the hypothesis that wildtype BRCA1 is specifically excluded from the nucleus in sporadic breast and ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8600523+7481765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Coene, E., Van Oostveldt, P., Willems, K., van Emmelo, J., De Potter, C. R. <strong>BRCA1 is localized in cytoplasmic tube-like invaginations in the nucleus. (Letter)</strong> Nature Genet. 16: 122-124, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171821/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171821</a>] [<a href="https://doi.org/10.1038/ng0697-122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9171821">Coene et al. (1997)</a> reported a well-defined localization of BRCA1 in the perinuclear compartment of the endoplasmic reticulum-Golgi complex and in tubes invaginating the nucleus. The nuclear detection was fixation dependent, which helped to explain the controversial findings previously reported. The nuclear tubes were not seen in every cell, and therefore the authors suggested that an involvement in the cell cycle was possible. These tubes probably enhance nuclear-cytoplasmic interactions by increasing the surface area. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9171821" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Chen, Y., Farmer, A. A., Chen, C.-F., Jones, D. C., Chen, P.-L., Lee, W.-H. <strong>BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner.</strong> Cancer Res. 56: 3168-3172, 1996. Note: Erratum: Cancer Res. 56: 4074 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8764100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8764100</a>]" pmid="8764100">Chen et al. (1996)</a> raised mouse polyclonal antibodies to 3 regions of the human BRCA1 protein and confirmed their earlier finding of a 220-kD nuclear phosphoprotein. They reported that expression and phosphorylation of the BRCA1 gene and protein are cell cycle dependent in a synchronized population of bladder carcinoma cells. The greatest levels of both expression and phosphorylation occurred in S and M phases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8764100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Chen, J., Silver, D. P., Walpita, D., Cantor, S. B., Gazdar, A. F., Tomlinson, G., Couch, F. J., Weber, B. L., Ashley, T., Livingston, D. M., Scully, R. <strong>Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.</strong> Molec. Cell 2: 317-328, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9774970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9774970</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80276-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9774970">Chen et al. (1998)</a> used mammalian expression vectors to transfect cells with BRCA1 and BRCA2 as well as with several antibodies to recognize these proteins in order to study their subcellular localizations. They showed that BRCA1 and BRCA2 coexist in a biochemical complex and colocalize in subnuclear foci in somatic cells and on the axial elements of developing synaptonemal complexes. Like BRCA1 and RAD51 (<a href="/entry/179617">179617</a>), BRCA2 relocates to replication sites following exposure of S phase cells to hydroxyurea or UV irradiation. Thus, BRCA1 and BRCA2 participate together in a pathway (or pathways) associated with the activation of double-strand break repair and/or homologous recombination. Dysfunction of this pathway may be a general phenomenon in the majority of cases of hereditary breast and/or ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9774970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#188" class="mim-tip-reference" title="Zhong, Q., Chen, C.-F., Li, S., Chen, Y., Wang, C.-C., Xiao, J., Chen, P.-L., Sharp, Z. D., Lee, W.-H. <strong>Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.</strong> Science 285: 747-750, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10426999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10426999</a>] [<a href="https://doi.org/10.1126/science.285.5428.747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10426999">Zhong et al. (1999)</a> showed that BRCA1 interacts in vitro and in vivo with RAD50 (<a href="/entry/604040">604040</a>), which forms a complex with MRE11 (<a href="/entry/600814">600814</a>) and p95/nibrin (NBS1; <a href="/entry/602667">602667</a>). Upon irradiation, BRCA1 was detected in the nucleus, in discrete foci which colocalize with RAD50. Formation of irradiation-induced foci positive for BRCA1, RAD50, MRE11, or p95 was dramatically reduced in HCC/1937 breast cancer cells carrying a homozygous mutation in BRCA1 but was restored by transfection of wildtype BRCA1. Ectopic expression of wildtype, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent methyl methanesulfonate. These data suggested to the authors that BRCA1 is important for the cellular responses to DNA damage that are mediated by the RAD50-MRE11-p95 complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10426999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#74" class="mim-tip-reference" title="Holt, J. T., Thompson, M. E., Szabo, C., Robinson-Benion, C., Arteaga, C. L., King, M.-C., Jensen, R. A. <strong>Growth retardation and tumour inhibition by BRCA1.</strong> Nature Genet. 12: 298-302, 1996. Note: Erratum: Nature Genet. 19: 102 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589721</a>] [<a href="https://doi.org/10.1038/ng0396-298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589721">Holt et al. (1996)</a> demonstrated that retroviral transfer of the wildtype BRCA1 gene inhibits growth in vitro of all breast cancer and ovarian cancer cell lines tested, but not colon or lung cancer cells or fibroblasts. Mutant BRCA1, however, had no effect on growth of breast cancer cells; ovarian cancer cell growth was not affected by BRCA1 mutations in the 5-prime portion of the gene but was inhibited by 3-prime BRCA1 mutations. Development of MCF-7 tumors in nude mice was inhibited when MCF-7 cells were transfected with wildtype, but not mutant, BRCA1. Among mice with established MCF-7 tumors, peritoneal treatment with a retroviral vector expressing wildtype BRCA1 significantly inhibited tumor growth and increased survival. The results of <a href="#74" class="mim-tip-reference" title="Holt, J. T., Thompson, M. E., Szabo, C., Robinson-Benion, C., Arteaga, C. L., King, M.-C., Jensen, R. A. <strong>Growth retardation and tumour inhibition by BRCA1.</strong> Nature Genet. 12: 298-302, 1996. Note: Erratum: Nature Genet. 19: 102 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589721</a>] [<a href="https://doi.org/10.1038/ng0396-298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589721">Holt et al. (1996)</a> were consistent with the previous observation that the site of BRCA1 mutation is associated with relative susceptibility to ovarian versus breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To identify downstream target genes of BRCA1, <a href="#68" class="mim-tip-reference" title="Harkin, D. P., Bean, J. M., Miklos, D., Song, Y.-H., Truong, V. B., Englert, C., Christians, F. C., Ellisen, L. W., Maheswaran, S., Oliner, J. D., Haber, D. A. <strong>Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1.</strong> Cell 97: 575-586, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10367887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10367887</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80769-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10367887">Harkin et al. (1999)</a> established cell lines with tightly regulated inducible expression of the BRCA1 gene. High-density oligonucleotide arrays were used to analyze gene expression profiles at various times following BRCA1 induction. A major target of BRCA1 is the DNA damage-inducible gene GADD45 (<a href="/entry/126335">126335</a>). Induction of BRCA1 triggers apoptosis through activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK; see <a href="/entry/601158">601158</a>), a signaling pathway potentially linked to GADD45 gene family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10367887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#95" class="mim-tip-reference" title="Lorick, K. L., Jensen, J. P., Fang, S., Ong, A. M., Hatakeyama, S., Weissman, A. M. <strong>RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination.</strong> Proc. Nat. Acad. Sci. 96: 11364-11369, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10500182/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10500182</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10500182[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.20.11364" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10500182">Lorick et al. (1999)</a> showed that like other RING finger proteins, the N-terminal 788 amino acids of BRCA1 expressed as a GST fusion protein facilitated E2-dependent ubiquitination. The authors noted that RING mutations in BRCA1 are associated with familial carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10500182" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an effort to understand the function of BRCA1, <a href="#174" class="mim-tip-reference" title="Wu, L. C., Wang, Z. W., Tsan, J. T., Spillman, M. A., Phung, A., Xu, X. L., Yang, M.-C. W., Hwang, L.-Y., Bowcock, A. M., Baer, R. <strong>Identification of a RING protein that can interact in vivo with the BRCA1 gene product.</strong> Nature Genet. 14: 430-440, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8944023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8944023</a>] [<a href="https://doi.org/10.1038/ng1296-430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8944023">Wu et al. (1996)</a> used a yeast 2-hybrid system to identify proteins that associate with BRCA1 in vivo. This analysis led to the identification of BARD1 (<a href="/entry/601593">601593</a>), a novel protein that interacts with the N-terminal region of BRCA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8944023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By Western and immunofluorescence analyses in synchronized T24 bladder cancer cells, <a href="#81" class="mim-tip-reference" title="Jin, Y., Xu, X. L., Yang, M.-C. W., Wei, F., Ayi, T.-C., Bowcock, A. M., Baer, R. <strong>Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains.</strong> Proc. Nat. Acad. Sci. 94: 12075-12080, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9342365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9342365</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9342365[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.22.12075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9342365">Jin et al. (1997)</a> studied the expression patterns of the BARD1 and BRCA1 proteins. They found that the steady-state levels of BARD1, unlike those of BRCA1, remain relatively constant during cell cycle progression. However, immunostaining revealed that BARD1 resides within BRCA1 nuclear dots during S phase of the cell cycle, but not during the G1 phase. Nevertheless, BARD1 polypeptides are found exclusively in the nuclear fractions of both G1- and S-phase cells. Therefore, progression to S phase is accompanied by the aggregation of nuclear BARD1 polypeptides into BRCA1 nuclear dots. This cell cycle-dependent colocalization of BARD1 and BRCA1 indicates a role for BARD1 in BRCA1-mediated tumor suppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9342365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#135" class="mim-tip-reference" title="Scully, R., Anderson, S. F., Chao, D. M., Wei, W., Ye, L., Young, R. A., Livingston, D. M., Parvin, J. D. <strong>BRCA1 is a component of the RNA polymerase II holoenzyme.</strong> Proc. Nat. Acad. Sci. 94: 5605-5610, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9159119/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9159119</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9159119[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.11.5605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9159119">Scully et al. (1997)</a> found that the BRCA1 gene product is a component of the RNA polymerase II holoenzyme (polII) by several criteria. BRCA1 was found to copurify with the holoenzyme over multiple chromatographic steps. Other tested transcription activators that could potentially contact the holoenzyme were not stably associated with the holoenzyme as determined by copurification. Antibody specific for the holoenzyme component SRB7 specifically purified BRCA1. (SRB proteins are a key component of the holoenzyme and were discovered in a yeast genetic screen as suppressors of RNA polymerase B mutations; hence, the designation SRB. A benign difference is that SRB proteins bind to the C-terminal domain of yeast polII and are found only in the polII holoenzyme.) Immunopurification of BRCA1 complexes also specifically purified transcriptionally active RNA polII and transcription factors TFIIF (see <a href="/entry/189968">189968</a>), TFIIE (see <a href="/entry/189962">189962</a>), and TFIIH (see <a href="/entry/189972">189972</a>), which are known components of the holoenzyme. Moreover, a BRCA1 domain, which is deleted in about 90% of clinically relevant mutations, participated in binding to the holoenzyme complex in cells. These data were considered consistent with other data identifying transcription activation domains in the BRCA1 protein, and link the BRCA1 tumor suppressor protein with the transcription process as a holoenzyme-bound protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9159119" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>RNA helicase A, or RHA (140 kD), was identified by <a href="#89" class="mim-tip-reference" title="Lee, C. G., Hurwitz, J. <strong>Human RNA helicase A is homologous to the maleless protein of Drosophila.</strong> J. Biol. Chem. 268: 16822-16830, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8344961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8344961</a>]" pmid="8344961">Lee and Hurwitz (1993)</a> and <a href="#185" class="mim-tip-reference" title="Zhang, S., Grosse, F. <strong>Domain structure of human nuclear DNA helicase II (RNA helicase A).</strong> J. Biol. Chem. 272: 11487-11494, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9111062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9111062</a>] [<a href="https://doi.org/10.1074/jbc.272.17.11487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9111062">Zhang and Grosse (1997)</a> as a helicase of unknown function with homology to the Drosophila 'maleless' gene, which functions to increase expression of genes from the male X chromosome. <a href="#7" class="mim-tip-reference" title="Anderson, S. F., Schlegel, B. P., Nakajima, T., Wolpin, E. S., Parvin, J. D. <strong>BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A.</strong> Nature Genet. 19: 254-256, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662397</a>] [<a href="https://doi.org/10.1038/930" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662397">Anderson et al. (1998)</a> showed that RHA protein links BRCA1 to the holoenzyme complex. These results were the first to identify specific protein interaction with the BRCA1 C-terminal domain and were consistent with the model that BRCA1 functions as a transcriptional coactivator. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9111062+9662397+8344961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Association of the BRCA1 protein with the DNA repair gene RAD51 (<a href="/entry/179617">179617</a>) and changes in the phosphorylation and cellular localization of the protein after exposure to DNA-damaging agents are consistent with a role for BRCA1 in DNA repair. Although <a href="#62" class="mim-tip-reference" title="Gowen, L. C., Avrutskaya, A. V., Latour, A. M., Koller, B. H., Leadon, S. A. <strong>BRCA1 required for transcription-coupled repair of oxidative DNA damage.</strong> Science 281: 1009-1012, 1998. Note: Retraction: Science 300: 1657 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9703501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9703501</a>] [<a href="https://doi.org/10.1126/science.281.5379.1009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9703501">Gowen et al. (1998)</a> reported that mouse embryonic stem cells deficient in BRCA1 are defective in the ability to carry out transcription-coupled repair of oxidative DNA damage and are hypersensitive to ionizing radiation and hydrogen peroxide, this article was later retracted because of the possibility of 'fabricated and falsified research findings' by one of the authors (<a href="#63" class="mim-tip-reference" title="Gowen, L. C., Avrutskaya, A. V., Latour, A. M., Koller, B. H., Leadon, S. A. <strong>Retraction. (Letter)</strong> Science 300: 1657 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12805518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12805518</a>] [<a href="https://doi.org/10.1126/science.300.5626.1657b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12805518">Gowen et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9703501+12805518" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using transient transfection assays, <a href="#43" class="mim-tip-reference" title="Fan, S., Wang, J.-A., Yuan, R., Ma, Y., Meng, Q., Erdos, M. R., Pestell, R. G., Yuan, F., Auborn, K. J., Goldberg, I. D., Rosen, E. M. <strong>BRCA1 inhibition of estrogen receptor signaling in transfected cells.</strong> Science 284: 1354-1356, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10334989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10334989</a>] [<a href="https://doi.org/10.1126/science.284.5418.1354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10334989">Fan et al. (1999)</a> demonstrated that BRCA1 inhibits signaling by the ligand-activated estrogen receptor ER-alpha (ESR1; <a href="/entry/133430">133430</a>) through the estrogen-responsive enhancer element and blocks the C-terminal transcriptional activation function AF2 of ER-alpha. These results suggested that wildtype BRCA1 protein may function, in part, to suppress estrogen-dependent mammary epithelial proliferation by inhibiting ER-alpha mediated transcriptional pathways related to cell proliferation, and that loss of this ability may contribute to tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10334989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#137" class="mim-tip-reference" title="Scully, R., Ganesan, S., Vlasakova, K., Chen, J., Socolovsky, M., Livingston, D. M. <strong>Genetic analysis of BRCA1 function in a defined tumor cell line.</strong> Molec. Cell 4: 1093-1099, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10635334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10635334</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80238-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10635334">Scully et al. (1999)</a> found that retrovirally expressed wildtype BRCA1 decreased the gamma irradiation (IR) sensitivity and increased the efficiency of double-strand DNA break repair of the BRCA1 -/- human breast cancer line, HCC1937. It also reduced the susceptibility of the cells to double-strand DNA break generation by IR. In contrast, multiple clinically validated BRCA1 products with missense mutations were nonfunctional in these assays. These data constituted the basis for a BRCA1 functional assay and suggested that efficient repair of double-strand DNA breaks is linked to BRCA1 tumor suppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10635334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>BRCA1 contains a C-terminal domain (BRCT) that is shared with several other proteins involved in maintaining genome integrity. In an effort to understand the function of BRCA1, <a href="#180" class="mim-tip-reference" title="Yarden, R. I., Brody, L. C. <strong>BRCA1 interacts with components of the histone deacetylase complex.</strong> Proc. Nat. Acad. Sci. 96: 4983-4988, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220405</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10220405[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.9.4983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220405">Yarden and Brody (1999)</a> sought to isolate proteins that interact with the BRCT domain. Purified BRCT polypeptide was used as a probe to screen a human placenta cDNA expression library by Far Western analysis. The authors reported that BRCA1 interacts in vivo and in vitro with the Rb-binding proteins RbAp46 (RBBP7; <a href="/entry/300825">300825</a>) and RbAp48 (RBBP4; <a href="/entry/602923">602923</a>), as well as with Rb (RB1; <a href="/entry/614041">614041</a>). Moreover, the BRCT domain associated with the histone deacetylases HDAC1 (<a href="/entry/601241">601241</a>) and HDAC2 (<a href="/entry/605164">605164</a>). These results demonstrated that BRCA1 interacts with components of the histone deacetylase complex, and therefore may explain the involvement of BRCA1 in multiple processes such as transcription, DNA repair, and recombination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10220405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#90" class="mim-tip-reference" title="Lee, J.-S., Collins, K. M., Brown, A. L., Lee, C.-H., Chung, J. H. <strong>hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response.</strong> Nature 404: 201-204, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10724175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10724175</a>] [<a href="https://doi.org/10.1038/35004614" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10724175">Lee et al. (2000)</a> reported that CHK2 (<a href="/entry/604373">604373</a>) regulates BRCA1 function after DNA damage by phosphorylating serine-988 of BRCA1. <a href="#90" class="mim-tip-reference" title="Lee, J.-S., Collins, K. M., Brown, A. L., Lee, C.-H., Chung, J. H. <strong>hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response.</strong> Nature 404: 201-204, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10724175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10724175</a>] [<a href="https://doi.org/10.1038/35004614" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10724175">Lee et al. (2000)</a> demonstrated that CHK2 and BRCA1 interact and colocalize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine-988 is required for the release of BRCA1 from CHK2. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937. However, BRCA1 phosphorylation may be complicated. For example, <a href="#29" class="mim-tip-reference" title="Cortez, D., Wang, Y., Qin, J., Elledge, S. J. <strong>Requirement of ATM-dependent phosphorylation of Brca1 in the DNA damage response to double-strand breaks.</strong> Science 286: 1162-1166, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10550055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10550055</a>] [<a href="https://doi.org/10.1126/science.286.5442.1162" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10550055">Cortez et al. (1999)</a> demonstrated that ATM (<a href="/entry/607585">607585</a>) can phosphorylate serines at positions 1423 and 1524 of BRCA1 after a high dose of gamma radiation. In addition, <a href="#128" class="mim-tip-reference" title="Ruffner, H., Jiang, W., Craig, A. G., Hunter, T., Verma, I. M. <strong>BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site.</strong> Molec. Cell. Biol. 19: 4843-4854, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10373534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10373534</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10373534[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.19.7.4843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10373534">Ruffner et al. (1999)</a> demonstrated that CDK2 (<a href="/entry/116953">116953</a>) phosphorylated serine-1497 during the G1/S phase of cell cycle. Phosphorylation of the different serine residues is likely to have different effects on BRCA1 function. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10724175+10373534+10550055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#97" class="mim-tip-reference" title="Maor, S. B., Abramovitch, S., Erdos, M. R., Brody, L. C., Werner, H. <strong>BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1.</strong> Molec. Genet. Metab. 69: 130-136, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10720440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10720440</a>] [<a href="https://doi.org/10.1006/mgme.1999.2958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10720440">Maor et al. (2000)</a> cotransfected a luciferase reporter gene under the control of the insulin-like growth factor-1 receptor (IGF1R; <a href="/entry/147370">147370</a>) promoter with a wildtype BRCA1-encoding expression vector into multiple cell lines. They observed a significant reduction in luciferase activity in all 3 cell lines tested, demonstrating suppression of promoter activity by BRCA1 in a dose-dependent manner. Functional interaction between BRCA1 and SP1 (<a href="/entry/189906">189906</a>) in the regulation of the IGF1R gene was studied in Schneider cells, a Drosophila cell line which lacks endogenous SP1. In these cells, BRCA1 suppressed 45% of the SP1-induced trans-activation of the IGF1R promoter. <a href="#97" class="mim-tip-reference" title="Maor, S. B., Abramovitch, S., Erdos, M. R., Brody, L. C., Werner, H. <strong>BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1.</strong> Molec. Genet. Metab. 69: 130-136, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10720440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10720440</a>] [<a href="https://doi.org/10.1006/mgme.1999.2958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10720440">Maor et al. (2000)</a> concluded that BRCA1 is capable of suppressing the IGF1R promoter in a number of cell lines, resulting in low levels of receptor mRNA protein. <a href="#97" class="mim-tip-reference" title="Maor, S. B., Abramovitch, S., Erdos, M. R., Brody, L. C., Werner, H. <strong>BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1.</strong> Molec. Genet. Metab. 69: 130-136, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10720440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10720440</a>] [<a href="https://doi.org/10.1006/mgme.1999.2958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10720440">Maor et al. (2000)</a> hypothesized that mutant versions of BRCA1 lacking trans-activational activity can potentially derepress the IGF1R promoter. Activation of the overexpressed receptor by locally produced or circulating IGFs may elicit a myogenic event which may be a key mechanism in the etiology of breast and ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10720440" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#92" class="mim-tip-reference" title="Li, S., Ting, N. S. Y., Zheng, L., Chen, P.-L., Ziv, Y., Shiloh, Y., Lee, E. Y.-H. P., Lee, W.-H. <strong>Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response.</strong> Nature 406: 210-215, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10910365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10910365</a>] [<a href="https://doi.org/10.1038/35018134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10910365">Li et al. (2000)</a> demonstrated that the BRCA1-associated protein CTIP (<a href="/entry/604124">604124</a>) becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase ATM (see <a href="/entry/607585">607585</a>). ATM phosphorylates CTIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CTIP, resulting in persistent repression of BRCA1-dependent induction of GADD45 upon ionizing radiation. <a href="#92" class="mim-tip-reference" title="Li, S., Ting, N. S. Y., Zheng, L., Chen, P.-L., Ziv, Y., Shiloh, Y., Lee, E. Y.-H. P., Lee, W.-H. <strong>Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response.</strong> Nature 406: 210-215, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10910365/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10910365</a>] [<a href="https://doi.org/10.1038/35018134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10910365">Li et al. (2000)</a> concluded that ATM, by phosphorylating CTIP upon ionizing radiation, may modulate BRCA1-mediated regulation of the DNA damage-response GADD45 gene, thus providing a potential link between ATM deficiency and breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10910365" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using human and mouse expression plasmids in several protein interaction assays, <a href="#152" class="mim-tip-reference" title="Sum, E. Y. M., Peng, B., Yu, X., Chen, J., Byrne, J., Lindeman, G. J., Visvader, J. E. <strong>The LIM domain protein LMO4 interacts with the cofactor CtIP and the tumor suppressor BRCA1 and inhibits BRCA1 activity.</strong> J. Biol. Chem. 277: 7849-7856, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11751867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11751867</a>] [<a href="https://doi.org/10.1074/jbc.M110603200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11751867">Sum et al. (2002)</a> identified CTIP and BRCA1 as LMO4 (<a href="/entry/603129">603129</a>)-binding proteins. The LMO4-BRCA1 interaction required the C-terminal BRCT domains of BRCA1. LDB1 (<a href="/entry/603451">603451</a>) also associated with a complex containing LMO4, CTIP, and BRCA1 in transfected human embryonic kidney cells. In functional assays, LMO4 repressed BRCA1-mediated transcriptional activation in both yeast and mammalian cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11751867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#75" class="mim-tip-reference" title="Huttley, G. A., Easteal, S., Southey, M. C., Tesoriero, A., Giles, G. G., McCredie, M. R. E., Hopper, J. L., Venter, D. J., Australian Breast Cancer Family Study. <strong>Adaptive evolution of the tumour suppressor BRCA1 in humans and chimpanzees.</strong> Nature Genet. 25: 410-413, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932184</a>] [<a href="https://doi.org/10.1038/78092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932184">Huttley et al. (2000)</a> used phylogeny-based maximum likelihood analysis of the BRCA1 sequences from primates and other animals and found that the ratios of replacement to silent nucleotide substitutions on the human and chimpanzee lineages were not different from one another but were different from those of other primate lineages, and were greater than 1. This is consistent with the historic occurrence of positive darwinian selection pressure on the BRCA1 protein in the human and chimpanzee lineages. Analysis of genetic variation in a sample of female Australians of northern European origin showed evidence for Hardy-Weinberg disequilibrium at polymorphic sites in BRCA1, consistent with the possibility that natural selection is affecting genotype frequencies in modern Europeans. The clustering of between-species variation in the region of the gene encoding the RAD51-interacting domain of BRCA1 suggests the maintenance of genomic integrity as a possible target of selection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a combination of affinity- and conventional chromatographic techniques, <a href="#15" class="mim-tip-reference" title="Bochar, D. A., Wang, L., Beniya, H., Kinev, A., Xue, Y., Lane, W. S., Wang, W., Kashanchi, F., Shiekhattar, R. <strong>BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer.</strong> Cell 102: 257-265, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10943845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10943845</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)00030-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10943845">Bochar et al. (2000)</a> isolated a predominant form of a multiprotein BRCA1-containing complex from human cells displaying chromatin-remodeling activity. Mass spectrometric sequencing of components of this complex indicated that BRCA1 is associated with a SWI/SNF-related complex, and the authors showed that BRCA1 can directly interact with the BRG1 (SMARCA4; <a href="/entry/603254">603254</a>) subunit of the SWI/SNF complex. Moreover, p53 (TP53; <a href="/entry/191170">191170</a>)-mediated stimulation of transcription by BRCA1 was completely abrogated by either a dominant-negative mutant of BRG1 (<a href="#85" class="mim-tip-reference" title="Khavari, P. A., Peterson, C. L., Tamkun, J. W., Mendel, D. B., Crabtree, G. R. <strong>BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription.</strong> Nature 366: 170-174, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8232556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8232556</a>] [<a href="https://doi.org/10.1038/366170a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8232556">Khavari et al., 1993</a>) or the cancer-causing deletion of exon 11 of BRCA1 (<a href="#179" class="mim-tip-reference" title="Xu, X., Weaver, Z., Linke, S. P., Li, C., Gotay, J., Wang, X.-W., Harris, C. C., Ried, T., Deng, C.-X. <strong>Centrosome amplification and a defective G(2)-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells.</strong> Molec. Cell 3: 389-395, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10198641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10198641</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80466-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10198641">Xu et al., 1999</a>). These findings revealed a direct function for BRCA1 in transcriptional control through modulation of chromatin structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10943845+10198641+8232556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#182" class="mim-tip-reference" title="Ye, Q., Hu, Y.-F., Zhong, H., Nye, A. C., Belmont, A. S., Li, R. <strong>BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations.</strong> J. Cell Biol. 155: 911-921, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11739404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11739404</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11739404[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.200108049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11739404">Ye et al. (2001)</a> found that BRCA1 induced large-scale chromatin decondensation in Chinese hamster ovary cells. COBRA1 (<a href="/entry/611180">611180</a>) bound one of the chromatin-unfolding domains of BRCA1, and by itself COBRA1 induced large-scale chromatin decondensation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11739404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#170" class="mim-tip-reference" title="Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., Qin, J. <strong>BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.</strong> Genes Dev. 14: 927-939, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10783165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10783165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10783165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10783165">Wang et al. (2000)</a> used immunoprecipitation and mass spectrometry analyses to identify BRCA1-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM, BLM (<a href="/entry/604610">604610</a>), MSH2 (<a href="/entry/609309">609309</a>), MSH6 (<a href="/entry/600678">600678</a>), MLH1 (<a href="/entry/120436">120436</a>), the RAD50-MRE11-NBS1 complex, and the RFC1 (<a href="/entry/102579">102579</a>)-RFC2 (<a href="/entry/600404">600404</a>)-RFC4 (<a href="/entry/102577">102577</a>) complex. Confocal microscopy demonstrated that BRCA1, BLM, and the RAD50-MRE11-NBS1 complex colocalize to large nuclear foci. <a href="#170" class="mim-tip-reference" title="Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., Qin, J. <strong>BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.</strong> Genes Dev. 14: 927-939, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10783165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10783165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10783165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10783165">Wang et al. (2000)</a> suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10783165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>BRCA1 is implicated in the transcriptional regulation of DNA damage-inducible genes that function in cell cycle arrest. To explore the mechanistic basis for this regulation, <a href="#187" class="mim-tip-reference" title="Zheng, L., Pan, H., Li, S., Flesken-Nikitin, A., Chen, P.-L., Boyer, T. G., Lee, W.-H. <strong>Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1.</strong> Molec. Cell 6: 757-768, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11090615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11090615</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)00075-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11090615">Zheng et al. (2000)</a> performed a yeast 2-hybrid screen for proteins associated with BRCA1 and isolated a cDNA encoding ZBRK1 (<a href="/entry/605422">605422</a>). ZBRK1 binds to a specific sequence, GGGxxxCAGxxxTTT, within GADD45 (<a href="/entry/126335">126335</a>) intron 3 that supports the assembly of a nuclear complex minimally containing both ZBRK1 and BRCA1. Through this recognition sequence, ZBRK1 represses transcription in a BRCA1-dependent manner. The results revealed a novel corepressor function for BRCA1 and provided a mechanistic basis for the biologic activity of BRCA1 through sequence-specific transcriptional regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11090615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The nonsense-mediated mRNA decay pathway minimizes the potential damage caused by nonsense mutations. In-frame nonsense codons located at a minimum distance upstream of the last exon-exon junction are recognized as premature termination codons, targeting the mRNA for degradation. Some nonsense mutations cause skipping of one or more exons, presumably during pre-mRNA splicing in the nucleus; this phenomenon is termed nonsense-mediated altered splicing (NAS). By analyzing NAS in BRCA1, <a href="#94" class="mim-tip-reference" title="Liu, H.-X., Cartegni, L., Zhang, M. Q., Krainer, A. R. <strong>A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes.</strong> Nature Genet. 27: 55-58, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11137998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11137998</a>] [<a href="https://doi.org/10.1038/83762" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11137998">Liu et al. (2001)</a> showed that inappropriate exon skipping can be reproduced in vitro and that it results from disruption of a splicing enhancer in the coding sequence. Enhancers can be disrupted by a single nonsense, missense, or translationally silent point mutation, without recognition of an open reading frame as such. These results argued against a nuclear reading-frame scanning mechanism for NAS. Coding region single-nucleotide polymorphisms within exonic splicing enhancers or silencers may affect the patterns or efficiency of mRNA splicing, which may in turn cause phenotypic variability and variable penetrance of mutations elsewhere in a gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11137998" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Hedenfalk, I., Duggan, D., Chen, Y., Radmacher, M., Bittner, M., Simon, R., Meltzer, P., Gusterson, B., Esteller, M., Kallioniemi, O.-P., Wilfond, B., Borg, A., Trent, J. <strong>Gene-expression profiles in hereditary breast cancer.</strong> New Eng. J. Med. 344: 539-548, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11207349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11207349</a>] [<a href="https://doi.org/10.1056/NEJM200102223440801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11207349">Hedenfalk et al. (2001)</a> used microarray technology to determine gene-expression profiles in BRCA1-positive breast cancers as contrasted with BRCA2-positive breast cancers. The suspicion that a difference might be found came from the fact that the 2 types of tumors are often histologically distinctive. Furthermore, tumors with BRCA1 mutations are generally negative for both estrogen and progesterone receptors, whereas most tumors with BRCA2 mutations are positive for these hormone receptors. RNA from samples of primary tumors from 7 carriers of the BRCA1 mutation and 7 carriers of the BRCA2 mutation was compared with a microarray of 6,512 cDNA clones of 5,361 genes. The authors found that significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11207349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Garcia-Higuera, I., Taniguchi, T., Ganesan, S., Meyn, M. S., Timmers, C., Hejna, J., Grompe, M., D'Andrea, A. D. <strong>Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.</strong> Molec. Cell 7: 249-262, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239454/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239454</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00173-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239454">Garcia-Higuera et al. (2001)</a> showed that a nuclear complex containing the FANCA (<a href="/entry/607139">607139</a>), FANCC (<a href="/entry/227645">227645</a>), FANCF (<a href="/entry/603467">603467</a>), and FANCG (<a href="/entry/602956">602956</a>) proteins is required for the activation of the FANCD2 protein (<a href="/entry/613984">613984</a>) to a monoubiquitinated isoform. In normal cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots). Activated FANCD2 protein colocalizes with BRCA1 in ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. The authors concluded that the FANCD2 protein therefore provides the missing link between the Fanconi anemia (FA) protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all subtypes of Fanconi anemia (see <a href="/entry/227650">227650</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239454" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The Fanconi anemia nuclear complex (composed of the FA proteins A, C, G, and F) is essential for protection against chromosome breakage. It activates the downstream protein FANCD2 by monoubiquitylation; this then forges an association with the BRCA1 protein at sites of DNA damage. <a href="#113" class="mim-tip-reference" title="Pace, P., Johnson, M., Tan, W. M., Mosedale, G., Sng, C., Hoatlin, M., de Winter, J., Joenje, H., Gergely, F., Patel, K. J. <strong>FANCE: the link between Fanconi anaemia complex assembly and activity.</strong> EMBO J. 21: 3414-3423, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12093742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12093742</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12093742[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/cdf355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12093742">Pace et al. (2002)</a> showed that the FANCE (<a href="/entry/600901">600901</a>) protein is part of this nuclear complex, binding both FANCC and FANCD2. Indeed, FANCE is required for the nuclear accumulation of FANCC and provides a critical bridge between the FA complex and FANCD2. Disease-associated FANCC mutants do not bind to FANCE, cannot accumulate in the nucleus and are unable to prevent chromosome breakage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12093742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#115" class="mim-tip-reference" title="Paull, T. T., Cortez, D., Bowers, B., Elledge, S. J., Gellert, M. <strong>Direct DNA binding by Brca1.</strong> Proc. Nat. Acad. Sci. 98: 6086-6091, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11353843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11353843</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11353843[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.111125998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11353843">Paull et al. (2001)</a> demonstrated that recombinant human BRCA1 protein binds strongly to DNA, an activity conferred by a domain in the center of the BRCA1 polypeptide. As a result of this binding, BRCA1 inhibits the nucleolytic activity of the MRE11/RAD50/NBS1 complex, an enzyme implicated in numerous aspects of double-strand break repair. BRCA1 displays a preference for branched DNA structures and forms protein-DNA complexes cooperatively between multiple DNA strands, but without DNA sequence specificity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11353843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Mutations in the TP53 tumor suppressor gene (<a href="/entry/191170">191170</a>) are found in 70 to 80% of BRCA1-mutated breast cancers but only 30% of those with wildtype BRCA1 (<a href="#134" class="mim-tip-reference" title="Schuyer, M., Berns, E. M. <strong>Is TP53 dysfunction required for BRCA1-associated carcinogenesis?</strong> Molec. Cell. Endocr. 155: 143-152, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10580847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10580847</a>] [<a href="https://doi.org/10.1016/s0303-7207(99)00117-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10580847">Schuyer and Berns, 1999</a>). The p53 protein regulates nucleotide excision repair (NER) through transcriptional regulation of genes involved in the recognition of adducts in genomic DNA. Loss of p53 function, as in Li-Fraumeni syndrome (<a href="/entry/151623">151623</a>), results in deficient global genomic repair (GGR), a subset of NER that targets and removes lesions from the whole genome (Ford and Hanawalt (<a href="#49" class="mim-tip-reference" title="Ford, J. M., Hanawalt, P. C. <strong>Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance.</strong> Proc. Nat. Acad. Sci. 92: 8876-8880, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7568035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7568035</a>] [<a href="https://doi.org/10.1073/pnas.92.19.8876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7568035">1995</a>, <a href="#50" class="mim-tip-reference" title="Ford, J. M., Hanawalt, P. C. <strong>Expression of wild-type p53 is required for efficient global genomic nucleotide excision repair in UV-irradiated human fibroblasts.</strong> J. Biol. Chem. 272: 28073-28080, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9346961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9346961</a>] [<a href="https://doi.org/10.1074/jbc.272.44.28073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9346961">1997</a>)). <a href="#70" class="mim-tip-reference" title="Hartman, A.-R., Ford, J. M. <strong>BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair.</strong> Nature Genet. 32: 180-184, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12195423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12195423</a>] [<a href="https://doi.org/10.1038/ng953" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12195423">Hartman and Ford (2002)</a> showed that BRCA1 specifically enhances the GGR pathway, independent of p53, and can induce p53-independent expression of the NER genes XPC (<a href="/entry/613208">613208</a>), DDB2 (<a href="/entry/600811">600811</a>), and GADD45. Defects in the NER pathway in BRCA1-associated breast cancers may be causal in tumor development, suggesting a multistep model of carcinogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12195423+7568035+9346961+10580847" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#181" class="mim-tip-reference" title="Yarden, R. I., Pardo-Reoyo, S., Sgagias, M., Cowan, K. H., Brody, L. C. <strong>BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage.</strong> Nature Genet. 30: 285-289, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11836499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11836499</a>] [<a href="https://doi.org/10.1038/ng837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11836499">Yarden et al. (2002)</a> showed that BRCA1 is essential for activating the Chk1 kinase (<a href="/entry/603078">603078</a>) that regulates DNA damage-induced G2/M arrest. BRCA1 controls the expression, phosphorylation, and cellular localization of Cdc25C (<a href="/entry/157680">157680</a>) and Cdc2/cyclin B kinase (<a href="/entry/116940">116940</a>)--proteins that are crucial for the G2/M transition. Since BRCA1 regulates key effectors that control the G2/M checkpoint, it is involved in regulating the onset of mitosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11836499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Ganesan, S., Silver, D. P., Greenberg, R. A., Avni, D., Drapkin, R., Miron, A., Mok, S. C., Randrianarison, V., Brodie, S., Salstrom, J., Rasmussen, T. P., Klimke, A., Marrese, C., Marahrens, Y., Deng, C.-X., Feunteun, J., Livingston, D. M. <strong>BRCA1 supports XIST RNA concentration on the inactive X chromosome.</strong> Cell 111: 393-405, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12419249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12419249</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)01052-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12419249">Ganesan et al. (2002)</a> found that BRCA1 colocalized with markers of the inactive X chromosome (Xi) on Xi in female somatic cells and associated with XIST (<a href="/entry/314670">314670</a>) RNA, as detected by chromatin immunoprecipitation. Breast and ovarian carcinoma cells lacking BRCA1 showed evidence of defects in Xi chromatin structure. Reconstitution of BRCA1-deficient cells with wildtype BRCA1 led to the appearance of focal XIST RNA staining without altering XIST abundance. Inhibiting BRCA1 synthesis in a suitable reporter line led to increased expression of an otherwise silenced Xi-located GFP transgene. These observations suggested that loss of BRCA1 in female cells may lead to Xi perturbation and destabilization of its silenced state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12419249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#48" class="mim-tip-reference" title="Folias, A., Matkovic, M., Bruun, D,, Reid, S., Hejna, J., Grompe, M., D'Andrea, A., Moses, R. <strong>BRCA1 interacts directly with the Fanconi anemia protein FANCA.</strong> Hum. Molec. Genet. 11: 2591-2597, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12354784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12354784</a>] [<a href="https://doi.org/10.1093/hmg/11.21.2591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12354784">Folias et al. (2002)</a> used yeast 2-hybrid analysis and coimmunoprecipitation methods to demonstrate a direct interaction between the FANCA and BRCA1 proteins. Direct interaction with other FANC proteins was not demonstrable. The amino terminal portion of FANCA and the central part (amino acids 740-1,083) of BRCA1 contained the sites of interaction. The interaction did not depend on DNA damage, suggesting that FANCA and BRCA1 may be constitutively interacting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12354784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#183" class="mim-tip-reference" title="Yu, X., Chini, C. C. S., He, M., Mer, G., Chen, J. <strong>The BRCT domain is a phospho-protein binding domain.</strong> Science 302: 639-642, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14576433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14576433</a>] [<a href="https://doi.org/10.1126/science.1088753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14576433">Yu et al. (2003)</a> demonstrated that the BRCA1 BRCT domain directly interacts with phosphorylated BRCA1-associated carboxyl-terminal helicase (BACH1; <a href="/entry/602751">602751</a>). The specific interaction between BRCA1 and phosphorylated BACH1 is cell cycle regulated and is required for DNA damage-induced checkpoint control during the transition from G2 to M phase of the cell cycle. Further, <a href="#183" class="mim-tip-reference" title="Yu, X., Chini, C. C. S., He, M., Mer, G., Chen, J. <strong>The BRCT domain is a phospho-protein binding domain.</strong> Science 302: 639-642, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14576433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14576433</a>] [<a href="https://doi.org/10.1126/science.1088753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14576433">Yu et al. (2003)</a> showed that 2 other BRCT domains interact with their respective physiologic partners in a phosphorylation-dependent manner. Thirteen additional BRCT domains also preferentially bind phosphopeptides rather than nonphosphorylated control peptides. <a href="#183" class="mim-tip-reference" title="Yu, X., Chini, C. C. S., He, M., Mer, G., Chen, J. <strong>The BRCT domain is a phospho-protein binding domain.</strong> Science 302: 639-642, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14576433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14576433</a>] [<a href="https://doi.org/10.1126/science.1088753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14576433">Yu et al. (2003)</a> concluded that their data implied that the BRCT domain is a phosphoprotein binding domain involved in cell cycle control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14576433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Dong, Y., Hakimi, M.-A., Chen, X., Kumaraswamy, E., Cooch, N. S., Godwin, A. K., Shiekhattar, R. <strong>Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair.</strong> Molec. Cell 12: 1087-1099, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14636569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14636569</a>] [<a href="https://doi.org/10.1016/s1097-2765(03)00424-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14636569">Dong et al. (2003)</a> isolated a holoenzyme complex containing BRCA1, BRCA2, BARD1 (<a href="/entry/601593">601593</a>), and RAD51 (<a href="/entry/179617">179617</a>), which they called the BRCA1- and BRCA2-containing complex (BRCC). The complex showed UBC5 (see UBE2D1; <a href="/entry/602961">602961</a>)-dependent ubiquitin E3 ligase activity. Inclusion of BRE (<a href="/entry/610497">610497</a>) and BRCC3 (<a href="/entry/300617">300617</a>) enhanced ubiquitination by the complex, and cancer-associated truncations in BRCA1 reduced the association of BRE and BRCC3 with the complex. RNA interference of BRE and BRCC3 in HeLa cells increased cell sensitivity to ionizing radiation and resulted in a defect in G2/M checkpoint arrest. <a href="#37" class="mim-tip-reference" title="Dong, Y., Hakimi, M.-A., Chen, X., Kumaraswamy, E., Cooch, N. S., Godwin, A. K., Shiekhattar, R. <strong>Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair.</strong> Molec. Cell 12: 1087-1099, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14636569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14636569</a>] [<a href="https://doi.org/10.1016/s1097-2765(03)00424-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14636569">Dong et al. (2003)</a> concluded that the BRCC is a ubiquitin E3 ligase that enhances cellular survival following DNA damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14636569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Deng, C.-X., Wang, R.-H. <strong>Roles of BRCA1 in DNA damage repair: a link between development and cancer.</strong> Hum. Molec. Genet. 12(R1): R113-R123, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668603</a>] [<a href="https://doi.org/10.1093/hmg/ddg082" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668603">Deng and Wang (2003)</a> discussed the functions of BRCA1 in DNA damage repair and cellular responses that link development and cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#106" class="mim-tip-reference" title="Morris, J. R., Solomon, E. <strong>BRCA1:BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair.</strong> Hum. Molec. Genet. 13: 807-817, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14976165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14976165</a>] [<a href="https://doi.org/10.1093/hmg/ddh095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14976165">Morris and Solomon (2004)</a> demonstrated an association of cellular BRCA1 with conjugated ubiquitin. The association was apparent at DNA replication structures in S-phase, following treatment with hydroxyurea, and at sites of double-strand break repair after exposure to ionizing radiation. Downregulation of endogenous, cellular BRCA1:BARD1 using siRNA resulted in abrogation of ubiquitin conjugation in these structures, suggesting that heterodimer activity may be required for their formation. Conversely, ectopically expressed full-length BRCA1, but not BRCA1 bearing specific N-terminal amino acid substitutions, was able to cooperate with BARD1 to increase ubiquitin conjugation in cells. Conjugation of ubiquitin in foci was inhibited by the expression of ubiquitin bearing a lysine-6 mutation, suggesting that the ubiquitin polymers formed at these sites may be dependent on lysine-6 for linkage. The authors concluded that BRCA1-directed ligation of ubiquitin occurs during S-phase and in response to replication stress and DNA damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14976165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#53" class="mim-tip-reference" title="Furuta, S., Jiang, X., Gu, B., Cheng, E., Chen, P.-L., Lee, W.-H. <strong>Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells.</strong> Proc. Nat. Acad. Sci. 102: 9176-9181, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15967981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15967981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15967981[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0503793102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15967981">Furuta et al. (2005)</a> found that reduction of BRCA1 by RNA interference enhanced proliferation and impaired acinus formation in a normal human mammary epithelial cell line. Depletion of BRCA1 upregulated the expression of genes involved in proliferation and downregulated genes involved in differentiation. The C-terminal BRCT domain of BRCA1 appeared to be necessary to induce differentiation. Growth medium that was conditioned by differentiating normal mammary epithelial cells could induce differentiation in breast cancer cells with reduced BRCA1 function. <a href="#53" class="mim-tip-reference" title="Furuta, S., Jiang, X., Gu, B., Cheng, E., Chen, P.-L., Lee, W.-H. <strong>Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells.</strong> Proc. Nat. Acad. Sci. 102: 9176-9181, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15967981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15967981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15967981[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0503793102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15967981">Furuta et al. (2005)</a> concluded that BRCA1 is involved in secretion of certain paracrine/autocrine factors that induce mammary epithelial cell differentiation in response to extracellular matrix signals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15967981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., Martin, N. M. B., Jackson, S. P., Smith, G. C. M., Ashworth, A. <strong>Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.</strong> Nature 434: 917-921, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829967</a>] [<a href="https://doi.org/10.1038/nature03445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15829967">Farmer et al. (2005)</a> showed that BRCA1 or BRCA2 (<a href="/entry/600185">600185</a>) dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP (<a href="/entry/173870">173870</a>) enzymatic activity, resulting in chromosomal instability, cell cycle arrest, and subsequent apoptosis. The authors suggested that this seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. <a href="#44" class="mim-tip-reference" title="Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., Martin, N. M. B., Jackson, S. P., Smith, G. C. M., Ashworth, A. <strong>Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.</strong> Nature 434: 917-921, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829967</a>] [<a href="https://doi.org/10.1038/nature03445" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15829967">Farmer et al. (2005)</a> concluded that their results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15829967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#84" class="mim-tip-reference" title="Joukov, V., Groen, A. C., Prokhorova, T., Gerson, R., White, E., Rodriguez, A., Walter, J. C., Livingston, D. M. <strong>The BRCA1/BARD1 heterodimer modulates Ran-dependent mitotic spindle assembly.</strong> Cell 127: 539-552, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17081976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17081976</a>] [<a href="https://doi.org/10.1016/j.cell.2006.08.053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17081976">Joukov et al. (2006)</a> found that the heterodimeric tumor suppressor complex BRCA1/BARD1 was required for mitotic spindle-pole assembly and for accumulation of TPX2 (<a href="/entry/605917">605917</a>), a major spindle organizer, on spindle poles in both HeLa cells and Xenopus egg extracts. This BRCA1/BARD1 function was centrosome independent, operated downstream of Ran GTPase (<a href="/entry/601179">601179</a>), and depended upon BRCA1/BARD1 E3 ubiquitin ligase activity. <a href="#84" class="mim-tip-reference" title="Joukov, V., Groen, A. C., Prokhorova, T., Gerson, R., White, E., Rodriguez, A., Walter, J. C., Livingston, D. M. <strong>The BRCA1/BARD1 heterodimer modulates Ran-dependent mitotic spindle assembly.</strong> Cell 127: 539-552, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17081976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17081976</a>] [<a href="https://doi.org/10.1016/j.cell.2006.08.053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17081976">Joukov et al. (2006)</a> concluded that BRCA1/BARD1 function in mitotic spindle assembly likely contributes to its role in chromosome stability control and tumor suppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17081976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The BRCT repeats of the breast and ovarian cancer predisposition protein BRCA1 are essential for tumor suppression. Using phosphopeptide affinity proteomic analysis, <a href="#166" class="mim-tip-reference" title="Wang, B., Matsuoka, S., Ballif, B. A., Zhang, D., Smogorzewska, A., Gygi, S. P., Elledge, S. J. <strong>Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response.</strong> Science 316: 1194-1198, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17525340[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1139476" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525340">Wang et al. (2007)</a> identified a protein, Abraxas (ABRA1; <a href="/entry/611143">611143</a>), that directly binds to the BRCA1 BRCT repeats through a phospho-ser-X-X-phe motif. Abraxas binds BRCA1 to the mutual exclusion of BACH1 (<a href="/entry/602751">602751</a>) and CTIP (<a href="/entry/604124">604124</a>), forming a third type of BRCA1 complex. Abraxas recruits the ubiquitin-interacting motif (UIM)-containing protein RAP80 (<a href="/entry/609433">609433</a>) to BRCA1. Both Abraxas and RAP80 were required for DNA damage resistance, G2/M checkpoint control, and DNA repair. RAP80 was required for optimal accumulation of BRCA1 on damaged DNA (foci) in response to ionizing radiation, and the UIM domains alone were capable of foci formation. <a href="#166" class="mim-tip-reference" title="Wang, B., Matsuoka, S., Ballif, B. A., Zhang, D., Smogorzewska, A., Gygi, S. P., Elledge, S. J. <strong>Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response.</strong> Science 316: 1194-1198, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17525340[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1139476" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525340">Wang et al. (2007)</a> concluded that the RAP80-Abraxas complex may help recruit BRCA1 to DNA damage sites in part through recognition of ubiquitinated proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17525340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#145" class="mim-tip-reference" title="Sobhian, B., Shao, G., Lilli, D. R., Culhane, A. C., Moreau, L. A., Xia, B., Livingston, D. M., Greenberg, R. A. <strong>RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites.</strong> Science 316: 1198-1202, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525341</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17525341[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1139516" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525341">Sobhian et al. (2007)</a> reported the interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein. RAP80 targets a complex containing the BRCA1-BARD1 (<a href="/entry/601593">601593</a>) E3 ligase and the deubiquitinating enzyme BRCC36 (<a href="/entry/300617">300617</a>) to MDC1 (<a href="/entry/607593">607593</a>)-gamma-H2AX (<a href="/entry/601772">601772</a>)-dependent lys6- and lys63-linked ubiquitin polymers at double-strand breaks. <a href="#145" class="mim-tip-reference" title="Sobhian, B., Shao, G., Lilli, D. R., Culhane, A. C., Moreau, L. A., Xia, B., Livingston, D. M., Greenberg, R. A. <strong>RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites.</strong> Science 316: 1198-1202, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525341</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17525341[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1139516" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525341">Sobhian et al. (2007)</a> stated that these events are required for cell cycle checkpoint and repair response to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of double-strand breaks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17525341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#86" class="mim-tip-reference" title="Kim, H., Chen, J., Yu, X. <strong>Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response.</strong> Science 316: 1202-1205, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525342</a>] [<a href="https://doi.org/10.1126/science.1139621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525342">Kim et al. (2007)</a> independently reported the identification of RAP80 as a BRCA1-interacting protein in humans. RAP80 contains a tandem UIM domain, which is required for its binding with ubiquitin in vitro and its damage-induced foci formation in vivo. Moreover, <a href="#86" class="mim-tip-reference" title="Kim, H., Chen, J., Yu, X. <strong>Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response.</strong> Science 316: 1202-1205, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525342</a>] [<a href="https://doi.org/10.1126/science.1139621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525342">Kim et al. (2007)</a> showed that RAP80 specifically recruits BRCA1 to DNA damage sites and functions with BRCA1 in G2/M checkpoint control. <a href="#86" class="mim-tip-reference" title="Kim, H., Chen, J., Yu, X. <strong>Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response.</strong> Science 316: 1202-1205, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17525342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17525342</a>] [<a href="https://doi.org/10.1126/science.1139621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17525342">Kim et al. (2007)</a> concluded that taken together, their results suggested the existence of ubiquitination-dependent signaling pathway involved in the DNA damage response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17525342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#167" class="mim-tip-reference" title="Wang, R.-H., Zheng, Y., Kim, H.-S., Xu, X., Cao, L., Luhasen, T., Lee, M.-H., Xiao, C., Vassilopoulos, A., Chen, W., Gardner, K., Man, Y.-G., Hung, M.-C., Finkel, T., Deng, C.-X. <strong>Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis.</strong> Molec. Cell 32: 11-20, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18851829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18851829</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18851829[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2008.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18851829">Wang et al. (2008)</a> found lower expression of SIRT1 (<a href="/entry/604479">604479</a>) in mouse and human BRCA1-associated breast cancers compared with controls. Reduced Sirt1 expression in Brca1-mutant mice was associated with increased expression of survivin (BIRC5; <a href="/entry/603352">603352</a>), and this expression pattern as reversed by induced expression of Brca1. <a href="#167" class="mim-tip-reference" title="Wang, R.-H., Zheng, Y., Kim, H.-S., Xu, X., Cao, L., Luhasen, T., Lee, M.-H., Xiao, C., Vassilopoulos, A., Chen, W., Gardner, K., Man, Y.-G., Hung, M.-C., Finkel, T., Deng, C.-X. <strong>Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis.</strong> Molec. Cell 32: 11-20, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18851829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18851829</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18851829[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.molcel.2008.09.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18851829">Wang et al. (2008)</a> showed that BRCA1 bound to the SIRT1 promoter and increased SIRT1 expression, which in turn inhibited survivin expression. Furthermore, inhibition of Brca1-mutant tumor growth by the anticancer agent resveratrol was associated with upregulation of Sirt1 activity, followed by reduction in survivin and apoptosis of the tumor cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18851829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using gene conformation analysis with BRCA1 from human breast cancer cell lines and mouse mammary tissue, <a href="#153" class="mim-tip-reference" title="Tan-Wong, S. M., French, J. D., Proudfoot, N. J., Brown, M. A. <strong>Dynamic interactions between the promoter and terminator regions of the mammalian BRCA1 gene.</strong> Proc. Nat. Acad. Sci. 105: 5160-5165, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18375767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18375767</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18375767[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0801048105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18375767">Tan-Wong et al. (2008)</a> found that chromatin loops were imposed on the BRCA1 gene by the juxtaposition of the promoter and 3-prime terminator regions in addition to internal sequences. The repressed BRCA1 conformation was predicted to resemble a 4-leaf clover. The interaction between the BRCA1 promoter and terminator regions was lost upon estrogen stimulation and during lactation development in the mouse. This activated conformation was predicted to have 3 loops and a long 3-prime tail. Loop formation was transcription-dependent, and the terminator region suppressed estrogen-induced transcription. <a href="#153" class="mim-tip-reference" title="Tan-Wong, S. M., French, J. D., Proudfoot, N. J., Brown, M. A. <strong>Dynamic interactions between the promoter and terminator regions of the mammalian BRCA1 gene.</strong> Proc. Nat. Acad. Sci. 105: 5160-5165, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18375767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18375767</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18375767[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0801048105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18375767">Tan-Wong et al. (2008)</a> also found that BRCA1 promoter and terminator interactions varied in different breast cancer cell lines. The authors concluded that estrogen-induced release of the terminator region from the promoter allows BRCA1 transcription, and that defects in BRCA1 chromatin structure may contribute to dysregulated BRCA1 expression in breast tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18375767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#184" class="mim-tip-reference" title="Yun, M. H., Hiom, K. <strong>CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle.</strong> Nature 459: 460-463, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19357644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19357644</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19357644[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19357644">Yun and Hiom (2009)</a> identified a role for CTIP in repair of DNA double-strand breaks (DSBs) in the avian B-cell line DT40. They established that CTIP is required not only for repair of DSBs by homologous recombination in S/G2 phase but also for microhomology-mediated end joining (MMEJ) in G1. The function of CTIP in homologous recombination, but not MMEJ, is dependent on the phosphorylation of serine residue 327 and recruitment of BRCA1. Cells expressing CTIP protein that cannot be phosphorylated at ser327 are specifically defective in homologous recombination and have a decreased level of single-stranded DNA after DNA damage, whereas MMEJ remains unaffected. <a href="#184" class="mim-tip-reference" title="Yun, M. H., Hiom, K. <strong>CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle.</strong> Nature 459: 460-463, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19357644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19357644</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19357644[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07955" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19357644">Yun and Hiom (2009)</a> concluded that their data support a model in which phosphorylation of ser327 of CTIP as cells enter S phase and the recruitment of BRCA1 functions as a molecular switch to shift the balance of DSB repair from error-prone DNA end joining to error-free homologous recombination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19357644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#105" class="mim-tip-reference" title="Morris, J. R., Boutell, C., Keppler, M., Densham, R., Weekes, D., Alamshah, A., Butler, L., Galanty, Y., Pangon, L., Kiuchi, T., Ng, T., Solomon, E. <strong>The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress.</strong> Nature 462: 886-890, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20016594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20016594</a>] [<a href="https://doi.org/10.1038/nature08593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20016594">Morris et al. (2009)</a> reported that BRCA1 is modified by SUMO in response to genotoxic stress, and colocalizes at sites of DNA damage with SUMO1 (<a href="/entry/601912">601912</a>), SUMO2 (<a href="/entry/603042">603042</a>)/SUMO3 (<a href="/entry/602231">602231</a>), and the SUMO conjugating-enzyme Ubc9 (<a href="/entry/601661">601661</a>). PIAS SUMO E3 ligases (PIAS1; <a href="/entry/603566">603566</a> and PIAS4 <a href="/entry/605989">605989</a>) colocalize with and modulate SUMO modification of BRCA1, and are required for BRCA1 ubiquitin ligase activity in cells. In vitro, SUMO modification of the BRCA1/BARD1 (<a href="/entry/601593">601593</a>) heterodimer greatly increases its ligase activity, identifying it as a SUMO-regulated ubiquitin ligase. Furthermore, PIAS SUMO ligases are required for complete accumulation of double-stranded DNA damage repair proteins subsequent to RNF8 (<a href="/entry/611685">611685</a>) accrual, and for proficient double-strand break repair. <a href="#105" class="mim-tip-reference" title="Morris, J. R., Boutell, C., Keppler, M., Densham, R., Weekes, D., Alamshah, A., Butler, L., Galanty, Y., Pangon, L., Kiuchi, T., Ng, T., Solomon, E. <strong>The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress.</strong> Nature 462: 886-890, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20016594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20016594</a>] [<a href="https://doi.org/10.1038/nature08593" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20016594">Morris et al. (2009)</a> concluded that the sumoylation pathway plays a significant role in mammalian DNA damage response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20016594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#175" class="mim-tip-reference" title="Wu, W., Sato, K., Koike, A., Nishikawa, H., Koizumi, H., Venkitaraman, A. R., Ohta, T. <strong>HERC2 is an E3 ligase that targets BRCA1 for degradation.</strong> Cancer Res. 70: 6384-6392, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631078</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-10-1304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20631078">Wu et al. (2010)</a> found that the E3 ubiquitin ligase HERC2 (<a href="/entry/605837">605837</a>) countered the stabilizing effect of BARD1 on BRCA1 and caused BRCA1 degradation. The HECT domain of HERC2 interacted with and caused ubiquitination of an N-terminal degradation domain of BRCA1, targeting BRCA1 for degradation. The HERC2-BRCA1 interaction and BRCA1 degradation were maximal during S phase in synchronized HeLa cells and rapidly diminished as cells entered G2-M. <a href="#175" class="mim-tip-reference" title="Wu, W., Sato, K., Koike, A., Nishikawa, H., Koizumi, H., Venkitaraman, A. R., Ohta, T. <strong>HERC2 is an E3 ligase that targets BRCA1 for degradation.</strong> Cancer Res. 70: 6384-6392, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20631078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20631078</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-10-1304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20631078">Wu et al. (2010)</a> concluded that HERC2 is an E3 ligase that counters the stabilizing effect of BARD1 and targets BRCA1 for degradation during S phase of the cell cycle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20631078" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid, immunoprecipitation, and immunoblot analyses, <a href="#176" class="mim-tip-reference" title="Wu-Baer, F., Ludwig, T., Baer, R. <strong>The UBXN1 protein associates with autoubiquitinated forms of the BRCA1 tumor suppressor and inhibits its enzymatic function.</strong> Molec. Cell. Biol. 30: 2787-2798, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20351172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20351172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20351172[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01056-09" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20351172">Wu-Baer et al. (2010)</a> showed that human UBXN1 (<a href="/entry/616378">616378</a>) interacted with the BRCA1/BARD1 heterodimer. UBXN1 could also interact with the N terminus of BRCA1 alone, but the presence of BARD1 enhanced the interaction. The C-terminal portion of UBXN1 was involved in interaction of UBXN1 with BRCA1, and the N-terminal UBA domain of UBXN1 bound lys6-linked polyubiquitin chains conjugated to BRCA1. UBXN1 inhibited the E3 ligase activity of BRCA1/BARD1, and this inhibition depended on the ubiquitin-binding activity of UBXN1. <a href="#176" class="mim-tip-reference" title="Wu-Baer, F., Ludwig, T., Baer, R. <strong>The UBXN1 protein associates with autoubiquitinated forms of the BRCA1 tumor suppressor and inhibits its enzymatic function.</strong> Molec. Cell. Biol. 30: 2787-2798, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20351172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20351172</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20351172[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.01056-09" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20351172">Wu-Baer et al. (2010)</a> proposed that UBXN1 regulates the enzymatic function of BRCA1 in a ubiquitination status-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20351172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid, coimmunoprecipitation, and microarray analyses, <a href="#69" class="mim-tip-reference" title="Harte, M. T., O'Brien, G. J., Ryan, N. M., Gorski, J. J., Savage, K. I., Crawford, N. T., Mullan, P. B., Harkin, D. P. <strong>BRD7, a subunit of SWI/SNF complexes, binds directly to BRCA1 and regulates BRCA1-dependent transcription.</strong> Cancer Res. 70: 2538-2547, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20215511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20215511</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-09-2089" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20215511">Harte et al. (2010)</a> found that human BRD7 (<a href="/entry/618489">618489</a>) and BRCA1 interacted and cooperated in regulation of BRCA1-dependent transcription. Chromatin immunoprecipitation assays revealed that BRD7 was present on the ESR1 promoter and was responsible for recruitment of BRCA1 and OCT1 (POU2F1; <a href="/entry/164175">164175</a>) to the ESR1 promoter. Depletion of either BRCA1 or BRD7 resulted in loss of ESR1 expression and resistance to antiestrogen treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20215511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#189" class="mim-tip-reference" title="Zhu, Q., Pao, G. M., Huynh, A. M., Suh, H., Tonnu, N., Nederlof, P. M., Gage, F. H., Verma, I. M. <strong>BRCA1 tumour suppression occurs via heterochromatin-mediated silencing.</strong> Nature 477: 179-184, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21901007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21901007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21901007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10371" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21901007">Zhu et al. (2011)</a> showed that loss of BRCA1 in mice results in transcriptional derepression of the tandemly repeated satellite DNA. Brca1 deficiency is accompanied by a reduction of condensed DNA regions in the genome and loss of ubiquitylation of histone H2A (see <a href="/entry/613499">613499</a>) at satellite repeats. BRCA1 binds to satellite DNA regions and ubiquitylates H2A in vivo. Ectopic expression of H2A fused to ubiquitin reverses the effects of BRCA1 loss, indicating that BRCA1 maintains heterochromatin structure via ubiquitylation of histone H2A. Satellite DNA derepression was also observed in mouse and human BRCA1-deficient breast cancers. Ectopic expression of satellite DNA can phenocopy BRCA1 loss in centrosome amplification, cell-cycle checkpoint defects, DNA damage, and genomic instability. <a href="#189" class="mim-tip-reference" title="Zhu, Q., Pao, G. M., Huynh, A. M., Suh, H., Tonnu, N., Nederlof, P. M., Gage, F. H., Verma, I. M. <strong>BRCA1 tumour suppression occurs via heterochromatin-mediated silencing.</strong> Nature 477: 179-184, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21901007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21901007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21901007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10371" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21901007">Zhu et al. (2011)</a> proposed that the role of BRCA1 in maintaining global heterochromatin integrity accounts for many of its tumor suppressor functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21901007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mouse embryonic stem cells, <a href="#23" class="mim-tip-reference" title="Chang, S., Wang, R.-H., Akagi, K., Kim, K.-A., Martin, B. K., Cavallone, L., Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Haines, D. C., Basik, M., Mai, P., Poggi, E., Isaacs, C., Looi, L. M., Mun, K. S., Greene, M. H., Byers, S. W., Teo, S. H., Deng, C.-X., Sharan, S. K. <strong>Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155.</strong> Nature Med. 17: 1275-1282, 2011. Note: Erratum: Nature Med. 17: 2 p following 1282, 2011. Erratum: Nature Med. 17: 1521 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21946536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21946536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21946536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21946536">Chang et al. (2011)</a> found that expression of human BRCA1 with the arg1699-to-gln (R1699Q; <a href="#0037">113705.0037</a>) mutation caused upregulation of microRNA-155 (MIR155; <a href="/entry/609337">609337</a>) and reduced embryonic stem cell survival. R1699Q interfered with differentiation of stem cells into embryoid bodies with distinct cell layers, which was associated with apoptotic cell death. In situ hybridization revealed 40-fold upregulation of Mir155 in a subset of cells from R1699Q embryoid bodies. Northern blot and RT-PCR analyses revealed that MIR155 was upregulated in all cell lines and breast cancer tumors with BRCA1 deficiency examined. Wildtype BRCA1, but not BRCA1 with the R1699Q substitution, downregulated mouse Mir155 expression by recruiting Hdac2 (<a href="/entry/605164">605164</a>) to the Mir155 promoter, resulting in deacetylation of histones H2a (see <a href="/entry/613499">613499</a>) and H3 (see <a href="/entry/602810">602810</a>). <a href="#23" class="mim-tip-reference" title="Chang, S., Wang, R.-H., Akagi, K., Kim, K.-A., Martin, B. K., Cavallone, L., Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Haines, D. C., Basik, M., Mai, P., Poggi, E., Isaacs, C., Looi, L. M., Mun, K. S., Greene, M. H., Byers, S. W., Teo, S. H., Deng, C.-X., Sharan, S. K. <strong>Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155.</strong> Nature Med. 17: 1275-1282, 2011. Note: Erratum: Nature Med. 17: 2 p following 1282, 2011. Erratum: Nature Med. 17: 1521 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21946536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21946536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21946536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21946536">Chang et al. (2011)</a> concluded that BRCA1 has a role in the epigenetic control of MIR155. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21946536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine whether the E3 ubiquitin ligase activity of BRCA1 is required for tumor suppression, <a href="#140" class="mim-tip-reference" title="Shakya, R., Reid, L. J., Reczek, C. R., Cole, F., Egli, D., Lin, C.-S., deRooij, D. G., Hirsch, S., Ravi, K., Hicks, J. B., Szabolcs, M., Jasin, M., Baer, R., Ludwig, T. <strong>BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity.</strong> Science 334: 525-528, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22034435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22034435</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22034435[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1209909" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22034435">Shakya et al. (2011)</a> generated mice that express an enzymatically defective Brca1. The enzymatically defective Brca1 prevented tumor formation to the same degree as did wildtype Brca1 in 3 different genetically engineered mouse models of cancer. In contrast, a mutation that ablated phosphoprotein recognition by the BRCA C terminus (BRCT) domains of BRCA1 elicited tumors in each of the 3 genetically engineered mouse models. Thus, <a href="#140" class="mim-tip-reference" title="Shakya, R., Reid, L. J., Reczek, C. R., Cole, F., Egli, D., Lin, C.-S., deRooij, D. G., Hirsch, S., Ravi, K., Hicks, J. B., Szabolcs, M., Jasin, M., Baer, R., Ludwig, T. <strong>BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity.</strong> Science 334: 525-528, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22034435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22034435</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22034435[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1209909" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22034435">Shakya et al. (2011)</a> concluded that BRCT phosphoprotein recognition, but not the E3 ligase activity, is required for BRCA1 tumor suppression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22034435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By expression screening, <a href="#91" class="mim-tip-reference" title="Lee, M.-H., Lahusen, T., Wang, R.-H., Xiao, C., Xu, X., Hwang, Y.-S., He, W.-W., Shi, Y., Deng, C.-X. <strong>Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation.</strong> Oncogene 31: 116-127, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21666725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21666725</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21666725[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/onc.2011.217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21666725">Lee et al. (2012)</a> found that YY1 (<a href="/entry/600013">600013</a>) was a potent positive regulator of BRCA1. YY1 directly bound the proximal promoter region of BRCA1. Expression of Yy1 and Brca1 correlated positively during the mammary cycle in mouse mammary gland. Expression of YY1 and BRCA1 correlated positively in histologic examination of normal human and tumor breast tissue, with generally lower expression of both proteins in breast cancers. Overexpression of YY1 caused cell cycle arrest in transfected breast cancer cells and inhibited tumor formation following injection in nude mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21666725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#172" class="mim-tip-reference" title="Willis, N. A., Chandramouly, G., Huang, B., Kwok, A., Follonier, C., Deng, C., Scully, R. <strong>BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks.</strong> Nature 510: 556-559, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24776801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24776801</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24776801[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13295" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24776801">Willis et al. (2014)</a> reported that the E. coli Tus/Ter complex can be engineered to induce site-specific replication fork stalling and chromosomal homologous recombination (HR)/sister chromatid recombination (SCR) in mouse cells. Tus/Ter-induced HR entails processing of bidirectionally arrested forks. <a href="#172" class="mim-tip-reference" title="Willis, N. A., Chandramouly, G., Huang, B., Kwok, A., Follonier, C., Deng, C., Scully, R. <strong>BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks.</strong> Nature 510: 556-559, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24776801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24776801</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24776801[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13295" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24776801">Willis et al. (2014)</a> found that the Brca1 C-terminal tandem BRCT repeat and regions of Brca1 encoded by exon 11, 2 Brca1 elements implicated in tumor suppression, control Tus/Ter-induced HR. Inactivation of either Brca1 or Brca2 (<a href="/entry/600185">600185</a>) increases the absolute frequency of 'long-tract' gene conversions at Tus/Ter-stalled forks, an outcome not observed in response to a site-specific endonuclease-mediated chromosomal double-strand break. Therefore, HR at stalled forks is regulated differently from HR at double-strand breaks arising independently of a replication fork. <a href="#172" class="mim-tip-reference" title="Willis, N. A., Chandramouly, G., Huang, B., Kwok, A., Follonier, C., Deng, C., Scully, R. <strong>BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks.</strong> Nature 510: 556-559, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24776801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24776801</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24776801[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13295" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24776801">Willis et al. (2014)</a> proposed that aberrant long-tract HR at stalled replication forks contributes to genomic instability and breast/ovarian cancer predisposition in BRCA mutant cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24776801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#112" class="mim-tip-reference" title="Orthwein, A., Noordermeer, S. M., Wilson, M. D., Landry, S., Enchev, R. I., Sherker, A., Munro, M., Pinder, J., Salsman, J., Dellaire, G., Xia, B., Peter, M., Durocher, D. <strong>A mechanism for the suppression of homologous recombination in G1 cells.</strong> Nature 528: 422-426, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26649820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26649820</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26649820[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature16142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26649820">Orthwein et al. (2015)</a> reported that the cell cycle controls the interaction of BRCA1 with PALB2 (<a href="/entry/610355">610355</a>)-BRCA2 to constrain BRCA2 function to the S/G2 phases in human cells. <a href="#112" class="mim-tip-reference" title="Orthwein, A., Noordermeer, S. M., Wilson, M. D., Landry, S., Enchev, R. I., Sherker, A., Munro, M., Pinder, J., Salsman, J., Dellaire, G., Xia, B., Peter, M., Durocher, D. <strong>A mechanism for the suppression of homologous recombination in G1 cells.</strong> Nature 528: 422-426, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26649820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26649820</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26649820[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature16142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26649820">Orthwein et al. (2015)</a> found that the BRCA1-interaction site on PALB2 is targeted by an E3 ubiquitin ligase composed of KEAP1 (<a href="/entry/606016">606016</a>), a PALB2-interacting protein, in complex with cullin-3 (<a href="/entry/603136">603136</a>)-RBX1 (<a href="/entry/603814">603814</a>). PALB2 ubiquitylation suppresses its interaction with BRCA1 and is counteracted by the deubiquitylase USP11 (<a href="/entry/300050">300050</a>), which is itself under cell-cycle control. Restoration of the BRCA1-PALB2 interaction combined with the activation of DNA-end resection is sufficient to induce homologous recombination in G1, as measured by RAD51 (<a href="/entry/179617">179617</a>) recruitment, unscheduled DNA synthesis, and a CRISPR-Cas9-based gene-targeting assay. <a href="#112" class="mim-tip-reference" title="Orthwein, A., Noordermeer, S. M., Wilson, M. D., Landry, S., Enchev, R. I., Sherker, A., Munro, M., Pinder, J., Salsman, J., Dellaire, G., Xia, B., Peter, M., Durocher, D. <strong>A mechanism for the suppression of homologous recombination in G1 cells.</strong> Nature 528: 422-426, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26649820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26649820</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26649820[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature16142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26649820">Orthwein et al. (2015)</a> concluded that the mechanism prohibiting homologous recombination in G1 minimally consists of the suppression of DNA-end resection coupled with a multistep block of the recruitment of BRCA2 to DNA damage sites that involves the inhibition of BRCA1-PALB2-BRCA2 complex assembly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26649820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Small, approximately 10-kilobase microhomology-mediated tandem duplications are abundant in the genomes of BRCA1-linked but not BRCA2-linked breast cancer. <a href="#173" class="mim-tip-reference" title="Willis, N. A., Frock, R. L., Menghi, F., Duffey, E. E., Panday, A., Camacho, V., Hasty, E. P., Liu, E. T., Alt, F. W., Scully, R. <strong>Mechanism of tandem duplication formation in BRCA1-mutant cells.</strong> Nature 551: 590-595, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29168504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29168504</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29168504[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature24477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29168504">Willis et al. (2017)</a> defined the mechanism underlying this rearrangement signature by showing that in primary mammalian cells, BRCA1, but not BRCA2, suppresses the formation of tandem duplications at a site-specific chromosomal replication fork barrier imposed by the binding of Tus proteins to an array of Ter sites. BRCA1 has no equivalent role at chromosomal double-stranded DNA breaks, indicating that tandem duplications form specifically at stalled forks. Tandem duplications in BRCA1 mutant cells arise by a replication restart-bypass mechanism terminated by end joining or by microhomology-mediated template switching, the latter forming complex tandem duplication breakpoints. Solitary DNA ends form directly at Tus-Ter, implicating misrepair of these lesions in tandem duplication formation. <a href="#173" class="mim-tip-reference" title="Willis, N. A., Frock, R. L., Menghi, F., Duffey, E. E., Panday, A., Camacho, V., Hasty, E. P., Liu, E. T., Alt, F. W., Scully, R. <strong>Mechanism of tandem duplication formation in BRCA1-mutant cells.</strong> Nature 551: 590-595, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29168504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29168504</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29168504[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature24477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29168504">Willis et al. (2017)</a> noted that BRCA1 inactivation is strongly associated with approximately 10-kilobase tandem duplications in ovarian cancer. This tandem duplicator phenotype may be a general signature of BRCA1-deficient cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29168504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By examining purified wildtype and mutant BRCA1-BARD1 (<a href="/entry/601593">601593</a>), <a href="#186" class="mim-tip-reference" title="Zhao, W., Steinfeld, J. B., Liang, F., Chen, X., Maranon, D. G., Ma, C. J., Kwon, Y., Rao, T., Wang, W., Sheng, C., Song, X., Deng, Y., Jimenez-Sainz, J., Lu, L., Jensen, R. B., Xiong, Y., Kupfer, G. M., Wiese, C., Greene, E. C., Sung, P. <strong>BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing.</strong> Nature 550: 360-36, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28976962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28976962</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28976962[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature24060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28976962">Zhao et al. (2017)</a> showed that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1-BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. <a href="#186" class="mim-tip-reference" title="Zhao, W., Steinfeld, J. B., Liang, F., Chen, X., Maranon, D. G., Ma, C. J., Kwon, Y., Rao, T., Wang, W., Sheng, C., Song, X., Deng, Y., Jimenez-Sainz, J., Lu, L., Jensen, R. B., Xiong, Y., Kupfer, G. M., Wiese, C., Greene, E. C., Sung, P. <strong>BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing.</strong> Nature 550: 360-36, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28976962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28976962</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28976962[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature24060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28976962">Zhao et al. (2017)</a> provided evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1-BARD1 mutants with weakened RAD51 interactions showed compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28976962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#114" class="mim-tip-reference" title="Panda, S., Setia, M., Kaur, N., Shepal, V., Arora, V., Singh, D. K., Mondal, A., Teli, A., Tathode, M., Gajula, R., Padhy, L. C., Shiras, A. <strong>Noncoding RNA Ginir functions as an oncogene by associating with centrosomal proteins.</strong> PLoS Biol. 16: e2004204, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30296263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30296263</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30296263[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pbio.2004204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30296263">Panda et al. (2018)</a> found that the centrosome-associated proteins Cep112 (<a href="/entry/618980">618980</a>) and Brca1 interacted in mouse cells. Both Cep112 and Brca1 also interacted with Ginir, a long intergenic noncoding RNA (lincRNA). When high levels of Ginir RNA were present in mouse cells, Ginir disrupted interaction between Cep112 and Brca1 and affected their expression levels and cellular localizations. Interference of Cep112-Brca1 interaction by Ginir resulted in replicative stress and mitotic dysregulation, causing genomic instability and propelling cells towards malignant transformation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30296263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Daza-Martin, M., Starowicz, K., Jamshad, M., Tye, S., Ronson, G. E., MacKay, H. L., Chauhan, A. S., Walker, A.K., Stone, H. R., Beesley, J. F. J., Coles, J. L., Garvin, A. J., Stewart, G. S., McCorvie, T. J., Zhang, X., Densham, R. M., Morris, J. R. <strong>Isomerization of BRCA1-BARD1 promotes replication fork protection.</strong> Nature 571: 521-527, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31270457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31270457</a>] [<a href="https://doi.org/10.1038/s41586-019-1363-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31270457">Daza-Martin et al. (2019)</a> showed that BRCA1 in complex with BARD1, and not the canonical BRCA1-PALB2 interaction, is required for fork protection. BRCA1-BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1 (<a href="/entry/601052">601052</a>). PIN1 activity enhances BRCA1-BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. <a href="#31" class="mim-tip-reference" title="Daza-Martin, M., Starowicz, K., Jamshad, M., Tye, S., Ronson, G. E., MacKay, H. L., Chauhan, A. S., Walker, A.K., Stone, H. R., Beesley, J. F. J., Coles, J. L., Garvin, A. J., Stewart, G. S., McCorvie, T. J., Zhang, X., Densham, R. M., Morris, J. R. <strong>Isomerization of BRCA1-BARD1 promotes replication fork protection.</strong> Nature 571: 521-527, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31270457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31270457</a>] [<a href="https://doi.org/10.1038/s41586-019-1363-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31270457">Daza-Martin et al. (2019)</a> identified genetic variants of BRCA1-BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1-BARD1 that are required for fork protection and associated with cancer development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31270457" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Familial Breast-Ovarian Cancer Susceptibility 1</em></strong></p><p>
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In affected members of 5 of 8 kindreds with hereditary breast-ovarian cancer linked to chromosome 17q (BROVCA1; <a href="/entry/604370">604370</a>), <a href="#101" class="mim-tip-reference" title="Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P. A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L. M., Ding, W., Bell, R., Rosenthal, J., and 33 others. <strong>A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.</strong> Science 266: 66-71, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7545954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7545954</a>] [<a href="https://doi.org/10.1126/science.7545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7545954">Miki et al. (1994)</a> identified 5 different heterozygous pathogenic mutations in the BRCA1 gene (see, e.g., <a href="#0035">113705.0035</a>). The mutations included an 11-bp deletion, a 1-bp insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Castilla, L. H., Couch, F. J., Erdos, M. R., Hoskins, K. F., Calzone, K., Garber, J. E., Boyd, J., Lubin, M. B., Deshano, M. L., Brody, L. C., Collins, F. S., Weber, B. L. <strong>Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.</strong> Nature Genet. 8: 387-391, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894491</a>] [<a href="https://doi.org/10.1038/ng1294-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894491">Castilla et al. (1994)</a> found 8 putative disease-causing mutations in the BRCA1 gene (see, e.g., <a href="#0001">113705.0001</a>; <a href="#0006">113705.0006</a>; <a href="#0013">113705.0013</a>; <a href="#0014">113705.0014</a>) in 50 probands with a family history of breast and/or ovarian cancer. The authors used single-strand conformation polymorphism (SSCP) analysis on PCR-amplified genomic DNA. The data were considered consistent with a tumor suppressor model. The heterogeneity of mutations, coupled with the large size of the gene, indicated that clinical application of BRCA1 mutation testing would be technically challenging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 10 families with breast-ovarian cancer, <a href="#52" class="mim-tip-reference" title="Friedman, L. S., Ostermeyer, E. A., Szabo, C. I., Dowd, P., Lynch, E. D., Rowell, S. E., King, M.-C. <strong>Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.</strong> Nature Genet. 8: 399-404, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894493</a>] [<a href="https://doi.org/10.1038/ng1294-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894493">Friedman et al. (1994)</a> used SSCP analysis and direct sequencing to identify 9 different heterozygous BRCA1 mutations (see, e.g., <a href="#0004">113705.0004</a>; <a href="#0007">113705.0007</a>-<a href="#0009">113705.0009</a>). The mutations in 7 instances led to protein truncation at sites throughout the gene. A missense mutation, which occurred independently in 2 families, led to loss of a cysteine in the zinc-binding domain. An intronic single basepair substitution destroyed an acceptor site and activated a cryptic splice site, leading to a 59-bp insertion and chain termination. In 4 families with both breast and ovarian cancer, chain termination mutations were found in the N-terminal half of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#143" class="mim-tip-reference" title="Simard, J., Tonin, P., Durocher, F., Morgan, K., Rommens, J., Gingras, S., Samson, C., Leblanc, J.-F., Belanger, C., Dion, F., Liu, Q., Skolnick, M., Goldgar, D., Shattuck-Eidens, D., Labrie, F., Narod, S. A. <strong>Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families.</strong> Nature Genet. 8: 392-398, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894492</a>] [<a href="https://doi.org/10.1038/ng1294-392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894492">Simard et al. (1994)</a> identified mutations in the BRCA1 gene in 12 of 30 Canadian families with breast-ovarian cancer syndrome (see, e.g., <a href="#0003">113705.0003</a>). Six frameshift mutations accounted for all 12 mutant alleles, including nucleotide insertions (2 mutations) and deletions (4 mutations). The same 1-bp insertion mutation in codon 1,755 was found in 4 independent families, whereas 4 other families shared a 2-bp deletion mutation in codons 22 to 23. These families were not known to be related, but haplotype analysis suggested that the carriers of each of these mutations had common ancestors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#54" class="mim-tip-reference" title="Futreal, P. A., Liu, Q., Shattuck-Eidens, D., Cochran, C., Harshman, K., Tavtigian, S., Bennett, L. M., Haugen-Strano, A., Swensen, J., Miki, Y., Eddington, K., McClure, M., and 15 others. <strong>BRCA1 mutation in primary breast and ovarian carcinomas.</strong> Science 266: 120-122, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7939630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7939630</a>] [<a href="https://doi.org/10.1126/science.7939630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7939630">Futreal et al. (1994)</a> demonstrated allelic loss at the BRCA1 locus in primary breast and ovarian tumors. Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all 4 mutations were germline alterations and occurred in cancers of early-onset type. These results were interpreted as indicating that mutation in the BRCA1 gene may not be critical to the development of most breast and ovarian cancers that arise in the absence of a mutant germline allele. This situation is unlike that in the APC gene (<a href="/entry/611731">611731</a>), which is involved in both hereditary polyposis coli and sporadic colorectal cancer, and that of some other genes involved in both familial and sporadic cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7939630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 of 47 sporadic ovarian cancers, <a href="#100" class="mim-tip-reference" title="Merajver, S. D., Pham, T. M., Caduff, R. F., Chen, M., Poy, E. L., Cooney, K. A., Weber, B. L., Collins, F. S., Johnston, C., Frank, T. S. <strong>Somatic mutations in the BRCA1 gene in sporadic ovarian tumours.</strong> Nature Genet. 9: 439-443, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795652</a>] [<a href="https://doi.org/10.1038/ng0495-439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7795652">Merajver et al. (1995)</a> examined tumor DNAs by SSCP and found 4 somatic mutations in the BRCA1 gene; all 4 had loss of heterozygosity (LOH) at a BRCA1 intragenic marker. The findings supported a tumor-suppressor mechanism for BRCA1; somatic mutation on one chromosome and LOH on the other may result in inactivation of BRCA1 in some sporadic ovarian cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7795652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Since more than 75% of the reported mutations in the BRCA1 gene result in truncated proteins, <a href="#72" class="mim-tip-reference" title="Hogervorst, F. B. L., Cornelis, R. S., Bout, M., van Vliet, M., Oosterwijk, J. C., Olmer, R., Bakker, B., Klijn, J. G. M., Vasen, H. F. A., Meijers-Heijboer, H., Menko, F. H., Cornelisse, C. J., den Dunnen, J. T., Devilee, P., van Ommen, G.-J. B. <strong>Rapid detection of BRCA1 mutations by the protein truncation test.</strong> Nature Genet. 10: 208-212, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7663517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7663517</a>] [<a href="https://doi.org/10.1038/ng0695-208" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7663517">Hogervorst et al. (1995)</a> used the protein truncation test (PTT) to screen for mutations in exon 11 which encodes 61% of the BRCA1 protein. In 45 patients from breast and/or ovarian cancer families, they found 6 novel mutations: 2 single nucleotide insertions, 3 small deletions (of 1-5 bp), and a nonsense mutation identified in 2 unrelated families. Furthermore, they were able to amplify the remaining coding region by RT-PCR using lymphocyte RNA. Combined with the protein truncation test, they detected aberrantly spliced products affecting exons 5 and 6 in 1 of 2 BRCA1-linked families examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7663517" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#139" class="mim-tip-reference" title="Serova, O., Montagna, M., Torchard, D., Narod, S. A., Tonin, P., Sylla, B., Lynch, H. T., Feunteun, J., Lenoir, G. M. <strong>A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families.</strong> Am. J. Hum. Genet. 58: 42-51, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8554067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8554067</a>]" pmid="8554067">Serova et al. (1996)</a> identified mutations in the BRCA1 gene in 16 of 20 families with breast-ovarian cancer, including 1 family with a case of male breast cancer. Nine of these mutations had not been reported previously. Most mutations generated a premature stop codon leading to the formation of a truncated BRCA1 protein of 2 to 88% of the expected normal length. The RING-finger domain was altered by 2 of the mutations. A reduced quantity of BRCA1 transcript was associated with 8 of the mutations. Of the 4 families with no detectable BRCA1 mutation, only 1 was clearly linked to the BRCA1 locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8554067" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Dunning, A. M., Chiano, M., Smith, N. R., Dearden, J., Gore, M., Oakes, S., Wilson, C., Stratton, M., Peto, J., Easton, D., Clayton, D., Ponder, B. A. J. <strong>Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population.</strong> Hum. Molec. Genet. 6: 285-289, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063749</a>] [<a href="https://doi.org/10.1093/hmg/6.2.285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063749">Dunning et al. (1997)</a> examined the frequency of 4 polymorphisms in the BRCA1 gene in a large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, the 4 sites generated only 3 haplotypes with a frequency more than 1.3%. The 2 most common haplotypes had frequencies of 0.57 and 0.32, respectively, and these frequencies did not differ significantly between patient and control groups. <a href="#40" class="mim-tip-reference" title="Dunning, A. M., Chiano, M., Smith, N. R., Dearden, J., Gore, M., Oakes, S., Wilson, C., Stratton, M., Peto, J., Easton, D., Clayton, D., Ponder, B. A. J. <strong>Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population.</strong> Hum. Molec. Genet. 6: 285-289, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063749</a>] [<a href="https://doi.org/10.1093/hmg/6.2.285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063749">Dunning et al. (1997)</a> concluded that the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, the data suggested that a gln356-to-arg (Q356R) allele may have a different genotype distribution in breast cancer patients than that in controls; arg356 homozygotes were more frequent in the control group (p = 0.01), indicating that it may be protective against breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9063749" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#87" class="mim-tip-reference" title="Langston, A. A., Malone, K. E., Thompson, J. D., Daling, J. R., Ostrander, E. A. <strong>BRCA1 mutations in a population-based sample of young women with breast cancer.</strong> New Eng. J. Med. 334: 137-142, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8531967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8531967</a>] [<a href="https://doi.org/10.1056/NEJM199601183340301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8531967">Langston et al. (1996)</a> found germline BRCA1 mutations in 6 of 80 women in whom breast cancer was diagnosed before the age of 35 and who were not selected on the basis of family history. Four additional rare sequence variants of unknown functional significance were also identified. Two of the mutations and 3 of the rare sequence variants were found among the 39 women who reported no family history of breast or ovarian cancer. None of the mutations and only 1 of the rare variants was identified in a reference population of 73 unrelated subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8531967" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="FitzGerald, M. G., MacDonald, D. J., Krainer, M., Hoover, I., O'Neil, E., Unsal, H., Silva-Arrieto, S., Finkelstein, D. M., Beer-Romero, P., Englert, C., Sgroi, D. C., Smith, B. L., Younger, J. W., Garber, J. E., Duda, R. B., Mayzel, K. A., Isselbacher, K. J., Friend, S. H., Haber, D. A. <strong>Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer.</strong> New Eng. J. Med. 334: 143-149, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8531968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8531968</a>] [<a href="https://doi.org/10.1056/NEJM199601183340302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8531968">FitzGerald et al. (1996)</a> obtained similar results in a study of 30 women with breast cancer before the age of 30: 4 (13%) had chain-terminating mutations and 1 had a missense mutation in the BRCA1 gene. Two of the 4 Jewish women in this cohort had the 185delAG mutation (<a href="#0003">113705.0003</a>). Among 39 Jewish women with breast cancer before the age of 40, <a href="#46" class="mim-tip-reference" title="FitzGerald, M. G., MacDonald, D. J., Krainer, M., Hoover, I., O'Neil, E., Unsal, H., Silva-Arrieto, S., Finkelstein, D. M., Beer-Romero, P., Englert, C., Sgroi, D. C., Smith, B. L., Younger, J. W., Garber, J. E., Duda, R. B., Mayzel, K. A., Isselbacher, K. J., Friend, S. H., Haber, D. A. <strong>Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer.</strong> New Eng. J. Med. 334: 143-149, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8531968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8531968</a>] [<a href="https://doi.org/10.1056/NEJM199601183340302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8531968">FitzGerald et al. (1996)</a> found that 8 (21%) carried the 185delAG mutation (95% CI, 9-36%). <a href="#46" class="mim-tip-reference" title="FitzGerald, M. G., MacDonald, D. J., Krainer, M., Hoover, I., O'Neil, E., Unsal, H., Silva-Arrieto, S., Finkelstein, D. M., Beer-Romero, P., Englert, C., Sgroi, D. C., Smith, B. L., Younger, J. W., Garber, J. E., Duda, R. B., Mayzel, K. A., Isselbacher, K. J., Friend, S. H., Haber, D. A. <strong>Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer.</strong> New Eng. J. Med. 334: 143-149, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8531968/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8531968</a>] [<a href="https://doi.org/10.1056/NEJM199601183340302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8531968">FitzGerald et al. (1996)</a> concluded that germline BRCA1 mutations can be present in young women with breast cancer who do not belong to families with multiple affected members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8531968" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#57" class="mim-tip-reference" title="Gayther, S. A., Harrington, P., Russell, P., Kharkevich, G., Garkavtseva, R. F., Ponder, B. A. J., UKCCCR Familial Ovarian Cancer Study Group. <strong>Rapid detection of regionally clustered germ-line BRCA1 mutations by multiplex heteroduplex analysis.</strong> Am. J. Hum. Genet. 58: 451-456, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644703</a>]" pmid="8644703">Gayther et al. (1996)</a> stated that more than 65 distinct mutations scattered throughout the coding region of BRCA1 had been detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8644703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Couch, F. J., Weber, B. L., Breast Cancer Information Core. <strong>Mutations and polymorphisms in the familial early-onset breast cancer (BRCA1) gene.</strong> Hum. Mutat. 8: 8-18, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8807330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8807330</a>] [<a href="https://doi.org/10.1002/humu.1380080102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8807330">Couch et al. (1996)</a> reported a total of 254 BRCA1 mutations, 132 (52%) of which were unique. These represented mutations entered into a database established by the Breast Cancer Information Core (BIC). A total of 221 (87%) of all mutations or 107 (81%) of the unique mutations are small deletions, insertions, nonsense point mutations, splice variants, and regulatory mutations that result in truncation or absence of the BRCA1 protein. A total of 11 disease-associated missense mutations (5 unique) and 21 variants (19 unique) as yet unclassified as missense mutations or polymorphisms had been detected. Thirty-five independent benign polymorphisms had been described. The most common mutations were 185delAG (<a href="#0003">113705.0003</a>) and 5382insC (<a href="#0018">113705.0018</a>), which accounted for 30 (11.7%) and 26 (10.1%), respectively, of all the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8807330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#148" class="mim-tip-reference" title="Stoppa-Lyonnet, D., Fricker, J. P., Essioux, L., Pages, S., Limacher, J. M., Sobol, H., Laurent-Puig, P., Thomas, G. <strong>Segregation of two BRCA1 mutations in a single family. (Letter)</strong> Am. J. Hum. Genet. 59: 479-481, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755940</a>]" pmid="8755940">Stoppa-Lyonnet et al. (1996)</a> described 2 independent BRCA1 mutations in a single family. A woman with breast cancer diagnosed at age 25 inherited a deleterious allele from her father. Her mother had ovarian and breast cancer caused by a separate mutation, which was the basis of breast cancer in 5 or more of her relatives. The authors pointed out that the segregation of 2 BRCA1 mutations resulted in the failure to demonstrate linkage to either chromosome 17 or chromosome 13 and could lead to the erroneous hypothesis of the involvement of a third locus in familial breast cancer. <a href="#108" class="mim-tip-reference" title="Narod, S., Ford, D., Devilee, P., Barkardottir, R. B., Eyfjord, J., Lenoir, G., Serova, O., Easton, D., Goldgar, D., Breast Cancer Linkage Consortium. <strong>Genetic heterogeneity of breast-ovarian cancer revisited. (Letter)</strong> Am. J. Hum. Genet. 57: 957-958, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7573057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7573057</a>]" pmid="7573057">Narod et al. (1995)</a> suggested that the fraction of familial breast cancer that is not accounted for by BRCA1 or BRCA2 may be small. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8755940+7573057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a screening of Hungarian breast/ovarian cancer families for germline mutations in BRCA1 and BRCA2, <a href="#125" class="mim-tip-reference" title="Ramus, S. J., Friedman, L. S., Gayther, S. A., Ponder, B. A. J., Bobrow, L. G., van der Looji, M., Papp, J., Olah, E. <strong>A breast/ovarian cancer patient with germline mutations in both BRCA1 and BRCA2. (Letter)</strong> Nature Genet. 15: 14-15, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988162</a>] [<a href="https://doi.org/10.1038/ng0197-14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988162">Ramus et al. (1997)</a> found 1 individual who carried the 185delAG mutation (<a href="#0003">113705.0003</a>) in BRCA1, as well as the 6174delT mutation (<a href="/entry/600185#0009">600185.0009</a>) in BRCA2. Each mutation had been shown to have a frequency of approximately 1% in the Ashkenazi Jewish population. Although the patient was not recorded as having a Jewish origin, haplotype analysis suggested that both mutations were of the Ashkenazi type. There was a maternal family history of breast cancer and the paternal family history was unknown. The patient was found to have breast cancer at age 48 and ovarian cancer at age 50 years. The ages at diagnosis and the tumor types were not different from those of patients with either BRCA1 or BRCA2 mutations. Both mutations were present in 3 different samples from the patient: breast tumor, ovarian tumor, and lymphocyte DNA. There was no evidence of LOH on either chromosome 13 or chromosome 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8988162" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#93" class="mim-tip-reference" title="Liede, A., Rehal, P., Vesprini, D., Jack, E., Abrahamson, J., Narod, S. A. <strong>A breast cancer patient of Scottish descent with germ-line mutations in BRCA1 and BRCA2. (Letter)</strong> Am. J. Hum. Genet. 62: 1543-1544, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585617</a>] [<a href="https://doi.org/10.1086/301889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585617">Liede et al. (1998)</a> found mutations of both BRCA1 and BRCA2 in a breast cancer patient of Scottish descent. Grade II adenocarcinoma of the breast was diagnosed at the age of 35 years. Simultaneous screening by protein truncation tests of both BRCA genes detected a 2508G-T mutation of the BRCA1 gene (<a href="#0023">113705.0023</a>) and a 3295insA mutation of BRCA2 (<a href="/entry/600185#0011">600185.0011</a>). The patient had both a maternal and a paternal history of breast cancer. The maternal side contained cases of postmenopausal breast cancer; the paternal side contained cases of premenopausal breast cancer. The mother, however, did not have either mutation, suggesting that both BRCA1 and BRCA2 germline mutations originated from the father of the proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a comprehensive screen of the entire BRCA1 coding region, <a href="#78" class="mim-tip-reference" title="Janezic, S. A., Ziogas, A., Krumroy, L. M., Krasner, M., Plummer, S. J., Cohen, P., Gildea, M., Barker, D., Haile, R., Casey, G., Anton-Culver, H. <strong>Germline BRCA1 alterations in a population-based series of ovarian cancer cases.</strong> Hum. Molec. Genet. 8: 889-897, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196379</a>] [<a href="https://doi.org/10.1093/hmg/8.5.889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196379">Janezic et al. (1999)</a> determined the prevalence of BRCA1 alterations in a population-based series of 107 consecutive ovarian cancer cases diagnosed in Orange County, California, between March 1, 1994 and February 28, 1995. The participation rate was 82%. BRCA1 alterations were sought using the RNase mismatch cleavage assay followed by direct sequencing. Two truncating mutations, 962del4 (<a href="#0024">113705.0024</a>) and 3600del11 (<a href="#0025">113705.0025</a>), were identified. Both patients had a family history of breast or ovarian cancer. Several novel as well as previously reported uncharacterized variants were also identified, some of which were associated with a family history of cancer. Using allele-specific amplification, <a href="#78" class="mim-tip-reference" title="Janezic, S. A., Ziogas, A., Krumroy, L. M., Krasner, M., Plummer, S. J., Cohen, P., Gildea, M., Barker, D., Haile, R., Casey, G., Anton-Culver, H. <strong>Germline BRCA1 alterations in a population-based series of ovarian cancer cases.</strong> Hum. Molec. Genet. 8: 889-897, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196379</a>] [<a href="https://doi.org/10.1093/hmg/8.5.889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196379">Janezic et al. (1999)</a> determined the frequency distribution of common polymorphisms in the 91 Caucasian cancer cases in this series and 24 sister controls. The rare form of the Q356R polymorphism was significantly (p = 0.03) associated with a family history of ovarian cancer, suggesting that this polymorphism may influence ovarian cancer risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#159" class="mim-tip-reference" title="Vallon-Christersson, J., Cayanan, C., Haraldsson, K., Loman, N., Bergthorsson, J. T., Brondum-Nielsen, K., Gerdes, A.-M., Moller, P., Kristoffersson, U., Olsson, H., Borg, A., Monteiro, A. N. A. <strong>Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families.</strong> Hum. Molec. Genet. 10: 353-360, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11157798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/10.4.353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157798">Vallon-Christersson et al. (2001)</a> characterized the effect of C-terminal germline variants identified in Scandinavian breast and ovarian cancer families. Seven familial missense mutations, a truncating mutation, 4 missense variants, and 1 in-frame deletion were studied using 2 separate reporter genes. The authors concluded that transactivation activity may reflect a tumor-suppressing function of BRCA1 and further support the role of BRCA1 missense mutations in disease predisposition. A discrepancy was noted between results from yeast- and mammalian-based assays, indicating that it may not be possible to unambiguously characterize variants with the yeast assay alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#117" class="mim-tip-reference" title="Perrin-Vidoz, L., Sinilnikova, O. M., Stoppa-Lyonnet, D., Lenoir, G. M., Mazoyer, S. <strong>The nonsense-mediated mRNA decay pathway triggers degradation of most BRCA1 mRNAs bearing premature termination codons.</strong> Hum. Molec. Genet. 11: 2805-2814, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12393792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12393792</a>] [<a href="https://doi.org/10.1093/hmg/11.23.2805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12393792">Perrin-Vidoz et al. (2002)</a> assessed the relative amount of transcripts encoded by BRCA1 alleles harboring 30 different truncating mutations in lymphoblastoid cell lines established from carriers from breast/ovarian cancer families. The authors observed that nonsense-mediated decay (NMD) was triggered by 80% of alleles containing a premature termination codon (PTC) and resulted in a 1.5- to 5-fold reduction in mRNA abundance. All truncating mutations located in the 3.4-kb long central exon were subject to NMD, irrespective of their distance to the downstream exon-exon junction. PTCs not leading to NMD were either located in the last exon or very close to the translation initiation codon. <a href="#117" class="mim-tip-reference" title="Perrin-Vidoz, L., Sinilnikova, O. M., Stoppa-Lyonnet, D., Lenoir, G. M., Mazoyer, S. <strong>The nonsense-mediated mRNA decay pathway triggers degradation of most BRCA1 mRNAs bearing premature termination codons.</strong> Hum. Molec. Genet. 11: 2805-2814, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12393792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12393792</a>] [<a href="https://doi.org/10.1093/hmg/11.23.2805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12393792">Perrin-Vidoz et al. (2002)</a> hypothesized that reinitiation could explain why transcripts carrying early PTCs escape NMD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12393792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#127" class="mim-tip-reference" title="Rostagno, P., Gioanni, J., Garino, E., Vallino, P., Namer, M., Frenay, M. <strong>A mutation analysis of the BRCA1 gene in 140 families from southeast France with a history of breast and/or ovarian cancer.</strong> J. Hum. Genet. 48: 362-366, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12827452/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12827452</a>] [<a href="https://doi.org/10.1007/s10038-003-0038-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12827452">Rostagno et al. (2003)</a> performed mutation analysis of the BRCA1 gene in 140 families from the southeast of France with a history of breast and/or ovarian cancer. As expected, BRCA1 gene alteration, including missense mutations of unknown biologic significance, were more frequent in families with a history of breast-ovarian cancer (32%) than in breast-cancer-only families (12%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12827452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#156" class="mim-tip-reference" title="The Scottish/Northern Irish BRCA1/BRCA2 Consortium. <strong>BRCA1 and BRCA2 mutations in Scotland and Northern Ireland.</strong> Brit. J. Cancer 88: 1256-1262, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12698193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12698193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12698193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.bjc.6600840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12698193">The Scottish/Northern Irish BRCA1/BRCA2 Consortium (2003)</a> identified 107 families in Scotland or Northern Ireland with mutations in the BRCA1 or BRCA2 genes: 59 had BRCA1 mutations and 46 had BRCA2 mutations. Two families had mutations in both genes. The most common mutations were the BRCA1 2800delAA mutation (<a href="#0008">113705.0008</a>) in 11 families and the BRCA2 6503delTT mutation (<a href="/entry/600185#0002">600185.0002</a>) in 12 families. Prevalence of breast cancer was similar for BRCA1 and BRCA2 mutation families (average 3.7 and 3.6 per family, respectively), but those with BRCA1 mutations had a much greater risk of ovarian cancer (average 1.5 and 0.6 per family, respectively). Mutations within the 5-prime two-thirds of BRCA1 carried a significantly higher relative risk of ovarian cancer, and the same was true for mutations within the central portion of BRCA2 (the 'OCCR'). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12698193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 349 Belgian families with breast-ovarian cancer, <a href="#27" class="mim-tip-reference" title="Claes, K., Poppe, B., Coene, I., De Paepe, A., Messiaen, L. <strong>BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families.</strong> Brit. J. Cancer 90: 1244-1251, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15026808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15026808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15026808[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.bjc.6601656" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15026808">Claes et al. (2004)</a> found that 49 had BRCA1 mutations and 26 had BRCA2 mutations. Male breast cancer was significantly indicative of a BRCA2 mutation. Mutations in the 5-prime ends of BRCA1 and BRCA2 were associated with a significantly increased risk of ovarian cancer relative to the center portion of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15026808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 64 Chilean families with breast-ovarian cancer, <a href="#79" class="mim-tip-reference" title="Jara, L., Ampuero, S., Santibanez, E., Seccia, L., Rodriguez, J., Bustamante, M., Martinez, V., Catenaccio, A., Lay-Son, G., Blanco, R., Reyes, J. M. <strong>BRCA1 and BRCA2 mutations in a South American population.</strong> Cancer Genet. Cytogenet. 166: 36-45, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16616110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16616110</a>] [<a href="https://doi.org/10.1016/j.cancergencyto.2005.08.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16616110">Jara et al. (2006)</a> found that 7 (10.9%) carried mutations in the BRCA1 gene and 3 (4.7%) carried mutations in the BRCA2 gene. Only 2 families had the same BRCA1 mutation, indicating heterogeneity in the spectrum of BRCA mutations in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16616110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 300 US probands from high-risk families who tested negative for BRCA1 or BRCA2 gene mutations by conventional testing, <a href="#164" class="mim-tip-reference" title="Walsh, T., Casadei, S., Coats, K. H., Swisher, E., Stray, S. M., Higgins, J., Roach, K. C., Mandell, J., Lee, M. K., Ciernikova, S., Foretova, L., Soucek, P., King, M.-C. <strong>Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer.</strong> JAMA 295: 1379-1388, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16551709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16551709</a>] [<a href="https://doi.org/10.1001/jama.295.12.1379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16551709">Walsh et al. (2006)</a> identified 31 with genomic rearrangements of BRCA1 and 4 with genomic rearrangements of BRCA2, totaling 35 (12%) of 300. Inherited rearrangements of BRCA1 or BRCA2 were found in a larger proportion of families with ovarian and/or male breast cancer (18%) than in those with only female breast cancer (4.2%). Fourteen probands (4%) had mutations in the CHEK2 gene (<a href="/entry/604373">604373</a>), and 3 (1%) had mutations in p53 (<a href="/entry/191170">191170</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16551709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analysis of BRCA1 mutations in the BIC database, <a href="#116" class="mim-tip-reference" title="Pavlicek, A., Noskov, V. N., Kouprina, N., Barrett, J. C., Jurka, J., Larionov, V. <strong>Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition.</strong> Hum. Molec. Genet. 13: 2737-2751, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385441</a>] [<a href="https://doi.org/10.1093/hmg/ddh301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385441">Pavlicek et al. (2004)</a> showed that distribution of reported missense mutations, but not frameshift and nonsense mutations, was positively correlated with BRCA1 protein conservation. Based on protein sequence conservation, they identified missense changes that are likely to compromise BRCA1 function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15385441" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Easton, D. F., Deffenbaugh, A. M., Pruss, D., Frye, C., Wenstrup, R. J., Allen-Brady, K., Tavtigian, S. V., Monteiro, A. N. A., Iversen, E. S., Couch, F. J., Goldgar, D. E. <strong>A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes.</strong> Am. J. Hum. Genet. 81: 873-883, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17924331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17924331</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17924331[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/521032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17924331">Easton et al. (2007)</a> undertook a systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer predisposition genes. <a href="#41" class="mim-tip-reference" title="Easton, D. F., Deffenbaugh, A. M., Pruss, D., Frye, C., Wenstrup, R. J., Allen-Brady, K., Tavtigian, S. V., Monteiro, A. N. A., Iversen, E. S., Couch, F. J., Goldgar, D. E. <strong>A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes.</strong> Am. J. Hum. Genet. 81: 873-883, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17924331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17924331</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17924331[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/521032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17924331">Easton et al. (2007)</a> identified 43 sequence variants with odds greater than 20 to 1 in favor of causality of breast cancer in BRCA1 and 17 in BRCA2. A total of 133 variants of unknown clinical significance had odds of at least 100 to 1 in favor of neutrality with respect to risk. Those with evidence in favor of causality were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17924331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#168" class="mim-tip-reference" title="Wang, X., Pankratz, V. S., Fredericksen, Z., Tarrell, R., Karaus, M., McGuffog, L., Pharaoh, P. D. P., Ponder, B. A. J., Dunning, A. M., Peock, S., Cook, M., Oliver, C., and 36 others. <strong>Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.</strong> Hum. Molec. Genet. 19: 2886-2897, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20418484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20418484</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20418484[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddq174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20418484">Wang et al. (2010)</a> genotyped 3,451 BRCA1 and 2,006 BRCA2 mutation carriers at 350 SNPs identified as candidate breast cancer risk factors in 2 breast cancer genomewide association studies (GWAS). Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk. The minor alleles of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs6138178;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs6138178</a> in SNRPB (<a href="/entry/182282">182282</a>) and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs6602595;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs6602595</a> in CAMK1D (<a href="/entry/607957">607957</a>) displayed the strongest associations in BRCA1 carriers (p(trend) = 3.6 x 10(-4), 95% CI 0.69-0.90 and p(trend) = 4.2 x 10(-4), 95% CI 1.10-1.41, respectively). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20418484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Fanconi Anemia, Complementation Group S</em></strong></p><p>
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In a 28-year-old woman with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; <a href="/entry/617883">617883</a>), <a href="#36" class="mim-tip-reference" title="Domchek, S. M., Tang, J., Stopfer, J., Lilli, D. R., Hamel, N., Tischkowitz, M., Monteiro, A. N. A., Messick, T. E., Powers, J., Yonker, A., Couch, F. J., Goldgar, D. E., Davidson, H. R., Nathanson, K. L., Foulkes, W. D., Greenberg, R. A. <strong>Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer.</strong> Cancer Discov. 3: 399-405, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23269703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23269703</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23269703[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1158/2159-8290.CD-12-0421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23269703">Domchek et al. (2012)</a> identified 2 mutations in the BRCA1 gene (V1736A, <a href="#0038">113705.0038</a> and c.2457delC, <a href="#0039">113705.0039</a>), as well as a variant of unknown significance in the BRCA2 gene (c.971G-C, R324T). In vitro functional expression studies showed that the BRCA1 V1736A variant was a hypomorphic allele, with decreased localization to double-strand breaks and decreased interaction with RAP80 (UIMC1; <a href="/entry/609433">609433</a>) compared to wildtype. No studies of the BRCA2 variant were performed. The patient's mother died of ovarian cancer at age 55; her DNA was not available. A maternal great-aunt with both breast and ovarian cancer (BROVCA1; <a href="/entry/604370">604370</a>) carried a heterozygous V1736A mutation, and another maternal great-aunt with peritoneal cancer carried the V1736A mutation and the BRCA2 R324T variant. A heterozygous V1736A mutation was also found in 2 unaffected family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23269703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#131" class="mim-tip-reference" title="Sawyer, S. L., Tian, L., Kahkonen, M., Schwartzentruber, J., Kircher, M., University of Washington Centre for Mendelian Genomics, FORGE Canada Consortium, Majewski, J., Dyment, D. A., Innes, A. M., Boycott, K. M., Moreau, L. A., Moilanen, J. S., Greenberg, R. A. <strong>Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype.</strong> Cancer Discov. 5: 135-142, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25472942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25472942</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25472942[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1158/2159-8290.CD-14-1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25472942">Sawyer et al. (2014)</a> reported a woman with FANCS who was compound heterozygous for mutations in the BRCA1 gene (R1699W, <a href="#0040">113705.0040</a> and c.594_597del4, <a href="#0041">113705.0041</a>). Patient lymphocytes showed increased chromosomal breakage and radial chromosome formation compared to controls. The patient's mother, who was heterozygous for the 4-bp deletion, had ovarian cancer. There was a strong family history of cancer, including ovarian, endometrial, and stomach cancer. Fibroblasts from the proband showed reduced expression of full-length BRCA1 protein, suggesting that the R1699W mutation leads to misfolding and reduced proteolytic stability. RT-PCR analysis suggested that the c.594_597 deletion resulted in nonsense-mediated mRNA decay. Further studies of patient cells showed decreased BRCA1 and RAD51 (<a href="/entry/179617">179617</a>) foci in response to insult, suggesting impaired double-strand break repair function. Ectopic expression of wildtype BRCA1 restored these repair functions. The R1699W mutation had previously been identified in heterozygous state in a Scandinavian family (LUND279) segregating breast and ovarian cancer by <a href="#159" class="mim-tip-reference" title="Vallon-Christersson, J., Cayanan, C., Haraldsson, K., Loman, N., Bergthorsson, J. T., Brondum-Nielsen, K., Gerdes, A.-M., Moller, P., Kristoffersson, U., Olsson, H., Borg, A., Monteiro, A. N. A. <strong>Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families.</strong> Hum. Molec. Genet. 10: 353-360, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11157798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/10.4.353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157798">Vallon-Christersson et al. (2001)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11157798+25472942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 2.5-year-old girl, born of consanguineous Brazilian parents, with FANCS, <a href="#51" class="mim-tip-reference" title="Freire, B. L., Homma, T. K., Funari, M. F. A., Lerario, A. M., Leal, A. M., Velloso, E. D. R. P., Malaquias, A. C., Jorge, A. A. L. <strong>Homozygous loss of function BRCA1 variant causing a Fanconi-anemia-like phenotype, a clinical report</strong> Europ. J. Med. Genet. 61: 130-133, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29133208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29133208</a>] [<a href="https://doi.org/10.1016/j.ejmg.2017.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29133208">Freire et al. (2018)</a> identified a homozygous nonsense mutation in the BRCA1 gene (C903X; <a href="#0042">113705.0042</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in her parents. Patient cells showed increased chromosomal breakage compared to controls. The patient's mother was subsequently screened and found to have breast cancer; there was additional family history of breast cancer on the maternal side. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29133208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 patients from 2 unrelated consanguineous Middle Eastern families with a complex phenotype consistent with FANCS, <a href="#138" class="mim-tip-reference" title="Seo, A., Steinberg-Shemer, O., Unal, S., Casadei, S., Walsh, T., Gumruk, F., Shalev, S., Shimamura, A., Akarsu, N. A., Tamary, H., King, M.-C. <strong>Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1.</strong> Proc. Nat. Acad. Sci. 115: 5241-5246, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29712865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29712865</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29712865[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1801796115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29712865">Seo et al. (2018)</a> identified homozygous nonsense mutations in the BRCA1 gene (W372X, <a href="#0043">113705.0043</a> and L431X, <a href="#0044">113705.0044</a>). Both mutations, as well as the previously reported C903X mutation (<a href="#51" class="mim-tip-reference" title="Freire, B. L., Homma, T. K., Funari, M. F. A., Lerario, A. M., Leal, A. M., Velloso, E. D. R. P., Malaquias, A. C., Jorge, A. A. L. <strong>Homozygous loss of function BRCA1 variant causing a Fanconi-anemia-like phenotype, a clinical report</strong> Europ. J. Med. Genet. 61: 130-133, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29133208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29133208</a>] [<a href="https://doi.org/10.1016/j.ejmg.2017.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29133208">Freire et al., 2018</a>), occurred in exon 11. Complete loss of BRCA1 was thought to be embryonic lethal; however, homozygosity for these nonsense mutations was viable in these patients due to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5-prime to the mutations and produces 2 short isoforms that lack the residues affected by the mutations. Fibroblasts derived from 1 patient showed no detectable full-length BRCA1 protein, but had protein levels corresponding to one of the normal isoforms that retain some capacity to repair DNA damage and can partially compensate for loss of the full-length protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=29712865+29133208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Prostate Cancer</em></strong></p><p>
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In Icelandic studies, <a href="#8" class="mim-tip-reference" title="Arason, A., Barkardottir, R. B., Egilsson, V. <strong>Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer.</strong> Am. J. Hum. Genet. 52: 711-717, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8460636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8460636</a>]" pmid="8460636">Arason et al. (1993)</a> suggested that male carriers of the BRCA1 gene may have an increased risk of prostate cancer. <a href="#88" class="mim-tip-reference" title="Langston, A. A., Stanford, J. L., Wicklund, K. G., Thompson, J. D., Blazej, R. G., Ostrander, E. A. <strong>Germ-line BRCA1 mutations in selected men with prostate cancer. (Letter)</strong> Am. J. Hum. Genet. 58: 881-885, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644752</a>]" pmid="8644752">Langston et al. (1996)</a> studied the BRCA1 gene in 61 men who met one or more of these criteria: (1) under 53 years of age at diagnosis prostate cancer; (2) a family history of breast cancer in a first-degree female relative diagnosed under 51 years of age; or (3) a family history of prostate cancer in 2 or more male relatives, with at least 1 relative diagnosed at less than 56 years of age. They found 1 germline mutation, 185delAG (<a href="#0003">113705.0003</a>), in 1 subject and 5 different rare sequence variants (1 of which was detected in 2 unrelated men). None of the rare variants were found in population-based controls. <a href="#76" class="mim-tip-reference" title="Isaacs, S. D., Kiemeney, L. A. L. M., Baffoe-Bonnie, A., Beaty, T. H., Walsh, P. C. <strong>Risk of cancer in relatives of prostate cancer probands.</strong> J. Nat. Cancer Inst. 87: 991-996, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7629886/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7629886</a>] [<a href="https://doi.org/10.1093/jnci/87.13.991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7629886">Isaacs et al. (1995)</a> failed to identify a significantly increased risk of breast cancer among relatives of prostate cancer probands. The findings of <a href="#88" class="mim-tip-reference" title="Langston, A. A., Stanford, J. L., Wicklund, K. G., Thompson, J. D., Blazej, R. G., Ostrander, E. A. <strong>Germ-line BRCA1 mutations in selected men with prostate cancer. (Letter)</strong> Am. J. Hum. Genet. 58: 881-885, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644752</a>]" pmid="8644752">Langston et al. (1996)</a> are not necessarily in conflict, since the contribution of germline BRCA1 mutations to the overall incidence of prostate cancer appears to be small, at most, and may be limited to specific subgroups of patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8460636+7629886+8644752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#109" class="mim-tip-reference" title="Nastiuk, K. L., Mansukhani, M., Terry, M. B., Kularatne, P., Rubin, M. A., Melamed, J., Gammon, M. D., Ittmann, M., Krolewski, J. J. <strong>Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men.</strong> Prostate 40: 172-177, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10398279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10398279</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10398279[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/(sici)1097-0045(19990801)40:3<172::aid-pros5>3.0.co;2-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10398279">Nastiuk et al. (1999)</a> set out to determine whether the common germline mutations of BRCA1 (<a href="#0003">113705.0003</a>) or BRCA2 (<a href="/entry/600185#0009">600185.0009</a>), which are frequent in the Ashkenazi Jewish population, predispose Ashkenazi Jewish men to prostate cancer. They found that each of these germline mutations occurred at an incidence in prostate cancer patients that closely matched that in the general Ashkenazi Jewish population. They suggested that unlike cases of breast and ovarian cancers, mutations in BRCA1 or BRCA2 do not significantly predispose men to prostate cancer. <a href="#161" class="mim-tip-reference" title="Vazina, A., Baniel, J., Yaacobi, Y., Shtriker, A., Engelstein, D., Leibovitz, I., Zehavi, M., Sidi, A. A., Ramon, Y., Tischler, T., Livne, P. M., Friedman, E. <strong>The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel.</strong> Brit. J. Cancer 83: 463-466, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10945492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10945492</a>] [<a href="https://doi.org/10.1054/bjoc.2000.1249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10945492">Vazina et al. (2000)</a> also concluded that BRCA1 and BRCA2 germline mutations that are common in Jewish populations probably contribute little to the occurrence of cancer of the prostate, to inherited predisposition, or to early-onset disease in Jewish individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10945492+10398279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 940 Ashkenazi Israelis with prostate cancer, <a href="#60" class="mim-tip-reference" title="Giusti, R. M., Rutter, J. L., Duray, P. H., Freedman, L. S., Konichezky, M., Fisher-Fischbein, J., Greene, M. H., Maslansky, B., Fischbein, A., Gruber, S. B., Rennert, G., Ronchetti, R. D., Hewitt, S. M., Struewing, J. P., Iscovich, J. <strong>A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology.</strong> J. Med. Genet. 40: 787-792, 2003. Note: Erratum: J. Med. Genet. 41: 51 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14569130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14569130</a>] [<a href="https://doi.org/10.1136/jmg.40.10.787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14569130">Giusti et al. (2003)</a> tested DNA obtained from paraffin sections for the 3 Jewish founder mutations: 185delAG (<a href="#0003">113705.0003</a>) and 5382insC (<a href="#0018">113705.0018</a>) in BRCA1 and 6174delT (<a href="/entry/600185#0009">600185.0009</a>) in BRCA2. They estimated that there is a 2-fold increase in BRCA mutation-related prostate cancer among Ashkenazi Israelis. No differences were noted between the histopathologic features of cases with or without founder mutations, and no difference was found in the mean age at diagnosis between cases with or without a founder mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14569130" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Other Cancers</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Al-Sukhni, W., Rothenmund, H., Eppel Borgida, A., Zogopoulos, G., O'Shea, A.-M., Pollett, A., Gallinger, S. <strong>Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.</strong> Hum. Genet. 124: 271-278, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18762988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18762988</a>] [<a href="https://doi.org/10.1007/s00439-008-0554-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18762988">Al-Sukhni et al. (2008)</a> found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer (see <a href="/entry/614320">614320</a>) who carried a heterozygous germline BRCA1 mutation (see, e.g., <a href="#0003">113705.0003</a> and <a href="#0018">113705.0018</a>). Pancreatic tumor DNA was available for sequencing in 4 cases, and 3 demonstrated loss of the wildtype allele. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. <a href="#3" class="mim-tip-reference" title="Al-Sukhni, W., Rothenmund, H., Eppel Borgida, A., Zogopoulos, G., O'Shea, A.-M., Pollett, A., Gallinger, S. <strong>Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.</strong> Hum. Genet. 124: 271-278, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18762988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18762988</a>] [<a href="https://doi.org/10.1007/s00439-008-0554-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18762988">Al-Sukhni et al. (2008)</a> concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18762988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#83" class="mim-tip-reference" title="Jonsson, P., Bandlamudi, C., Cheng, M. L., Srinivasan, P., Chavan, S. S., Friedman, N. D., Rosen, E. Y., Richards, A. L., Bouvier, N., Selcuklu, S. D., Bielski, C. M., Abida, W., and 19 others. <strong>Tumour lineage shapes BRCA-mediated phenotypes.</strong> Nature 571: 576-579, 2019. Note: Erratum: Nature 577: E1, 2020. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31292550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31292550</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31292550[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1382-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31292550">Jonsson et al. (2019)</a> analyzed the germline, blood, and matched tumor tissue of 17,152 patients with cancer diagnosed with 1 of 55 cancer types in whom prospective clinical sequencing of up to 468 cancer-associated genes was performed to guide treatment decisions for advanced and metastatic disease. <a href="#83" class="mim-tip-reference" title="Jonsson, P., Bandlamudi, C., Cheng, M. L., Srinivasan, P., Chavan, S. S., Friedman, N. D., Rosen, E. Y., Richards, A. L., Bouvier, N., Selcuklu, S. D., Bielski, C. M., Abida, W., and 19 others. <strong>Tumour lineage shapes BRCA-mediated phenotypes.</strong> Nature 571: 576-579, 2019. Note: Erratum: Nature 577: E1, 2020. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31292550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31292550</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31292550[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1382-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31292550">Jonsson et al. (2019)</a> defined somatic loss-of-function alterations in the BRCA1 and BRCA2 genes, and identified germline pathogenic and probable pathogenic variants in BRCA1 and BRCA2. <a href="#83" class="mim-tip-reference" title="Jonsson, P., Bandlamudi, C., Cheng, M. L., Srinivasan, P., Chavan, S. S., Friedman, N. D., Rosen, E. Y., Richards, A. L., Bouvier, N., Selcuklu, S. D., Bielski, C. M., Abida, W., and 19 others. <strong>Tumour lineage shapes BRCA-mediated phenotypes.</strong> Nature 571: 576-579, 2019. Note: Erratum: Nature 577: E1, 2020. Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31292550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31292550</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31292550[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1382-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31292550">Jonsson et al. (2019)</a> showed that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1 or BRCA2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP (<a href="/entry/173870">173870</a>) inhibition were observed only in tumor types associated with increased heritable cancer risk in BRCA1/2 carriers. Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumor pathogenesis that was independent of mutant BRCA1 or BRCA2. Overall, mutant BRCA is an indispensable founding event for some tumors, but in a considerable proportion of other cancers, it appears to be biologically neutral, a difference predominantly conditioned by tumor lineage, with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31292550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Mutation Detection Methodology</em></strong></p><p>
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<a href="#65" class="mim-tip-reference" title="Hacia, J. G., Brody, L. C., Chee, M. S., Fodor, S. P. A., Collins, F. S. <strong>Detection of heterozygous mutations in BRCA1 using high density oligonucleotide arrays and two-colour fluorescence analysis.</strong> Nature Genet. 14: 441-447, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8944024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8944024</a>] [<a href="https://doi.org/10.1038/ng1296-441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8944024">Hacia et al. (1996)</a> noted that all of the then-current methods used to detect BRCA1 mutations began with PCR amplification and required gel electrophoresis, which seriously complicated the challenge of scale-up, automation, and cost reduction. They demonstrated the feasibility of using oligonucleotide arrays in a DNA chip-based assay to screen for a wide range of heterozygous mutations in the 3.45-kb exon 11 of the BRCA1 gene. They concluded that DNA chip-based assays provided a valuable new technology for high throughput, cost-efficient detection of genetic alterations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8944024" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The detection of inactivating mutations in tumor suppressor genes is critical to their characterization, as well as to the development of diagnostic testing. Most approaches for mutational screening of germline specimens are complicated by the fact that mutations are heterozygous and that missense mutations are difficult to interpret in the absence of information about protein function. <a href="#77" class="mim-tip-reference" title="Ishioka, C., Suzuki, T., Fitzgerald, M., Krainer, M., Shimodaira, H., Shimada, A., Nomizu, T., Isselbacher, K. J., Haber, D., Kanamaru, R. <strong>Detection of heterozygous truncating mutations in the BRCA1 and APC genes by using a rapid screening assay in yeast.</strong> Proc. Nat. Acad. Sci. 94: 2449-2453, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9122215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9122215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9122215[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.6.2449" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9122215">Ishioka et al. (1997)</a> described a novel method using Saccharomyces cerevisiae for detecting protein-truncating mutations in any gene of interest. In their procedure, the PCR-amplified coding sequence of the gene is inserted by homologous recombination into a yeast URA3 fusion protein, and transformants are assayed for growth in the absence of uracil. The high efficiency of homologous recombination in yeast ensures that both alleles are represented among transformants and achieves separation of alleles, which facilitates subsequent nucleotide sequencing of the mutated transcript. The specificity of translational initiation of the URA3 gene leads to minimal enzymatic activity in transformants harboring an inserted stop codon, and hence to reliable distinction between specimens with wildtype alleles and those with a heterozygous truncating mutation. This yeast-based codon assay accurately detected heterozygous truncating mutations in the BRCA1 gene in patients with early onset of breast cancer and in the APC gene (<a href="/entry/611731">611731</a>) in patients with familial adenomatous polyposis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9122215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#118" class="mim-tip-reference" title="Petrij-Bosch, A., Peelen, T., van Vliet, M., van Eijk, R., Olmer, R., Drusedau, M., Hogervorst, F. B. L., Hageman, S., Arts, P. J. W., Ligtenberg, M. J. L., Meijers-Heijboer, H., Klijn, J. G. M., Vasen, H. F. A., Cornelisse, C. J., van't Veer, L. J., Bakker, E., van Ommen, G.-J. B., Devilee, P. <strong>BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients.</strong> Nature Genet. 17: 341-345, 1997. Note: Erratum: Nature Genet. 17: 503 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9354803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9354803</a>] [<a href="https://doi.org/10.1038/ng1197-341" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9354803">Petrij-Bosch et al. (1997)</a> reported that the mutation spectrum of BRCA1 available at that time had been biased by PCR-based mutation-screening methods, such as SSCP, the protein truncation test (PPT), and direct sequencing, using genomic DNA as template. Three large genomic deletions that were not detectable by those approaches comprised 36% of all BRCA1 mutations found in Dutch breast cancer families up to that time. A 510-bp Alu-mediated deletion comprising exon 22 was found in 8 of 170 breast cancer families recruited for research purposes and in 6 of 49 probands referred to the Amsterdam Family Cancer Clinic for genetic counseling. In addition, a 3,835-bp Alu-mediated deletion encompassing exon 13 was detected in 4 of the 170 research families, while a deletion of approximately 14 kb was detected in a single family. Haplotype analyses indicated that each recurrent mutation had a single common ancestor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9354803" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#160" class="mim-tip-reference" title="van Orsouw, N. J., Dhanda, R. K., Elhaji, Y., Narod, S. A., Li, F. P., Eng, C., Vijg, J. <strong>A highly accurate, low cost test for BRCA1 mutations.</strong> J. Med. Genet. 36: 747-753, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10528853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10528853</a>] [<a href="https://doi.org/10.1136/jmg.36.10.747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10528853">Van Orsouw et al. (1999)</a> reported an inexpensive system for mutation analysis based on a combination of multiplex PCR amplification and 2-dimensional electrophoresis. In a panel of 60 samples, 14 mutations were confirmed, and an additional 5 mutations were found. Fifteen different polymorphic variants were also identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10528853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#103" class="mim-tip-reference" title="Montagna, M., Dalla Palma, M., Menin, C., Agata, S., De Nicolo, A., Chieco-Bianchi, L., D'Andrea, E. <strong>Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families.</strong> Hum. Molec. Genet. 12: 1055-1061, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700174</a>] [<a href="https://doi.org/10.1093/hmg/ddg120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12700174">Montagna et al. (2003)</a> applied multiplex ligation-dependent probe amplification (MLPA) methodology to 37 hereditary breast-ovarian cancer families. All had a high prior probability of BRCA1 mutation, and 15 were previously shown to carry a mutation in either the BRCA2 gene (5 families) or the BRCA1 gene (10 families, including 1 genomic rearrangement). The application of BRCA1 MLPA to the remaining 22 uninformative families allowed the identification of 5 additional genomic rearrangements. Loss of constitutive heterozygosity of polymorphic markers in linkage disequilibrium was predictive of such BRCA1 alterations. BRCA1 genomic deletions accounted for more than one-third (6 of 15) of the pathogenic BRCA1 mutations in this series. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12700174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a method that combines sequence alignment with calculation of Grantham variation and deviation (A-GVGD), <a href="#154" class="mim-tip-reference" title="Tavtigian, S. V., Deffenbaugh, A. M., Yin, L., Judkins, T., Scholl, T., Samollow, P. B., de Silva, D., Zharkikh, A., Thomas, A. <strong>Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral.</strong> J. Med. Genet. 43: 295-305, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16014699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16014699</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16014699[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.033878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16014699">Tavtigian et al. (2006)</a> analyzed most of the missense substitutions observed in BRCA1 and resolved known neutral and deleterious missense substitutions into distinct sets. In addition, 8 previously unclassified BRCA1 missense substitutions observed in trans with 1 or more deleterious mutations, and within the cross-species range of variation observed at their position in the protein, were classified as neutral. <a href="#154" class="mim-tip-reference" title="Tavtigian, S. V., Deffenbaugh, A. M., Yin, L., Judkins, T., Scholl, T., Samollow, P. B., de Silva, D., Zharkikh, A., Thomas, A. <strong>Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral.</strong> J. Med. Genet. 43: 295-305, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16014699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16014699</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16014699[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2005.033878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16014699">Tavtigian et al. (2006)</a> stated that these combined methods can classify as neutral about 50% of missense substitutions that have been observed with 2 or more clearly deleterious mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16014699" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Findlay, G. M., Daza, R. M., Martin, B., Zhang, M. D., Leith, A. P., Gasperini, M., Janizek, J. D., Huang, X., Starita, L. M., Shendure, J. <strong>Accurate classification of BRCA1 variants with saturation genome editing.</strong> Nature 562: 217-222, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30209399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30209399</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30209399[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0461-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30209399">Findlay et al. (2018)</a> used saturation genome editing to assay 96.5% of all possible single-nucleotide variants (SNVs) in 13 exons that encode functionally critical domains of BRCA1. Functional effects for nearly 4,000 SNVs were bimodally distributed and almost perfectly concordant with established assessments of pathogenicity. Over 400 nonfunctional missense SNVs were identified as well as 300 SNVs that disrupt expression. <a href="#45" class="mim-tip-reference" title="Findlay, G. M., Daza, R. M., Martin, B., Zhang, M. D., Leith, A. P., Gasperini, M., Janizek, J. D., Huang, X., Starita, L. M., Shendure, J. <strong>Accurate classification of BRCA1 variants with saturation genome editing.</strong> Nature 562: 217-222, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30209399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30209399</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30209399[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-018-0461-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30209399">Findlay et al. (2018)</a> concluded that these results will be useful for clinical interpretation of BRCA1 variants, and noted that their approach can be applied to other genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30209399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#59" class="mim-tip-reference" title="Gayther, S. A., Warren, W., Mazoyer, S., Russell, P. A., Harrington, P. A., Chiano, M., Seal, S., Hamoudi, R., van Rensburg, E. J., Dunning, A. M., Love, R., Evans, G., Easton, D., Clayton, D., Stratton, M. R., Ponder, B. A. J. <strong>Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.</strong> Nature Genet. 11: 428-433, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7493024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7493024</a>] [<a href="https://doi.org/10.1038/ng1295-428" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7493024">Gayther et al. (1995)</a> analyzed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. In 32 families (53%), a total of 22 different mutations were detected, of which 14 were previously unreported. They observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within the family. The data suggested to the authors a transition in risk such that mutations in the 3-prime third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supported previous data suggesting that some BRCA1 mutation carriers have common ancestors; however, <a href="#59" class="mim-tip-reference" title="Gayther, S. A., Warren, W., Mazoyer, S., Russell, P. A., Harrington, P. A., Chiano, M., Seal, S., Hamoudi, R., van Rensburg, E. J., Dunning, A. M., Love, R., Evans, G., Easton, D., Clayton, D., Stratton, M. R., Ponder, B. A. J. <strong>Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.</strong> Nature Genet. 11: 428-433, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7493024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7493024</a>] [<a href="https://doi.org/10.1038/ng1295-428" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7493024">Gayther et al. (1995)</a> found at least 2 examples where recurrent mutations appeared to have arisen independently, judging from the different haplotype background. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7493024" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Studies of a number of diseases have indicated that fine-structure haplotype analysis can provide insight into the 'genetic history' of a particular mutation (or presumed mutation for rare diseases where the disease gene is not yet identified). To address both the question of mutation origin and the relationship between mutation and phenotype, <a href="#110" class="mim-tip-reference" title="Neuhausen, S. L., Mazoyer, S., Friedman, L., Stratton, M., Offit, K., Caligo, A., Tomlinson, G., Cannon-Albright, L., Bishop, T., Kelsell, D., Solomon, E., Weber, B., Couch, F., Struewing, J., Tonin, P., Durocher, F., Narod, S., Skolnick, M. H., Lenoir, G., Serova, O., Ponder, B., Stoppa-Lyonnet, D., Easton, D., King, M.-C., Goldgar, D. E. <strong>Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.</strong> Am. J. Hum. Genet. 58: 271-280, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8571953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8571953</a>]" pmid="8571953">Neuhausen et al. (1996)</a> constructed a haplotype of 9 polymorphic STR markers within or immediately flanking the BRCA1 locus in a set of 61 families (selected to contain 1 of 6 BRCA1 mutations that had been identified a minimum of 4 times). The mutation appeared to have an effect on the relative proportion of cases of breast and ovarian cancer: 57% of women presumed affected because of the 1294del40 mutation (<a href="#0006">113705.0006</a>) had ovarian cancer, compared with 14% of affected women with the splice site mutation in intron 5 of BRCA1 (<a href="#0034">113705.0034</a>). A high degree of haplotype conservation across the region was observed. Any haplotype differences found were most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. One mutation, 4184del4 (<a href="#0015">113705.0015</a>), had the same ancestral haplotype in two-thirds of the families studied. <a href="#110" class="mim-tip-reference" title="Neuhausen, S. L., Mazoyer, S., Friedman, L., Stratton, M., Offit, K., Caligo, A., Tomlinson, G., Cannon-Albright, L., Bishop, T., Kelsell, D., Solomon, E., Weber, B., Couch, F., Struewing, J., Tonin, P., Durocher, F., Narod, S., Skolnick, M. H., Lenoir, G., Serova, O., Ponder, B., Stoppa-Lyonnet, D., Easton, D., King, M.-C., Goldgar, D. E. <strong>Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.</strong> Am. J. Hum. Genet. 58: 271-280, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8571953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8571953</a>]" pmid="8571953">Neuhausen et al. (1996)</a> estimated that this mutation had arisen 170 generations ago. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8571953" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine whether hereditary ovarian cancers have distinct clinical and pathologic features compared with sporadic (nonhereditary) ovarian cancers, <a href="#16" class="mim-tip-reference" title="Boyd, J., Sonoda, Y., Federici, M. G., Bogomolniy, F., Rhei, E., Maresco, D. L., Saigo, P. E., Almadrones, L. A., Barakat, R. R., Brown, C. L., Chi, D. S., Curtin, J. P., Poynor, E. A., Hoskins, W. J. <strong>Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.</strong> JAMA 283: 2260-2265, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10807385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10807385</a>] [<a href="https://doi.org/10.1001/jama.283.17.2260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10807385">Boyd et al. (2000)</a> performed a retrospective cohort study of a consecutive series of 933 ovarian cancers diagnosed and treated at the Sloan-Kettering Cancer Center. This study was restricted to patients of Jewish origin because of the ease of BRCA1 and BRCA2 genotyping in this ethnic group. Of the 189 patients who identified themselves as Jewish, 88 hereditary cases were identified with the presence of a germline founder mutation in BRCA1 or BRCA2. The remaining 101 cases from the same series not associated with a BRCA mutation, and 2 additional groups with ovarian cancer from clinical trials (for survival analysis), were included for comparison. Hereditary cancers were rarely diagnosed before age 40 years and were common after age 60 years, with mean age at diagnosis being significantly younger for BRCA1- versus BRCA2-linked patients (54 vs 62 years). Histology, grade, stage, and success of cytoreductive surgery were similar for hereditary and sporadic cases. The hereditary group had a longer disease-free interval following primary chemotherapy in comparison with the nonhereditary group, with a median time to recurrence of 14 months and 7 months, respectively (p less than 0.001). Those with hereditary cancers had improved survival compared with the nonhereditary group. <a href="#16" class="mim-tip-reference" title="Boyd, J., Sonoda, Y., Federici, M. G., Bogomolniy, F., Rhei, E., Maresco, D. L., Saigo, P. E., Almadrones, L. A., Barakat, R. R., Brown, C. L., Chi, D. S., Curtin, J. P., Poynor, E. A., Hoskins, W. J. <strong>Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.</strong> JAMA 283: 2260-2265, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10807385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10807385</a>] [<a href="https://doi.org/10.1001/jama.283.17.2260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10807385">Boyd et al. (2000)</a> concluded that although BRCA-associated hereditary ovarian cancers in this population have surgical and pathologic characteristics similar to those of sporadic cancers, advanced-stage hereditary cancer patients survive longer than nonhereditary cancer patients. Age penetrance is greater for BRCA1-linked than for BRCA2-linked cancers in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10807385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#73" class="mim-tip-reference" title="Hohenstein, P., Fodde, R. <strong>Of mice and (wo)men: genotype-phenotype correlations in BRCA1.</strong> Hum. Molec. Genet. 12: R271-R277, 2003. Note: Erratum: Hum. Molec. Genet. 13: 473 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915453</a>] [<a href="https://doi.org/10.1093/hmg/ddg258" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915453">Hohenstein and Fodde (2003)</a> reviewed genotype/phenotype correlations at the BRCA1 locus in humans and mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Basal-like breast cancer is a subtype of breast cancer that is highly proliferative, poorly differentiated, and has a poor prognosis. These tumor cells express cytokeratin markers typical of basally oriented epithelial cells of the normal mammary gland. <a href="#129" class="mim-tip-reference" title="Saal, L. H., Gruvberger-Saal, S. K., Persson, C., Lovgren, K., Jumppanen, M., Staaf, J., Jonsson, G., Pires, M. M., Maurer, M., Holm, K., Koujak, S., Subramaniyam, S., and 13 others. <strong>Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair.</strong> Nature Genet. 40: 102-107, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18066063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18066063</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18066063[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2007.39" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18066063">Saal et al. (2008)</a> found that loss of PTEN (<a href="/entry/601728">601728</a>) protein expression was significantly associated with the basal-like cancer subtype in both nonhereditary breast cancer and hereditary BRCA1-deficient breast cancer. Loss of PTEN in the BRCA1-deficient basal-like breast cancer tumors was associated with frequent gross PTEN mutations, including intragenic chromosome breaks, inversions, deletions, and micro copy number alterations, consistent with a mechanism involving inappropriate repair of double-strand DNA breaks. The findings indicated a specific and recurrent oncogenic consequence of BRCA1-dependent dysfunction in DNA repair and implied that the PTEN pathway is directly involved in transformation of basal-like progenitor cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18066063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>To establish the role of missense changes in the BRCA1 gene in breast cancer susceptibility, <a href="#47" class="mim-tip-reference" title="Fleming, M. A., Potter, J. D., Ramirez, C. J., Ostrander, G. K., Ostrander, E. A. <strong>Understanding missense mutations in the BRCA1 gene: an evolutionary approach.</strong> Proc. Nat. Acad. Sci. 100: 1151-1156, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12531920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12531920</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12531920[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0237285100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12531920">Fleming et al. (2003)</a> used comparative evolutionary methods to identify potential functionally important amino acid sites in exon 11. By aligning sequences from 57 eutherian mammals and categorizing amino acid sites by degree of conservation, they identified 41 missense mutations in exon 11 (38 in conserved and 3 in rapidly evolving regions) likely to influence gene function and thereby contribute to breast cancer susceptibility. They used Bayesian phylogenetic analyses to determine relationships among orthologs and identify codons evolving under positive selection. Most conserved residues occurred in a region with the highest concentration of protein-interacting domains. Rapidly evolving residues were concentrated in the RAD51-interacting domain, suggesting that selection is acting most strongly on the role of BRCA1 in DNA repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12531920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#116" class="mim-tip-reference" title="Pavlicek, A., Noskov, V. N., Kouprina, N., Barrett, J. C., Jurka, J., Larionov, V. <strong>Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition.</strong> Hum. Molec. Genet. 13: 2737-2751, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385441/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385441</a>] [<a href="https://doi.org/10.1093/hmg/ddh301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385441">Pavlicek et al. (2004)</a> isolated and characterized full-size BRCA1 homologs from rhesus macaque, orangutan, gorilla, and chimpanzee. Analysis of human and nonhuman primate BRCA1 sequence revealed an unusually high proportion of insertion/deletions in noncoding DNA that were associated with Alu repeats. Most Alu elements involved in genomic rearrangement in humans were retained in nonhuman primates, indicating that structural instability of this locus may be intrinsic in anthropoids. Analysis of the nonsynonymous/synonymous mutation ratio in BRCA1 coding sequence showed that most of the internal sequence is variable between primates and evolved under positive selection. In contrast, the terminal regions of BRCA1, which encode the RING finger and BRCT domains, experienced negative selection and are almost identical between the compared primates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15385441" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#64" class="mim-tip-reference" title="Gowen, L. C., Johnson, B. L., Latour, A. M., Sulik, K. K., Koller, B. H. <strong>Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities.</strong> Nature Genet. 12: 191-194, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8563759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8563759</a>] [<a href="https://doi.org/10.1038/ng0296-191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8563759">Gowen et al. (1996)</a> described homozygous mice lacking the mouse Brca1 gene. The mice, possessing a deletion of the large exon 11, died between days 10 and 13 of embryonic development, suffering from a variety of neuroepithelial defects. <a href="#67" class="mim-tip-reference" title="Hakem, R., de la Pompa, J. L., Sirard, C., Mo, R., Woo, M., Hakem, A., Wakeham, A., Potter, J., Reitmair, A., Billia, F., Firpo, E., Hui, C. C., Roberts, J., Rossant, J., Mak, T. W. <strong>The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse.</strong> Cell 85: 1009-1023, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8674108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8674108</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81302-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8674108">Hakem et al. (1996)</a> described another strain of homozygous mice for a putative Brca1-null mutation produced by targeted deletion of exons 5 and 6. These mutant mice were more severely affected, dying at about embryonic day 7.5 with no signs of mesoderm formation and exhibiting reduced cell proliferation. There were also strong signs of disruptive cell cycle regulation via altered expression levels of cyclin E (<a href="/entry/123837">123837</a>), mdm2 (<a href="/entry/164785">164785</a>) and p21 (<a href="/entry/116899">116899</a>). <a href="#67" class="mim-tip-reference" title="Hakem, R., de la Pompa, J. L., Sirard, C., Mo, R., Woo, M., Hakem, A., Wakeham, A., Potter, J., Reitmair, A., Billia, F., Firpo, E., Hui, C. C., Roberts, J., Rossant, J., Mak, T. W. <strong>The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse.</strong> Cell 85: 1009-1023, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8674108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8674108</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81302-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8674108">Hakem et al. (1996)</a> speculated that the death of mutant embryos was due to failure of the proliferative burst required for germ layer development. <a href="#67" class="mim-tip-reference" title="Hakem, R., de la Pompa, J. L., Sirard, C., Mo, R., Woo, M., Hakem, A., Wakeham, A., Potter, J., Reitmair, A., Billia, F., Firpo, E., Hui, C. C., Roberts, J., Rossant, J., Mak, T. W. <strong>The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse.</strong> Cell 85: 1009-1023, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8674108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8674108</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81302-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8674108">Hakem et al. (1996)</a> reported that after about 1 year of age, Brca1 heterozygous female mice showed no evidence of cancer. <a href="#64" class="mim-tip-reference" title="Gowen, L. C., Johnson, B. L., Latour, A. M., Sulik, K. K., Koller, B. H. <strong>Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities.</strong> Nature Genet. 12: 191-194, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8563759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8563759</a>] [<a href="https://doi.org/10.1038/ng0296-191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8563759">Gowen et al. (1996)</a> also had been unable to detect tumors in 1-year-old heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8563759+8674108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To study mechanisms underlying BRCA1-related tumorigenesis, <a href="#179" class="mim-tip-reference" title="Xu, X., Weaver, Z., Linke, S. P., Li, C., Gotay, J., Wang, X.-W., Harris, C. C., Ried, T., Deng, C.-X. <strong>Centrosome amplification and a defective G(2)-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells.</strong> Molec. Cell 3: 389-395, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10198641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10198641</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80466-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10198641">Xu et al. (1999)</a> derived mouse embryonic fibroblast cells carrying a targeted deletion of exon 11 of the Brca1 gene. The mutant cells maintained an intact G1-S cell cycle checkpoint and proliferated poorly. However, a defective G2-M checkpoint in these cells was accompanied by extensive chromosomal abnormalities. Mutant fibroblasts contained multiple functional centrosomes, leading to unequal chromosome segregation, abnormal nuclear division, and aneuploidy. These data uncovered an essential role for BRCA1 in maintaining genetic stability through the regulation of centrosome duplication and the G2-M checkpoint. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10198641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#107" class="mim-tip-reference" title="Moynahan, M. E., Chiu, J. W., Koller, B. H., Jasin, M. <strong>Brca1 controls homology-directed DNA repair.</strong> Molec. Cell 4: 511-518, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10549283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10549283</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80202-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10549283">Moynahan et al. (1999)</a> reported that Brca1-deficient mouse embryonic stem cells had impaired repair of chromosomal double-strand breaks by homologous recombination. The relative frequencies of homologous and nonhomologous DNA integration and double-strand break repair were also altered. The results demonstrated a caretaker role for BRCA1 in preserving genomic integrity by promoting homologous recombination and limiting mutagenic nonhomologous repair processes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10549283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#66" class="mim-tip-reference" title="Hakem, R., de la Pompa, J. L., Elia, A., Potter, J., Mak, T. W. <strong>Partial rescue of Brca1(5-6) early embryonic lethality by p53 or p21 null mutation.</strong> Nature Genet. 16: 298-302, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9207798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9207798</a>] [<a href="https://doi.org/10.1038/ng0797-298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9207798">Hakem et al. (1997)</a> generated mice double mutant for Brca1(5-6) and p53, or Brca1(5-6) and p21. Mutation in either p53 or p21 prolonged the survival of Brca1(5-6) mutant embryos from embryonic day 7.5 to embryonic day 9.5. The development of most Brca1(5-6)/p21 double-mutant embryos was comparable to that of their wildtype littermates, although no mutant survived past embryonic day 10.5. Because mutation of neither p53 nor p21 completely rescued Brca1(5-6) embryos, the authors suggested that the lethality of the embryos is likely due to a multifactorial process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9207798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#96" class="mim-tip-reference" title="Ludwig, T., Chapman, D. L., Papaioannou, V. E., Efstratiadis, A. <strong>Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos.</strong> Genes Dev. 11: 1226-1241, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171368</a>] [<a href="https://doi.org/10.1101/gad.11.10.1226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9171368">Ludwig et al. (1997)</a> created mice deficient for Brca1 by targeted disruption, resulting in deletion of exon 2. They also disrupted Brca2 by replacing a segment of exon 11. Heterozygotes were indistinguishable from wildtype littermates. Nullizygous embryos became developmentally retarded and disorganized, and died early in development. In Brca1 mutants, the onset of abnormalities was earlier by 1 day and their phenotypic features and time of death were highly variable, whereas the phenotype of Brca2-null embryos was more uniform, and they survived for at least 8.5 embryonic days. Brca1/Brca2 double mutants were similar to Brca1-null mutants. <a href="#96" class="mim-tip-reference" title="Ludwig, T., Chapman, D. L., Papaioannou, V. E., Efstratiadis, A. <strong>Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos.</strong> Genes Dev. 11: 1226-1241, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171368</a>] [<a href="https://doi.org/10.1101/gad.11.10.1226" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9171368">Ludwig et al. (1997)</a> reported that the impact of Brca1- or Brca2-null mutation was less severe in a p53-null background. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9171368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#178" class="mim-tip-reference" title="Xu, X., Qiao, W., Linke, S. P., Cao, L., Li, W.-M., Furth, P. A., Harris, C. C., Deng, C.-X. <strong>Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis.</strong> Nature Genet. 28: 266-271, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11431698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11431698</a>] [<a href="https://doi.org/10.1038/90108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11431698">Xu et al. (2001)</a> found that mouse embryos homozygous for deletion of exon 11 of the Brca1 gene died late in gestation because of widespread apoptosis. Elimination of 1 p53 allele completely rescued this embryonic lethality and restored normal mammary gland development. However, most female mice homozygous for the Brca1 exon 11 deletion and heterozygous for loss of the p53 gene developed mammary tumors with loss of the remaining p53 allele within 6 to 12 months. Lymphomas and ovarian tumors also occurred at lower frequencies. Heterozygous mutation of the p53 gene decreased p53 and resulted in attenuated apoptosis and G1-S checkpoint control, allowing the homozygous Brca1 exon 11-deleted cells to proliferate. The p53 protein regulates Brca1 transcription both in vitro and in vivo, and Brca1 participates in p53 accumulation after gamma irradiation. These findings provided a mechanism for BRCA1-associated breast carcinogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11431698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#98" class="mim-tip-reference" title="McCarthy, E. E., Celebi, J. T., Baer, R., Ludwig, T. <strong>Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability.</strong> Molec. Cell. Biol. 23: 5056-5063, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12832489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12832489</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12832489[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.23.14.5056-5063.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12832489">McCarthy et al. (2003)</a> determined that mouse embryos with double mutant Bard1 -/- ; Brca1 -/- genotype were phenotypically indistinguishable from either single Bard1 or single Brca1 homozygous mutants. Embryos that carried at least 1 wildtype allele of both Bard1 and Brca1 were normal and had 20 to 25 somites, while each embryo that was null for either Bard1 or Brca1 exhibited the characteristic phenotype of severe growth retardation, degeneration, and embryonic lethality. The similarity of phenotypes indicated to <a href="#98" class="mim-tip-reference" title="McCarthy, E. E., Celebi, J. T., Baer, R., Ludwig, T. <strong>Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability.</strong> Molec. Cell. Biol. 23: 5056-5063, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12832489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12832489</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12832489[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.23.14.5056-5063.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12832489">McCarthy et al. (2003)</a> that the developmental functions of Brca1 and Bard1 are mediated by the Brca1/Bard1 heterodimer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12832489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Mouse embryonic fibroblasts carrying targeted deletion of exon 11 of the Brca1 gene or a Gadd45a null mutation suffer centrosome amplification. <a href="#169" class="mim-tip-reference" title="Wang, X., Wang, R.-H., Li, W., Xu, X., Hollander, M. C., Fornace, A. J., Jr., Deng, C.-X. <strong>Genetic interactions between Brca1 and Gadd45a in centrosome duplication, genetic stability, and neural tube closure.</strong> J. Biol. Chem. 279: 29606-29614, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15123655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15123655</a>] [<a href="https://doi.org/10.1074/jbc.M312279200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15123655">Wang et al. (2004)</a> found that mouse embryos carrying both mutations were exencephalic and exhibited a high incidence of apoptosis accompanied by altered levels of Bax (<a href="/entry/600040">600040</a>), Bcl2 (<a href="/entry/151430">151430</a>), and p53. They concluded that BRCA1 and GADD45A have a synergistic role in regulating centrosome duplication and maintaining genome integrity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15123655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#120" class="mim-tip-reference" title="Poole, A. J., Li, Y., Kim, Y., Lin, S.-C. J., Lee, W.-H., Lee, E. Y.-H. P. <strong>Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist.</strong> Science 314: 1467-1470, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17138902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17138902</a>] [<a href="https://doi.org/10.1126/science.1130471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17138902">Poole et al. (2006)</a> demonstrated that mammary glands of nulliparous Brca1/p53-deficient mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype that occurs only during pregnancy in wildtype mice. Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway. Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis. <a href="#120" class="mim-tip-reference" title="Poole, A. J., Li, Y., Kim, Y., Lin, S.-C. J., Lee, W.-H., Lee, E. Y.-H. P. <strong>Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist.</strong> Science 314: 1467-1470, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17138902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17138902</a>] [<a href="https://doi.org/10.1126/science.1130471" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17138902">Poole et al. (2006)</a> concluded that their findings revealed a tissue-specific function for the BRCA1 protein and raised the possibility that antiprogesterone treatment may be useful for breast cancer prevention in individuals with BRCA1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17138902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#141" class="mim-tip-reference" title="Shakya, R., Szabolcs, M., McCarthy, E., Ospina, E., Basso, K., Nandula, S., Murty, V., Baer, R., Ludwig, T. <strong>The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression.</strong> Proc. Nat. Acad. Sci. 105: 7040-7045, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18443292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18443292</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18443292[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0711032105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18443292">Shakya et al. (2008)</a> found that conditional inactivation of Bard1 in mouse mammary epithelial cells induced basal-like mammary carcinomas with a frequency, latency, and histopathology indistinguishable from those developed in conditional Brca1-mutant mice and in double conditional Bard1/Brca1-mutant mice. Reminiscent of human breast carcinomas due to BRCA1 mutation, the mouse tumors were triple negative for estrogen receptor (see <a href="/entry/133430">133430</a>) and progesterone receptor (PGR; <a href="/entry/607311">607311</a>) expression and Her2/neu (ERBB2; <a href="/entry/164870">164870</a>) amplification. They also expressed basal cytokeratins Ck5 (KRT5; <a href="/entry/148040">148040</a>) and Ck14 (KRT14; <a href="/entry/148066">148066</a>), had elevated frequency of p53 lesions, and displayed high levels of chromosomal instability. <a href="#141" class="mim-tip-reference" title="Shakya, R., Szabolcs, M., McCarthy, E., Ospina, E., Basso, K., Nandula, S., Murty, V., Baer, R., Ludwig, T. <strong>The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression.</strong> Proc. Nat. Acad. Sci. 105: 7040-7045, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18443292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18443292</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18443292[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0711032105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18443292">Shakya et al. (2008)</a> concluded that the tumor suppressor activities of both BARD1 and BRCA1 are mediated through the BRCA1/BARD1 heterodimer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18443292" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a kindred in which 8 members had breast cancer and 5 members had ovarian cancer (<a href="/entry/604370">604370</a>), <a href="#22" class="mim-tip-reference" title="Castilla, L. H., Couch, F. J., Erdos, M. R., Hoskins, K. F., Calzone, K., Garber, J. E., Boyd, J., Lubin, M. B., Deshano, M. L., Brody, L. C., Collins, F. S., Weber, B. L. <strong>Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.</strong> Nature Genet. 8: 387-391, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894491</a>] [<a href="https://doi.org/10.1038/ng1294-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894491">Castilla et al. (1994)</a> found a TGT-to-GGT transversion in codon 64 of the BRCA1 gene, leading to substitution of glycine for cysteine (C64G). Analysis of tumor DNA in 2 affected members of this kindred showed that the wildtype allele had been lost and only the C64G mutant allele remained, thus supporting the tumor suppressor model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28897672 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28897672;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28897672?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28897672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28897672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019229 OR RCV000047597 OR RCV000131902 OR RCV000159935 OR RCV000239114 OR RCV000412714 OR RCV000415051 OR RCV000785199 OR RCV001270967 OR RCV004802937 OR RCV005003390" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019229, RCV000047597, RCV000131902, RCV000159935, RCV000239114, RCV000412714, RCV000415051, RCV000785199, RCV001270967, RCV004802937, RCV005003390" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019229...</a>
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<p><a href="#61" class="mim-tip-reference" title="Gorski, B., Byrski, T., Huzarski, T., Jakubowska, A., Menkiszak, J., Gronwald, J., Pluzanska, A., Bebenek, M., Fischer-Maliszewska, L., Grzybowska, E., Narod, S. A., Lubinski, J. <strong>Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.</strong> Am. J. Hum. Genet. 66: 1963-1968, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10788334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10788334</a>] [<a href="https://doi.org/10.1086/302922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10788334">Gorski et al. (2000)</a> identified a cys61-to-gly (C61G) mutation in the BRCA1 gene to be a founder mutation in Polish families with breast-ovarian cancer (<a href="/entry/604370">604370</a>), accounting for 20% of identified mutations. They studied 66 families in which at least 3 related females were affected with breast or ovarian cancer and at least 1 of these 3 had been diagnosed with cancer before the age of 50. Mutations were identified in 35 (53%) of the 66 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10788334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#100" class="mim-tip-reference" title="Merajver, S. D., Pham, T. M., Caduff, R. F., Chen, M., Poy, E. L., Cooney, K. A., Weber, B. L., Collins, F. S., Johnston, C., Frank, T. S. <strong>Somatic mutations in the BRCA1 gene in sporadic ovarian tumours.</strong> Nature Genet. 9: 439-443, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795652</a>] [<a href="https://doi.org/10.1038/ng0495-439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7795652">Merajver et al. (1995)</a> analyzed genomic DNA of tumor and normal fractions of 47 ovarian cancers for mutations in BRCA1 using the SSCP technique. Somatic mutations in the BRCA1 gene were identified in 4 tumors, all of which also had loss of heterozygosity at a BRCA1 intragenic marker. One of these, found in an endometrioid ovarian carcinoma in a 53-year-old woman, was a C61G substitution in the zinc finger motif. The data supported a tumor-suppressor mechanism for BRCA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7795652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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PANCREATIC CANCER, SUSCEPTIBILITY TO, 4, INCLUDED
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BRCA1, 2-BP DEL, 185AG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80357914 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357914;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357914" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019230 OR RCV000019231 OR RCV000034761 OR RCV000056295 OR RCV000131394 OR RCV000213650 OR RCV000735481 OR RCV000785197 OR RCV001353942 OR RCV001836711 OR RCV003128128 OR RCV003225925 OR RCV004554604 OR RCV004566751 OR RCV005003391" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019230, RCV000019231, RCV000034761, RCV000056295, RCV000131394, RCV000213650, RCV000735481, RCV000785197, RCV001353942, RCV001836711, RCV003128128, RCV003225925, RCV004554604, RCV004566751, RCV005003391" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019230...</a>
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<p><strong><em>Breast-Ovarian Cancer Susceptibility</em></strong></p><p>
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<a href="#143" class="mim-tip-reference" title="Simard, J., Tonin, P., Durocher, F., Morgan, K., Rommens, J., Gingras, S., Samson, C., Leblanc, J.-F., Belanger, C., Dion, F., Liu, Q., Skolnick, M., Goldgar, D., Shattuck-Eidens, D., Labrie, F., Narod, S. A. <strong>Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families.</strong> Nature Genet. 8: 392-398, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894492</a>] [<a href="https://doi.org/10.1038/ng1294-392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894492">Simard et al. (1994)</a> studied 30 Canadian families with breast and/or ovarian cancer (<a href="/entry/604370">604370</a>) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 2-bp (AG185) deletion in the normal sequence TTA GAG of codons 22-23 in exon 3. The AGAG presumably predisposed to the deletion. This mutation changes the reading frame of the mRNA and causes a premature termination codon at position 39. This mutation was detected in index cases from 4 families that were not known to be related and originated from different areas in Canada. In these 4 families there were a total of 12 cases of breast cancer and 11 cases of ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#150" class="mim-tip-reference" title="Struewing, J. P., Abeliovich, D., Peretz, T., Avishai, N., Kaback, M. M., Collins, F. S., Brody, L. C. <strong>The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals.</strong> Nature Genet. 11: 198-200, 1995. Note: Erratum: Nature Genet. 12: 110 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550349</a>] [<a href="https://doi.org/10.1038/ng1095-198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550349">Struewing et al. (1995)</a> pointed out that all 10 published families with the 185delAG mutation (also called 187delAG) were Ashkenazi Jewish (of Eastern European origin). They knew of an eleventh Ashkenazi breast/ovarian cancer family with the 185delAG mutation; furthermore, only 1 Ashkenazi Jewish family was known to have a BRCA1 mutation other than 185delAG. In addition, Ashkenazi families with the 185delAG mutation appeared to share a common haplotype. In a study of 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, they observed the 185delAG mutation in 0.9% (95% confidence limit, 0.4%-1.8%), and in 815 reference individuals not selected for ethnic origin, none had the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#126" class="mim-tip-reference" title="Roa, B. B., Boyd, A. A., Volcik, K., Richards, C. S. <strong>Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2.</strong> Nature Genet. 14: 185-187, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841191</a>] [<a href="https://doi.org/10.1038/ng1096-185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841191">Roa et al. (1996)</a> found the 185delAG mutation in 1.09% of approximately 3,000 Ashkenazi Jewish individuals and found the 5382insC mutation (<a href="#0018">113705.0018</a>) in 0.13%. BRCA2 analysis on 3,085 individuals from the same population showed a carrier frequency of 1.52% for the 6174delT mutation (<a href="/entry/600185#0009">600185.0009</a>). The expanded population-based study confirmed that the BRCA1 185delAG mutation and the BRCA2 6174delT mutation constituted the 2 most frequent mutant alleles predisposing to hereditary breast cancer among Ashkenazim and suggested a relatively lower penetrance for the 6174delT mutation in BRCA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8841191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Bar-Sade, R. B., Theodor, L., Gak, E., Kruglikova, A., Hirsch-Yechezkel, G., Modan, B., Kuperstein, G., Seligsohn, U., Rechavi, G., Friedman, E. <strong>Could the 185delAG BRCA1 mutation be an ancient Jewish mutation?</strong> Europ. J. Hum. Genet. 5: 413-416, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9450187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9450187</a>]" pmid="9450187">Bar-Sade et al. (1997)</a> examined 639 unrelated healthy Jews of Iraqi extraction, a presumed low-risk group for the 185delAG mutation which occurs predominantly in Ashkenazim. Three individuals were identified as 185delAG mutation carriers, and haplotype analysis of the Iraqi mutation carriers showed that 2 of the Iraqis shared a haplotype in common with 6 Ashkenazi mutation carriers, and a third had a haplotype that differed by a single marker. This suggested to <a href="#11" class="mim-tip-reference" title="Bar-Sade, R. B., Theodor, L., Gak, E., Kruglikova, A., Hirsch-Yechezkel, G., Modan, B., Kuperstein, G., Seligsohn, U., Rechavi, G., Friedman, E. <strong>Could the 185delAG BRCA1 mutation be an ancient Jewish mutation?</strong> Europ. J. Hum. Genet. 5: 413-416, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9450187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9450187</a>]" pmid="9450187">Bar-Sade et al. (1997)</a> that the BRCA1 185delAG mutation may have arisen before the dispersion of the Jewish people in the Diaspora, at least at the time of Christ. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9450187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Bar-Sade, R. B., Kruglikova, A., Modan, B., Gak, E., Hirsh-Yechezkel, G., Theodor, L., Novikov, I., Gershoni-Baruch, R., Risel, S., Papa, M. Z., Ben-Baruch, G., Friedman, E. <strong>The 185delAG BRCA1 mutation originated before the dispersion of Jews in the Diaspora and is not limited to Ashkenazim.</strong> Hum. Molec. Genet. 7: 801-805, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9536083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9536083</a>] [<a href="https://doi.org/10.1093/hmg/7.5.801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9536083">Bar-Sade et al. (1998)</a> extended their analyses to other non-Ashkenazi subsets: 354 of Moroccan origin, 200 Yemenites, and 150 Iranian Jews. Four of Moroccan origin (1.1%) and none of the Yemenites or Iranians were carriers of the 185delAG mutation. BRCA1 allelic patterns (haplotypes) were determined for 4 of these individuals and for 12 additional non-Ashkenazi 185delAG mutation carriers who had breast/ovarian cancer. The common 'Ashkenazi haplotype' was shared by 6 non-Ashkenazi individuals; 4 had a closely related pattern, and the rest (n = 6) displayed a distinct BRCA1 allelic pattern. The authors concluded that the 185delAG BRCA1 mutation occurs in some non-Ashkenazi populations at rates comparable with that of Ashkenazim. The majority of Jewish 185delAG mutation carriers have the same haplotype, supporting the founder effect notion, but dating the mutation's origin to an earlier date than previously estimated. The different allelic pattern at the BRCA1 locus in some Jewish mutation carriers might suggest that the mutation arose independently. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9536083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Bandera, C. A., Muto, M. G., Schorge, J. O., Berkowitz, R. S., Rubin, S. C., Mok, S. C. <strong>BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum.</strong> Obstet. Gynec. 92: 596-600, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9764635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9764635</a>] [<a href="https://doi.org/10.1016/s0029-7844(98)00223-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9764635">Bandera et al. (1998)</a> demonstrated the 185delAG mutation in 2 women with a personal or family history of breast cancer and papillary serous carcinoma of the peritoneum (PSCP). PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma and it may develop years after oophorectomy. <a href="#132" class="mim-tip-reference" title="Schorge, J. O., Muto, M. G., Welch, W. R., Bandera, C. A., Rubin, S. C., Bell, D. A., Berkowitz, R. S., Mok, S. C. <strong>Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations.</strong> J. Nat. Cancer Inst. 90: 841-845, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9625172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9625172</a>] [<a href="https://doi.org/10.1093/jnci/90.11.841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9625172">Schorge et al. (1998)</a> demonstrated that the tumors were multifocal in these cases, indicating that patients with germline BRCA1 mutations may develop PSCP in addition to breast and ovarian carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9764635+9625172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Ah Mew, N., Hamel, N., Galvez, M., Al-Saffar, M., Foulkes, W. D. <strong>Haplotype analysis of a BRCA1:185delAG mutation in a Chilean family supports its Ashkenazi origins.</strong> Clin. Genet. 62: 151-156, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12220453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12220453</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.620208.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12220453">Ah Mew et al. (2002)</a> reported the 185delAG mutation in a non-Jewish Chilean family with no reported Jewish ancestry. The linked haplotype present in this family was identical to that identified in the Ashkenazi Jewish population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12220453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Buisson, M., Anczukow, O., Zetoune, A. B., Ware, M. D., Mazoyer, S. <strong>The 185delAG mutation (c.68_69delAG) in the BRCA1 gene triggers translation reinitiation at a downstream AUG codon.</strong> Hum. Mutat. 27: 1024-1029, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16941470/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16941470</a>] [<a href="https://doi.org/10.1002/humu.20384" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16941470">Buisson et al. (2006)</a> found that BRCA1 transcripts bearing the 185delAG mutation are not degraded by nonsense-mediated mRNA decay. Using Western blot analysis, they examined HeLa cells transfected with minigenes for this transcript and another with a premature termination codon at position 36 and found that translation from these transcripts was reinitiated at codon 128. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16941470" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pancreatic Cancer Susceptibility</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Al-Sukhni, W., Rothenmund, H., Eppel Borgida, A., Zogopoulos, G., O'Shea, A.-M., Pollett, A., Gallinger, S. <strong>Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.</strong> Hum. Genet. 124: 271-278, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18762988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18762988</a>] [<a href="https://doi.org/10.1007/s00439-008-0554-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18762988">Al-Sukhni et al. (2008)</a> found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer (PNCA4; <a href="/entry/614320">614320</a>) who carried a heterozygous germline BRCA1 mutation. Three patients carried the 185delAG mutation. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. <a href="#3" class="mim-tip-reference" title="Al-Sukhni, W., Rothenmund, H., Eppel Borgida, A., Zogopoulos, G., O'Shea, A.-M., Pollett, A., Gallinger, S. <strong>Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.</strong> Hum. Genet. 124: 271-278, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18762988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18762988</a>] [<a href="https://doi.org/10.1007/s00439-008-0554-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18762988">Al-Sukhni et al. (2008)</a> concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18762988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80358061 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80358061;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80358061?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80358061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80358061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000031030 OR RCV000047725 OR RCV000074570 OR RCV000131898 OR RCV000469831 OR RCV000735531 OR RCV004758603 OR RCV004802959" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000031030, RCV000047725, RCV000074570, RCV000131898, RCV000469831, RCV000735531, RCV004758603, RCV004802959" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000031030...</a>
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<p><a href="#52" class="mim-tip-reference" title="Friedman, L. S., Ostermeyer, E. A., Szabo, C. I., Dowd, P., Lynch, E. D., Rowell, S. E., King, M.-C. <strong>Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.</strong> Nature Genet. 8: 399-404, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894493</a>] [<a href="https://doi.org/10.1038/ng1294-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894493">Friedman et al. (1994)</a> studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (<a href="/entry/604370">604370</a>). They identified a T-to-G transversion at nucleotide 332 in exon 5 of the BRCA1 gene, leading to a premature termination codon at position 75 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80357569 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357569;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80357569?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000047310 OR RCV000074359 OR RCV000129421 OR RCV000190459 OR RCV000735524 OR RCV000785394 OR RCV004803951" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000047310, RCV000074359, RCV000129421, RCV000190459, RCV000735524, RCV000785394, RCV004803951" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000047310...</a>
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<p><a href="#143" class="mim-tip-reference" title="Simard, J., Tonin, P., Durocher, F., Morgan, K., Rommens, J., Gingras, S., Samson, C., Leblanc, J.-F., Belanger, C., Dion, F., Liu, Q., Skolnick, M., Goldgar, D., Shattuck-Eidens, D., Labrie, F., Narod, S. A. <strong>Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families.</strong> Nature Genet. 8: 392-398, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894492</a>] [<a href="https://doi.org/10.1038/ng1294-392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894492">Simard et al. (1994)</a> studied 30 Canadian families with breast and/or ovarian cancer (<a href="/entry/604370">604370</a>) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp (A) insertion in the normal sequence GAA AAA AAG of codons 337-339 in exon 11, changing the reading frame of the mRNA and causing a premature termination codon at position 345. This mutation was detected in the index case of a Canadian family with a total of 4 cases of breast cancer and 3 cases of ovarian cancer, bringing the probability of linkage to BRCA1 to 98.3%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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BRCA1, 40-BP DEL, NT1294
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80359874 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359874;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80359874?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80359874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80359874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019234 OR RCV000047372 OR RCV000131965 OR RCV000159899 OR RCV000238898 OR RCV001353523 OR RCV001798011 OR RCV004802938" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019234, RCV000047372, RCV000131965, RCV000159899, RCV000238898, RCV001353523, RCV001798011, RCV004802938" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019234...</a>
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<p><a href="#22" class="mim-tip-reference" title="Castilla, L. H., Couch, F. J., Erdos, M. R., Hoskins, K. F., Calzone, K., Garber, J. E., Boyd, J., Lubin, M. B., Deshano, M. L., Brody, L. C., Collins, F. S., Weber, B. L. <strong>Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.</strong> Nature Genet. 8: 387-391, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894491</a>] [<a href="https://doi.org/10.1038/ng1294-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894491">Castilla et al. (1994)</a> studied 50 probands with a family history of breast and/or ovarian cancer (<a href="/entry/604370">604370</a>) for germline mutations in the coding region of the BRCA1 candidate gene. <a href="#143" class="mim-tip-reference" title="Simard, J., Tonin, P., Durocher, F., Morgan, K., Rommens, J., Gingras, S., Samson, C., Leblanc, J.-F., Belanger, C., Dion, F., Liu, Q., Skolnick, M., Goldgar, D., Shattuck-Eidens, D., Labrie, F., Narod, S. A. <strong>Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families.</strong> Nature Genet. 8: 392-398, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894492</a>] [<a href="https://doi.org/10.1038/ng1294-392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894492">Simard et al. (1994)</a> studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They both identified a 40-bp deletion from position 1294 to 1333, which led to a premature termination codon that was 5 codons distal to the deletion and predicted a truncated BRCA1 protein of 396 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7894491+7894492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80357780 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357780;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80357780?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019235 OR RCV000214000 OR RCV000496882 OR RCV000759504 OR RCV001170823" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019235, RCV000214000, RCV000496882, RCV000759504, RCV001170823" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019235...</a>
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<p><a href="#52" class="mim-tip-reference" title="Friedman, L. S., Ostermeyer, E. A., Szabo, C. I., Dowd, P., Lynch, E. D., Rowell, S. E., King, M.-C. <strong>Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.</strong> Nature Genet. 8: 399-404, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894493</a>] [<a href="https://doi.org/10.1038/ng1294-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894493">Friedman et al. (1994)</a> studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (<a href="/entry/604370">604370</a>). They identified a 2-bp (AG) deletion at nucleotide 2415 in exon 11 of the BRCA1 gene, leading to a premature termination codon in place of serine-766 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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BRCA1, 2-BP DEL, 2800AA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80357971 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357971;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019236 OR RCV000047927 OR RCV000074575 OR RCV000131876 OR RCV000735499" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019236, RCV000047927, RCV000074575, RCV000131876, RCV000735499" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019236...</a>
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<p><a href="#52" class="mim-tip-reference" title="Friedman, L. S., Ostermeyer, E. A., Szabo, C. I., Dowd, P., Lynch, E. D., Rowell, S. E., King, M.-C. <strong>Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.</strong> Nature Genet. 8: 399-404, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894493</a>] [<a href="https://doi.org/10.1038/ng1294-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894493">Friedman et al. (1994)</a> studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (<a href="/entry/604370">604370</a>). They identified a 2-bp (AA) deletion at nucleotide 2800 in exon 11 of the BRCA1 gene, leading to a premature termination codon at position 901 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80357540 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357540;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000047955 OR RCV000132272 OR RCV000167766" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000047955, RCV000132272, RCV000167766" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000047955...</a>
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<p><a href="#52" class="mim-tip-reference" title="Friedman, L. S., Ostermeyer, E. A., Szabo, C. I., Dowd, P., Lynch, E. D., Rowell, S. E., King, M.-C. <strong>Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.</strong> Nature Genet. 8: 399-404, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894493</a>] [<a href="https://doi.org/10.1038/ng1294-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894493">Friedman et al. (1994)</a> studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (<a href="/entry/604370">604370</a>). They identified a 2-bp (TC) deletion at nucleotide 2863 in exon 11 of the BRCA1 gene, leading to a premature termination codon in place of serine-915 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80357601 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357601;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80357601?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019238 OR RCV000048039 OR RCV000159912 OR RCV000163096" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019238, RCV000048039, RCV000159912, RCV000163096" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019238...</a>
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<p><a href="#143" class="mim-tip-reference" title="Simard, J., Tonin, P., Durocher, F., Morgan, K., Rommens, J., Gingras, S., Samson, C., Leblanc, J.-F., Belanger, C., Dion, F., Liu, Q., Skolnick, M., Goldgar, D., Shattuck-Eidens, D., Labrie, F., Narod, S. A. <strong>Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families.</strong> Nature Genet. 8: 392-398, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894492</a>] [<a href="https://doi.org/10.1038/ng1294-392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894492">Simard et al. (1994)</a> studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp deletion (3121delA) in the normal sequence GAA AAC of codons 1001-1002 in exon 11, changing the reading frame of the mRNA and causing a premature termination codon at position 1023. This mutation was detected in the index case of a Canadian family with a total of 5 cases of breast cancer and 1 case of ovarian cancer (<a href="/entry/604370">604370</a>), bringing the probability of linkage to BRCA1 to 90%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs4986852 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4986852;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs4986852?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs4986852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs4986852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019239 OR RCV000034739 OR RCV000048074 OR RCV000120293 OR RCV000128951 OR RCV000456692 OR RCV002476991" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019239, RCV000034739, RCV000048074, RCV000120293, RCV000128951, RCV000456692, RCV002476991" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019239...</a>
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<p>This variant, formerly titled BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, has been reclassified based on the findings of <a href="#102" class="mim-tip-reference" title="Millot, G. A., Carvalho, M. A., Caputo, S. M., Vreeswijk, M. P. G., Brown, M. A., Webb, M., Rouleau, E., Neuhausen, S. L., Hansen, T., Galli, A., Brandao, R. D., Blok, M. J., Velkova, A., Couch, F. J., Monteiro, A. N. A. <strong>A guide for functional analysis of BRCA1 variants of uncertain significance.</strong> Hum. Mutat. 33: 1526-1537, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22753008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22753008</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22753008[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22753008">Millot et al. (2012)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22753008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Friedman, L. S., Ostermeyer, E. A., Szabo, C. I., Dowd, P., Lynch, E. D., Rowell, S. E., King, M.-C. <strong>Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.</strong> Nature Genet. 8: 399-404, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894493</a>] [<a href="https://doi.org/10.1038/ng1294-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894493">Friedman et al. (1994)</a> studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (<a href="/entry/604370">604370</a>). They identified a G-to-A transition at nucleotide 3238 in exon 11 of the BRCA1 gene, changing serine to asparagine at position 1040 (S1040N). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Functional assays used to assess the impact of the S1040N variant indicated that S1040N is a class 1 variant (not pathogenic or of no clinical significance), according to the International Agency for Research on Cancer (IARC) class system (<a href="#102" class="mim-tip-reference" title="Millot, G. A., Carvalho, M. A., Caputo, S. M., Vreeswijk, M. P. G., Brown, M. A., Webb, M., Rouleau, E., Neuhausen, S. L., Hansen, T., Galli, A., Brandao, R. D., Blok, M. J., Velkova, A., Couch, F. J., Monteiro, A. N. A. <strong>A guide for functional analysis of BRCA1 variants of uncertain significance.</strong> Hum. Mutat. 33: 1526-1537, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22753008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22753008</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22753008[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22753008">Millot et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22753008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs62625308 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs62625308;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs62625308?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs62625308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs62625308" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019240 OR RCV000048251 OR RCV000131818 OR RCV000148389 OR RCV000159978 OR RCV000239343 OR RCV000677815 OR RCV000735444 OR RCV000785373 OR RCV001642230 OR RCV003162256 OR RCV003332084 OR RCV004554605 OR RCV004802939 OR RCV004808551 OR RCV005016279" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019240, RCV000048251, RCV000131818, RCV000148389, RCV000159978, RCV000239343, RCV000677815, RCV000735444, RCV000785373, RCV001642230, RCV003162256, RCV003332084, RCV004554605, RCV004802939, RCV004808551, RCV005016279" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019240...</a>
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<p><a href="#52" class="mim-tip-reference" title="Friedman, L. S., Ostermeyer, E. A., Szabo, C. I., Dowd, P., Lynch, E. D., Rowell, S. E., King, M.-C. <strong>Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.</strong> Nature Genet. 8: 399-404, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894493</a>] [<a href="https://doi.org/10.1038/ng1294-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894493">Friedman et al. (1994)</a> studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (<a href="/entry/604370">604370</a>). They identified a C-to-T substitution in exon 11 at position 3726 of the BRCA1 gene, leading to a premature termination codon in place of arginine-1203 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28897686 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28897686;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28897686?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28897686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28897686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019241 OR RCV000048311 OR RCV000074586 OR RCV000131811 OR RCV000465125 OR RCV000506391 OR RCV004802940" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019241, RCV000048311, RCV000074586, RCV000131811, RCV000465125, RCV000506391, RCV004802940" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019241...</a>
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<p><a href="#22" class="mim-tip-reference" title="Castilla, L. H., Couch, F. J., Erdos, M. R., Hoskins, K. F., Calzone, K., Garber, J. E., Boyd, J., Lubin, M. B., Deshano, M. L., Brody, L. C., Collins, F. S., Weber, B. L. <strong>Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.</strong> Nature Genet. 8: 387-391, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894491</a>] [<a href="https://doi.org/10.1038/ng1294-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894491">Castilla et al. (1994)</a> studied 50 probands with a family history of breast and/or ovarian cancer (<a href="/entry/604370">604370</a>) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a G-to-T substitution in exon 11 at position 3867, leading to a premature termination codon in place of glutamic acid-1250 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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BRCA1, 4-BP DEL, NT3875
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80357868 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357868;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80357868?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019242 OR RCV000048314 OR RCV000131810 OR RCV000167859 OR RCV000239051 OR RCV000735506 OR RCV000782127 OR RCV000785410 OR RCV004758594" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019242, RCV000048314, RCV000131810, RCV000167859, RCV000239051, RCV000735506, RCV000782127, RCV000785410, RCV004758594" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019242...</a>
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<p><a href="#22" class="mim-tip-reference" title="Castilla, L. H., Couch, F. J., Erdos, M. R., Hoskins, K. F., Calzone, K., Garber, J. E., Boyd, J., Lubin, M. B., Deshano, M. L., Brody, L. C., Collins, F. S., Weber, B. L. <strong>Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.</strong> Nature Genet. 8: 387-391, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894491</a>] [<a href="https://doi.org/10.1038/ng1294-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894491">Castilla et al. (1994)</a> studied 50 probands with a family history of breast and/or ovarian cancer (<a href="/entry/604370">604370</a>) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 4-bp deletion at position 3875, leading to a premature termination codon at position 1252 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80357508 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357508;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80357508?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019243 OR RCV000048431 OR RCV000131887 OR RCV000159924 OR RCV000238776 OR RCV000476410 OR RCV000735453 OR RCV001353670 OR RCV004802941 OR RCV004808552 OR RCV005003392" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019243, RCV000048431, RCV000131887, RCV000159924, RCV000238776, RCV000476410, RCV000735453, RCV001353670, RCV004802941, RCV004808552, RCV005003392" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019243...</a>
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<p><a href="#52" class="mim-tip-reference" title="Friedman, L. S., Ostermeyer, E. A., Szabo, C. I., Dowd, P., Lynch, E. D., Rowell, S. E., King, M.-C. <strong>Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.</strong> Nature Genet. 8: 399-404, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894493</a>] [<a href="https://doi.org/10.1038/ng1294-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894493">Friedman et al. (1994)</a> studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (<a href="/entry/604370">604370</a>). <a href="#143" class="mim-tip-reference" title="Simard, J., Tonin, P., Durocher, F., Morgan, K., Rommens, J., Gingras, S., Samson, C., Leblanc, J.-F., Belanger, C., Dion, F., Liu, Q., Skolnick, M., Goldgar, D., Shattuck-Eidens, D., Labrie, F., Narod, S. A. <strong>Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families.</strong> Nature Genet. 8: 392-398, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894492</a>] [<a href="https://doi.org/10.1038/ng1294-392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894492">Simard et al. (1994)</a> studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. In both studies, a 4-bp (TCAA) deletion in exon 11 at position 4184, leading to a premature termination codon at position 1364 and a truncated protein, was identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7894492+7894493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs41293455 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41293455;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs41293455?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs41293455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs41293455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019244 OR RCV000048523 OR RCV000131880 OR RCV000159989 OR RCV000235131 OR RCV000239083 OR RCV000735445 OR RCV000763000 OR RCV001353404 OR RCV004802942" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019244, RCV000048523, RCV000131880, RCV000159989, RCV000235131, RCV000239083, RCV000735445, RCV000763000, RCV001353404, RCV004802942" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019244...</a>
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<p><a href="#22" class="mim-tip-reference" title="Castilla, L. H., Couch, F. J., Erdos, M. R., Hoskins, K. F., Calzone, K., Garber, J. E., Boyd, J., Lubin, M. B., Deshano, M. L., Brody, L. C., Collins, F. S., Weber, B. L. <strong>Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.</strong> Nature Genet. 8: 387-391, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894491</a>] [<a href="https://doi.org/10.1038/ng1294-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894491">Castilla et al. (1994)</a> studied 50 probands with a family history of breast and/or ovarian cancer (<a href="/entry/604370">604370</a>) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a C-to-T substitution at position 4446 of the BRCA1 gene, leading to a premature termination codon in place of arginine-1443 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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BRCA1, ARG1443GLY
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<p><a href="#22" class="mim-tip-reference" title="Castilla, L. H., Couch, F. J., Erdos, M. R., Hoskins, K. F., Calzone, K., Garber, J. E., Boyd, J., Lubin, M. B., Deshano, M. L., Brody, L. C., Collins, F. S., Weber, B. L. <strong>Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.</strong> Nature Genet. 8: 387-391, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894491</a>] [<a href="https://doi.org/10.1038/ng1294-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894491">Castilla et al. (1994)</a> studied 50 probands with a family history of breast and/or ovarian cancer (<a href="/entry/604370">604370</a>) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a C-to-G transition at position 4446, changing arginine-1443 to glycine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0018 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019246 OR RCV000019247 OR RCV000056287 OR RCV000119097 OR RCV000131328 OR RCV000258962 OR RCV000412924 OR RCV000415060 OR RCV000495973 OR RCV000735471 OR RCV001353680 OR RCV003128129 OR RCV004554607 OR RCV004802943 OR RCV005003393" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019246, RCV000019247, RCV000056287, RCV000119097, RCV000131328, RCV000258962, RCV000412924, RCV000415060, RCV000495973, RCV000735471, RCV001353680, RCV003128129, RCV004554607, RCV004802943, RCV005003393" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019246...</a>
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<p><strong><em>Breast-Ovarian Cancer Susceptibility</em></strong></p><p>
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<a href="#143" class="mim-tip-reference" title="Simard, J., Tonin, P., Durocher, F., Morgan, K., Rommens, J., Gingras, S., Samson, C., Leblanc, J.-F., Belanger, C., Dion, F., Liu, Q., Skolnick, M., Goldgar, D., Shattuck-Eidens, D., Labrie, F., Narod, S. A. <strong>Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families.</strong> Nature Genet. 8: 392-398, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894492</a>] [<a href="https://doi.org/10.1038/ng1294-392" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894492">Simard et al. (1994)</a> studied 30 Canadian families with breast and/or ovarian cancer (<a href="/entry/604370">604370</a>) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp (C) insertion at position 5382 in exon 20, changing the reading frame of the mRNA and causing a premature termination codon at position 1829 in exon 24. This mutation was detected in the index case of 4 Canadian families. In 1 of these families, 10 cases of cancer appeared in a single large sibship, including 3 cases of breast cancer, 2 ovarian cancers, 2 leukemias, 2 pancreatic cancers, and 1 prostate cancer. A case of leukemia and a case of Hodgkin disease were seen in more recent generations. In the 4 families with the 5382insC mutation, there were 14 cases of breast cancer and 5 cases of ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#58" class="mim-tip-reference" title="Gayther, S. A., Harrington, P., Russell, P., Kharkevich, G., Garkavtseva, R. F., Ponder, B. A. J. <strong>Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia. (Letter)</strong> Am. J. Hum. Genet. 60: 1239-1242, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150173</a>]" pmid="9150173">Gayther et al. (1997)</a> found that the 5382insC and 4153delA (<a href="#0030">113705.0030</a>) mutations in the BRCA1 gene may account for 86% of cases of familial ovarian cancer in Russia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#61" class="mim-tip-reference" title="Gorski, B., Byrski, T., Huzarski, T., Jakubowska, A., Menkiszak, J., Gronwald, J., Pluzanska, A., Bebenek, M., Fischer-Maliszewska, L., Grzybowska, E., Narod, S. A., Lubinski, J. <strong>Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.</strong> Am. J. Hum. Genet. 66: 1963-1968, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10788334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10788334</a>] [<a href="https://doi.org/10.1086/302922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10788334">Gorski et al. (2000)</a> found that 5382insC is a founder mutation in Polish families with breast-ovarian cancer, accounting for 51% of identified mutations. They studied 66 families in which at least 3 related females were affected with breast or ovarian cancer and at least 1 of these 3 had been diagnosed with cancer before the age of 50. Mutations were found in 35 (53%) of the 66 families; 18 of the families carried the 5382insC mutation. <a href="#32" class="mim-tip-reference" title="De Los Rios, P., Jack, E., Kuperstein, G., Lynch, H., Lubinski, J., Narod, S. A. <strong>Founder mutations in BRCA1 and BRCA2 in North American families of Polish origin that are affected with breast cancer. (Letter)</strong> Am. J. Hum. Genet. 68: 546 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170903</a>] [<a href="https://doi.org/10.1086/318211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170903">De Los Rios et al. (2001)</a> reported findings in Canadian families suggesting that most of the mutation-carrying families of Polish ancestry have the BRCA1 5382insC mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10788334+11170903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#121" class="mim-tip-reference" title="Porhanova, N. V., Sokolenko, A. P., Sherina, N. Y., Ponomariova, D. N., Tkachenko, N. N., Matsko, D. E., Imyanitov, E. N. <strong>Ovarian cancer patient with germline mutations in both BRCA1 and NBN genes. (Letter)</strong> Cancer Genet. Cytogenet. 186: 122-124, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18940477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18940477</a>] [<a href="https://doi.org/10.1016/j.cancergencyto.2008.06.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18940477">Porhanova et al. (2008)</a> reported a 52-year-old Russian woman with ovarian cancer who was found to be compound heterozygous for the 5382inC mutation and a common Slavic mutation in the NBN gene (<a href="/entry/602667#0001">602667.0001</a>). Investigation of the ovarian cancer tissue showed somatic loss of heterozygosity for NBN, but retention of heterozygosity for BRCA1. The patient did not have a particularly severe cancer-prone phenotype, and her parents did not have cancer, although 3 sibs developed cancer as adults. <a href="#121" class="mim-tip-reference" title="Porhanova, N. V., Sokolenko, A. P., Sherina, N. Y., Ponomariova, D. N., Tkachenko, N. N., Matsko, D. E., Imyanitov, E. N. <strong>Ovarian cancer patient with germline mutations in both BRCA1 and NBN genes. (Letter)</strong> Cancer Genet. Cytogenet. 186: 122-124, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18940477/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18940477</a>] [<a href="https://doi.org/10.1016/j.cancergencyto.2008.06.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18940477">Porhanova et al. (2008)</a> commented that haploinsufficiency of the BRCA1 gene may contribute to cancer progression without somatic changes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18940477" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pancreatic Cancer Susceptibility</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Al-Sukhni, W., Rothenmund, H., Eppel Borgida, A., Zogopoulos, G., O'Shea, A.-M., Pollett, A., Gallinger, S. <strong>Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.</strong> Hum. Genet. 124: 271-278, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18762988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18762988</a>] [<a href="https://doi.org/10.1007/s00439-008-0554-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18762988">Al-Sukhni et al. (2008)</a> found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer (PNCA4; <a href="/entry/614320">614320</a>) who carried a heterozygous germline BRCA1 mutation. Three patients carried the 5382insC mutation. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. <a href="#3" class="mim-tip-reference" title="Al-Sukhni, W., Rothenmund, H., Eppel Borgida, A., Zogopoulos, G., O'Shea, A.-M., Pollett, A., Gallinger, S. <strong>Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.</strong> Hum. Genet. 124: 271-278, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18762988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18762988</a>] [<a href="https://doi.org/10.1007/s00439-008-0554-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18762988">Al-Sukhni et al. (2008)</a> concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18762988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80357629 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357629;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000049050 OR RCV000074357 OR RCV000163976 OR RCV000265181" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049050, RCV000074357, RCV000163976, RCV000265181" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049050...</a>
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<p><a href="#52" class="mim-tip-reference" title="Friedman, L. S., Ostermeyer, E. A., Szabo, C. I., Dowd, P., Lynch, E. D., Rowell, S. E., King, M.-C. <strong>Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.</strong> Nature Genet. 8: 399-404, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894493</a>] [<a href="https://doi.org/10.1038/ng1294-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894493">Friedman et al. (1994)</a> studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (<a href="/entry/604370">604370</a>). They identified a 1-bp (A) insertion at nucleotide 5677 in exon 24 of the BRCA1 gene, leading to a premature termination codon in place of tyrosine-1853 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019249" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019249" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019249</a>
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<p><a href="#22" class="mim-tip-reference" title="Castilla, L. H., Couch, F. J., Erdos, M. R., Hoskins, K. F., Calzone, K., Garber, J. E., Boyd, J., Lubin, M. B., Deshano, M. L., Brody, L. C., Collins, F. S., Weber, B. L. <strong>Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.</strong> Nature Genet. 8: 387-391, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894491</a>] [<a href="https://doi.org/10.1038/ng1294-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894491">Castilla et al. (1994)</a> studied 50 probands with a family history of breast and/or ovarian cancer (<a href="/entry/604370">604370</a>) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 19-bp deletion between basepairs 5085 and 5103, leading to a termination codon at position 1656 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0021 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80357823 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357823;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000048927 OR RCV000074358 OR RCV000131363 OR RCV000478417 OR RCV000735454 OR RCV004804021" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000048927, RCV000074358, RCV000131363, RCV000478417, RCV000735454, RCV004804021" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000048927...</a>
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<p><a href="#22" class="mim-tip-reference" title="Castilla, L. H., Couch, F. J., Erdos, M. R., Hoskins, K. F., Calzone, K., Garber, J. E., Boyd, J., Lubin, M. B., Deshano, M. L., Brody, L. C., Collins, F. S., Weber, B. L. <strong>Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.</strong> Nature Genet. 8: 387-391, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894491</a>] [<a href="https://doi.org/10.1038/ng1294-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894491">Castilla et al. (1994)</a> studied 50 probands with a family history of breast and/or ovarian cancer (<a href="/entry/604370">604370</a>) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp (C) insertion at nucleotide 5438, leading to a termination codon at position 1773 and a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0022 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1800709 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800709;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1800709?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1800709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1800709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019251 OR RCV000034733 OR RCV000047867 OR RCV000120283 OR RCV000162566 OR RCV000457953 OR RCV001170820 OR RCV002490393" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019251, RCV000034733, RCV000047867, RCV000120283, RCV000162566, RCV000457953, RCV001170820, RCV002490393" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019251...</a>
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<p>This variant, formerly titled BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, has been reclassified based on the findings of <a href="#102" class="mim-tip-reference" title="Millot, G. A., Carvalho, M. A., Caputo, S. M., Vreeswijk, M. P. G., Brown, M. A., Webb, M., Rouleau, E., Neuhausen, S. L., Hansen, T., Galli, A., Brandao, R. D., Blok, M. J., Velkova, A., Couch, F. J., Monteiro, A. N. A. <strong>A guide for functional analysis of BRCA1 variants of uncertain significance.</strong> Hum. Mutat. 33: 1526-1537, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22753008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22753008</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22753008[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22753008">Millot et al. (2012)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22753008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Barker, D. F., Almeida, E. R. A., Casey, G., Fain, P. R., Liao, S. Y., Masunaka, I., Noble, B., Kurosaki, T., Anton-Culver, H. <strong>BRCA1 R841W: a strong candidate for a common mutation with moderate phenotype.</strong> Genet. Epidemiol. 13: 595-604, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968716</a>] [<a href="https://doi.org/10.1002/(SICI)1098-2272(1996)13:6<595::AID-GEPI5>3.0.CO;2-#" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968716">Barker et al. (1996)</a> reported an arg841-to-trp (R814W) mutation in the BRCA1 gene as a common mutation identified in patients with breast-ovarian cancer (<a href="/entry/604370">604370</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Functional assays used to assess the impact of the R814W variant indicated that R814W is a class 1 variant (not pathogenic or of no clinical significance), according to the International Agency for Research on Cancer (IARC) class system (<a href="#102" class="mim-tip-reference" title="Millot, G. A., Carvalho, M. A., Caputo, S. M., Vreeswijk, M. P. G., Brown, M. A., Webb, M., Rouleau, E., Neuhausen, S. L., Hansen, T., Galli, A., Brandao, R. D., Blok, M. J., Velkova, A., Couch, F. J., Monteiro, A. N. A. <strong>A guide for functional analysis of BRCA1 variants of uncertain significance.</strong> Hum. Mutat. 33: 1526-1537, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22753008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22753008</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22753008[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.22150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22753008">Millot et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22753008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0023 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs62625306 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs62625306;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs62625306?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs62625306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs62625306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019252 OR RCV000162856 OR RCV000212169 OR RCV000496416 OR RCV000769717" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019252, RCV000162856, RCV000212169, RCV000496416, RCV000769717" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019252...</a>
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<p>In a patient of Scottish descent with breast cancer (<a href="/entry/604370">604370</a>), <a href="#93" class="mim-tip-reference" title="Liede, A., Rehal, P., Vesprini, D., Jack, E., Abrahamson, J., Narod, S. A. <strong>A breast cancer patient of Scottish descent with germ-line mutations in BRCA1 and BRCA2. (Letter)</strong> Am. J. Hum. Genet. 62: 1543-1544, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585617</a>] [<a href="https://doi.org/10.1086/301889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585617">Liede et al. (1998)</a> found double heterozygosity for 2 high-penetrance mutations: a 2508G-T transversion in BRCA1, resulting in a conversion of glutamic acid to a stop codon, and a 3295insA mutation (<a href="/entry/600185#0011">600185.0011</a>) in BRCA2. Both mutations were thought to have come from the father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80357919 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357919;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357919" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357919" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019253 OR RCV000049168 OR RCV000131872 OR RCV000412670 OR RCV000735511 OR RCV002496415 OR RCV003992160" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019253, RCV000049168, RCV000131872, RCV000412670, RCV000735511, RCV002496415, RCV003992160" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019253...</a>
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<p>In a Caucasian patient with a positive family history of breast or ovarian cancer (<a href="/entry/604370">604370</a>) in a first-degree relative, <a href="#78" class="mim-tip-reference" title="Janezic, S. A., Ziogas, A., Krumroy, L. M., Krasner, M., Plummer, S. J., Cohen, P., Gildea, M., Barker, D., Haile, R., Casey, G., Anton-Culver, H. <strong>Germline BRCA1 alterations in a population-based series of ovarian cancer cases.</strong> Hum. Molec. Genet. 8: 889-897, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196379</a>] [<a href="https://doi.org/10.1093/hmg/8.5.889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196379">Janezic et al. (1999)</a> identified a 962delCTCA mutation in the BRCA1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0025 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80357877 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357877;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019254 OR RCV000048211 OR RCV000131815 OR RCV000159917 OR RCV000785408 OR RCV001271012 OR RCV004760336 OR RCV004802944" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019254, RCV000048211, RCV000131815, RCV000159917, RCV000785408, RCV001271012, RCV004760336, RCV004802944" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019254...</a>
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<p>In a Caucasian patient with a positive family history of breast or ovarian cancer (<a href="/entry/604370">604370</a>) in a first-degree relative, <a href="#78" class="mim-tip-reference" title="Janezic, S. A., Ziogas, A., Krumroy, L. M., Krasner, M., Plummer, S. J., Cohen, P., Gildea, M., Barker, D., Haile, R., Casey, G., Anton-Culver, H. <strong>Germline BRCA1 alterations in a population-based series of ovarian cancer cases.</strong> Hum. Molec. Genet. 8: 889-897, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10196379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10196379</a>] [<a href="https://doi.org/10.1093/hmg/8.5.889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10196379">Janezic et al. (1999)</a> identified a 3600del11 mutation in the BRCA1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10196379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80357662 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357662;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Two BRCA1 founder mutations had been identified in the Norwegian population: 1675delA (<a href="#39" class="mim-tip-reference" title="Dorum, A., Moller, P., Kamsteeg, E. J., Scheffer, H., Burton, M., Heimdal, K. R., Maehle, L. O., Hovig, E., Trope, C. G., van der Hout, A. H., van der Meulen, M. A., Buys, C. H. C. M., te Meerman, G. J. <strong>A BRCA1 founder mutation, identified with haplotype analysis, allowing genotype/phenotype determination and predictive testing.</strong> Europ. J. Cancer 33: 2390-2392, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9616287/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9616287</a>] [<a href="https://doi.org/10.1016/s0959-8049(97)00328-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9616287">Dorum et al., 1997</a>) and 1135insA (<a href="#0027">113705.0027</a>) (<a href="#6" class="mim-tip-reference" title="Andersen, T. I., Borresen, A.-L., Moller, P. <strong>A common BRCA1 mutation in Norwegian breast and ovarian cancer families?</strong> Am. J. Hum. Genet. 59: 486-487, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755943</a>]" pmid="8755943">Andersen et al., 1996</a>). Both result in a frameshift and a stop in exon 11. <a href="#38" class="mim-tip-reference" title="Dorum, A., Heimdal, K., Hovig, E., Inganas, M., Moller, P. <strong>Penetrances of BRCA1 1675delA and 1135insA with respect to breast cancer and ovarian cancer.</strong> Am. J. Hum. Genet. 65: 671-679, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441573</a>] [<a href="https://doi.org/10.1086/302530" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441573">Dorum et al. (1999)</a> ascertained 20 patients with breast-ovarian cancer (<a href="/entry/604370">604370</a>) with the BRCA1 1675delA mutation and 10 with the 1135insA mutation. Their relatives were described with respect to absence/presence of breast and/or ovarian cancer. Of 133 living female relatives, 83 (62%) were tested for the presence of a mutation. No difference in penetrance or expression between the 2 mutations was found, whereas differences according to method of ascertainment were seen. The overall findings were that disease started to occur at age 30 years and that by age 50 years 48% of the mutation-carrying women had experienced breast and/or ovarian cancer. More ovarian cancers than breast cancers were recorded. Both penetrance and expression (breast cancer vs ovarian cancer) were different from those in reports of the Ashkenazi founder mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10441573+8755943+9616287" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000047310 OR RCV000074359 OR RCV000129421 OR RCV000190459 OR RCV000735524 OR RCV000785394 OR RCV004803951" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000047310, RCV000074359, RCV000129421, RCV000190459, RCV000735524, RCV000785394, RCV004803951" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000047310...</a>
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<p>See <a href="#0026">113705.0026</a> and <a href="#38" class="mim-tip-reference" title="Dorum, A., Heimdal, K., Hovig, E., Inganas, M., Moller, P. <strong>Penetrances of BRCA1 1675delA and 1135insA with respect to breast cancer and ovarian cancer.</strong> Am. J. Hum. Genet. 65: 671-679, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441573</a>] [<a href="https://doi.org/10.1086/302530" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441573">Dorum et al. (1999)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80357579 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357579;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000031127 OR RCV000048325 OR RCV000131814 OR RCV000235232 OR RCV000677799 OR RCV000785411 OR RCV001391223 OR RCV001554258 OR RCV004758609 OR RCV004802973 OR RCV005016307" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000031127, RCV000048325, RCV000131814, RCV000235232, RCV000677799, RCV000785411, RCV001391223, RCV001554258, RCV004758609, RCV004802973, RCV005016307" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000031127...</a>
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<p><a href="#155" class="mim-tip-reference" title="Tesoriero, A., Andersen, C., Southey, M., Somers, G., McKay, M., Armes, J., McCredie, M., Giles, G., Hopper, J. L., Venter, D. <strong>De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. (Letter)</strong> Am. J. Hum. Genet. 65: 567-569, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10417300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10417300</a>] [<a href="https://doi.org/10.1086/302503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10417300">Tesoriero et al. (1999)</a> identified a woman who developed high-grade breast cancer with axillary nodal metastases before the age of 40 years (<a href="/entry/604370">604370</a>). Her father developed prostate cancer during his early fifties. Her mother had no cancer. The patient was found to have a de novo 2-bp deletion (GA) at nucleotide 3888 in exon 11 of the BRCA1 gene (3888delGA), and a 1-bp deletion (T) at nucleotide 6174 in exon 11 of the BRCA2 gene (<a href="/entry/600185#0009">600185.0009</a>), which had been inherited from the father. Studies of a heterozygous polymorphism indicated that the 3888delGA mutation of BRCA1 originated from the father. The authors noted that despite the large number of variants identified in the BRCA1 and BRCA2 (<a href="/entry/600185">600185</a>) genes, there appeared to be no earlier published report of a de novo mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10417300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906563 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906563;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387906563?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019258 OR RCV000049156 OR RCV000074602 OR RCV000129599 OR RCV000468976 OR RCV000735513 OR RCV002496721" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019258, RCV000049156, RCV000074602, RCV000129599, RCV000468976, RCV000735513, RCV002496721" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019258...</a>
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<p><a href="#99" class="mim-tip-reference" title="Mefford, H. C., Baumbach, L., Panguluri, R. C. K., Whitfield-Broome, C., Szabo, C., Smith, S., King, M.-C., Dunston, G., Stoppa-Lyonnet, D., Arena, F. <strong>Evidence for a BRCA1 founder mutation in families of West African ancestry. (Letter)</strong> Am. J. Hum. Genet. 65: 575-578, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10417303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10417303</a>] [<a href="https://doi.org/10.1086/302511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10417303">Mefford et al. (1999)</a> suggested that a 10-bp insertion at nucleotide 943 of the BRCA1 gene represents a founder mutation of African origin in patients with breast-ovarian cancer (<a href="/entry/604370">604370</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10417303" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000031141 OR RCV000048413 OR RCV000074587 OR RCV000130638 OR RCV000239274 OR RCV001271017 OR RCV004758610 OR RCV004772833 OR RCV004802977" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000031141, RCV000048413, RCV000074587, RCV000130638, RCV000239274, RCV001271017, RCV004758610, RCV004772833, RCV004802977" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000031141...</a>
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<p>By mutation analysis of the BRCA1 gene in families with breast-ovarian cancer (<a href="/entry/604370">604370</a>) in Russia, <a href="#58" class="mim-tip-reference" title="Gayther, S. A., Harrington, P., Russell, P., Kharkevich, G., Garkavtseva, R. F., Ponder, B. A. J. <strong>Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia. (Letter)</strong> Am. J. Hum. Genet. 60: 1239-1242, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150173</a>]" pmid="9150173">Gayther et al. (1997)</a> identified a novel 4153delA mutation. They stated that this mutation and the 5382insC (<a href="#0018">113705.0018</a>) mutation in the BRCA1 gene may account for 86% of cases of familial ovarian cancer in Russia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019260" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019260" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019260</a>
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<p><a href="#124" class="mim-tip-reference" title="Puget, N., Stoppa-Lyonnet, D., Sinilnikova, O. M., Pages, S., Lynch, H. T., Lenoir, G. M., Mazoyer, S. <strong>Screening for germline rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions.</strong> Cancer Res. 59: 455-461, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9927062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9927062</a>]" pmid="9927062">Puget et al. (1999)</a> described a 6-kb duplication of exon 13 of the BRCA1 gene that created a frameshift in the coding sequence in 3 unrelated U.S. families of European ancestry and 1 Portuguese family with breast-ovarian cancer (<a href="/entry/604370">604370</a>). To estimate the frequency and geographic diversity of carriers of this duplication, the <a href="#17" class="mim-tip-reference" title="BRCA1 Exon 13 Duplication Screening Group. <strong>The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations.</strong> Am. J. Hum. Genet. 67: 207-212, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10827109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10827109</a>]" pmid="10827109">BRCA1 Exon 13 Duplication Screening Group (2000)</a> studied 3,580 unrelated individuals with a family history of breast cancer and 934 early-onset breast and/or ovarian cancer cases ascertained through 39 institutions in 19 countries. A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2). Haplotyping showed that they were likely to have derived from a common ancestor, possibly of northern British origin. The screening group suggested that BRCA1 screening protocols, either in English-speaking countries or in countries with historic links with Great Britain, should include the PCR-based assay described in their report. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9927062+10827109" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80357571 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357571;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80357571?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000112140 OR RCV000574479 OR RCV001269640 OR RCV002298457" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000112140, RCV000574479, RCV001269640, RCV002298457" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000112140...</a>
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<p><a href="#130" class="mim-tip-reference" title="Sarantaus, L., Huusko, P., Eerola, H., Launonen, V., Vehmanen, P., Rapakko, K., Gillanders, E., Syrjakoski, K., Kainu, T., Vahteristo, P., Krahe, R., Paakkonen, K., and 14 others. <strong>Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland.</strong> Europ. J. Hum. Genet. 8: 757-763, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11039575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11039575</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200529" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11039575">Sarantaus et al. (2000)</a> performed haplotype analysis of 26 Finnish patients with breast-ovarian cancer (<a href="/entry/604370">604370</a>) carrying a 3744delT mutation in exon 11 of the BRCA1 gene. They estimated that the mutation could be traced back 23 to 36 generations (500-700 years). The mutation was observed in Swedish families also. Most of the Finnish families had lived in Central Ostrobothnia for at least 300 years, whereas the Swedish families came from the opposite side of the Gulf of Bothnia. Thus, the mutation could have been brought across the sea from Sweden to Finland with Swedish settlers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11039575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80357856 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357856;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80357856?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019262 OR RCV000048059 OR RCV000131332 OR RCV000159913 OR RCV001353931" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019262, RCV000048059, RCV000131332, RCV000159913, RCV001353931" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019262...</a>
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<p><a href="#14" class="mim-tip-reference" title="Bergman, A., Einbeigi, Z., Olofsson, U., Taib, Z., Wallgren, A., Karlsson, P., Wahlstrom, J., Martinsson, T., Nordling, M. <strong>The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation.</strong> Europ. J. Hum. Genet. 9: 787-793, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781691</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781691">Bergman et al. (2001)</a> stated that the 3171ins5 mutation in the BRCA1 gene (originally reported by <a href="#82" class="mim-tip-reference" title="Johannsson, O., Ostermeyer, E. A., Hakansson, S., Friedman, L. S., Johansson, U., Sellberg, G., Brondum-Nielsen, K., Sele, V., Olsson, H., King, M.-C., Borg, A. <strong>Founding BRCA1 mutations in hereditary breast and ovarian cancer in Southern Sweden.</strong> Am. J. Hum. Genet. 58: 441-450, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644702</a>]" pmid="8644702">Johannsson et al. (1996)</a> as 3166insTGAGA), is the most recurrent germline BRCA1/BRCA2 mutation in Sweden. <a href="#14" class="mim-tip-reference" title="Bergman, A., Einbeigi, Z., Olofsson, U., Taib, Z., Wallgren, A., Karlsson, P., Wahlstrom, J., Martinsson, T., Nordling, M. <strong>The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation.</strong> Europ. J. Hum. Genet. 9: 787-793, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781691</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781691">Bergman et al. (2001)</a> constructed haplotypes with polymorphic microsatellite markers within and flanking the BRCA1 gene in 18 apparently unrelated families with hereditary breast and/or ovarian cancer (<a href="/entry/604370">604370</a>) with a confirmed 3171ins5 mutation. All affected families originated from the same geographic area along the west coast of Sweden. The microsatellite markers spanned a region of 17.3 cM, and all of the analyzed families shared a common 3.7 cM haplotype in the 3171ins5 carriers spanning over 4 markers located within or very close to the BRCA1 gene. This haplotype was not present in any of the 116 control chromosomes, and the 3171ins5 mutation was likely to be identical by descent, i.e., a true founder. The estimated age of the mutation was calculated to be approximately 50 generations, or a first appearance some time around the 6th century (<a href="#14" class="mim-tip-reference" title="Bergman, A., Einbeigi, Z., Olofsson, U., Taib, Z., Wallgren, A., Karlsson, P., Wahlstrom, J., Martinsson, T., Nordling, M. <strong>The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation.</strong> Europ. J. Hum. Genet. 9: 787-793, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781691</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781691">Bergman et al., 2001</a>). No obvious correlation between the geographic origin and genotype was observed. This is probably a reflection of how the population of western Sweden historically has been a migrating people along the west coast, with limited migration beyond this distinct geographic area. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11781691+8644702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80357382 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357382;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80357382?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019263 OR RCV000047713 OR RCV000131899 OR RCV000195359 OR RCV000469732 OR RCV000508177 OR RCV000763009 OR RCV004758595 OR RCV004802945" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019263, RCV000047713, RCV000131899, RCV000195359, RCV000469732, RCV000508177, RCV000763009, RCV004758595, RCV004802945" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019263...</a>
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<p><a href="#163" class="mim-tip-reference" title="Vega, A., Torres, M., Martinez, J. I., Ruiz-Ponte, C., Barros, F., Carracedo, A. <strong>Analysis of BRCA1 and BRCA2 in breast and breast/ovarian cancer families shows population substructure in the Iberian peninsula.</strong> Ann. Hum. Genet. 66: 29-36, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12014998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12014998</a>] [<a href="https://doi.org/10.1017/S0003480001001014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12014998">Vega et al. (2002)</a> studied 30 Spanish breast and breast/ovarian cancer (<a href="/entry/604370">604370</a>) families for mutations in the BRCA1 and BRCA2 genes. Mutations were found in 8 of the 30 families (26.66%). All mutations were in the BRCA1 gene. The 330A-G transition in the BRCA1 gene, which resulted in an arg71-to-gly (R71G) substitution, was found in 4 unrelated families and accounted for 50% of all identified mutations. It had been described as a founder Spanish mutation, leading to aberrant splicing (<a href="#162" class="mim-tip-reference" title="Vega, A., Campos, B., Bressac-de-Paillerets, B., Bond, P. M., Janin, N., Douglas, F. S., Domenech, M., Baena, M., Pericay, C., Alonso, C., Carracedo, A., Baiget, M., Diez, O. <strong>The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript.</strong> Hum. Mutat. 17: 520-521, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11385711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11385711</a>] [<a href="https://doi.org/10.1002/humu.1136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11385711">Vega et al., 2001</a>). The proband in 1 family had bilateral breast cancer at 27 and 30 years of age. Her mother, who also had the mutation, was diagnosed as having ovarian cancer at the age of 50. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12014998+11385711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Diez, O., Osorio, A., Duran, M., Martinez-Ferrandis, J. I., de la Hoya, M., Salazar, R., Vega, A., Campos, B., Rodriguez-Lopez, R., Velasco, E., Chaves, J., Diaz-Rubio, E., and 13 others. <strong>Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects.</strong> Hum. Mutat. 22: 301-312, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12955716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12955716</a>] [<a href="https://doi.org/10.1002/humu.10260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12955716">Diez et al. (2003)</a> stated that the 330A-G mutation affected the splice donor site in intron 5; it caused aberrant splicing which resulted in a deletion of 22 nucleotides in exon 5 and a stop at codon 64 (C64X). <a href="#35" class="mim-tip-reference" title="Diez, O., Osorio, A., Duran, M., Martinez-Ferrandis, J. I., de la Hoya, M., Salazar, R., Vega, A., Campos, B., Rodriguez-Lopez, R., Velasco, E., Chaves, J., Diaz-Rubio, E., and 13 others. <strong>Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects.</strong> Hum. Mutat. 22: 301-312, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12955716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12955716</a>] [<a href="https://doi.org/10.1002/humu.10260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12955716">Diez et al. (2003)</a> observed this mutation in 7 families, most of them of known Galician origin. As reported in the BRCA1 database, the 330A-G mutation had been observed in families with probable Spanish origin in diverse geographic locations in Europe other than Spain (France and the United Kingdom), and in Caribbean and South American families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12955716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a family with breast-ovarian cancer (<a href="/entry/604370">604370</a>), <a href="#101" class="mim-tip-reference" title="Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P. A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L. M., Ding, W., Bell, R., Rosenthal, J., and 33 others. <strong>A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.</strong> Science 266: 66-71, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7545954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7545954</a>] [<a href="https://doi.org/10.1126/science.7545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7545954">Miki et al. (1994)</a> identified a heterozygous T-to-G transversion in exon 21 of the BRCA1 gene, resulting in a met1775-to-arg (M1775R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the germline of patients with breast or ovarian cancer, <a href="#104" class="mim-tip-reference" title="Monteiro, A. N. A., August, A., Hanafusa, H. <strong>Evidence for a transcriptional activation function of BRCA1 C-terminal region.</strong> Proc. Nat. Acad. Sci. 93: 13595-13599, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8942979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8942979</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=8942979[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.93.24.13595" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8942979">Monteiro et al. (1996)</a> identified the M1775R mutation in the BRCA1 gene. This mutation has impaired transcriptional activity on BRCA1. <a href="#171" class="mim-tip-reference" title="Williams, R. S., Glover, J. N. <strong>Structural consequences of a cancer-causing BRCA1-BRCT missense mutation.</strong> J. Biol. Chem. 278: 2630-2635, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12427738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12427738</a>] [<a href="https://doi.org/10.1074/jbc.M210019200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12427738">Williams and Glover (2003)</a> performed structural studies on the effect of this mutation. The mutated side chain is extruded from the protein hydrophobic core, thereby altering the protein surface. Charge-charge repulsion, rearrangement of the hydrophobic core, and disruption of the native hydrogen bonding network at the interface between the 2 BRCT repeats contribute to the conformational instability of the mutant protein. <a href="#171" class="mim-tip-reference" title="Williams, R. S., Glover, J. N. <strong>Structural consequences of a cancer-causing BRCA1-BRCT missense mutation.</strong> J. Biol. Chem. 278: 2630-2635, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12427738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12427738</a>] [<a href="https://doi.org/10.1074/jbc.M210019200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12427738">Williams and Glover (2003)</a> concluded that destabilization and global unfolding of the mutated BRCT domain at physiologic temperatures explained the pleiotropic molecular and genetic defects associated with the mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8942979+12427738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Aglipay, J. A., Martin, S. A., Tawara, H., Lee, S. W., Ouchi, T. <strong>ATM activation by ionizing radiation requires BRCA1-associated BAAT1.</strong> J. Biol. Chem. 281: 9710-9718, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16452482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16452482</a>] [<a href="https://doi.org/10.1074/jbc.M510332200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16452482">Aglipay et al. (2006)</a> showed that the M1775R mutation abrogated interaction of BRCA1 with BRAT1 (<a href="/entry/614506">614506</a>), which is required for activation of ATM (<a href="/entry/607585">607585</a>) following ionizing radiation-induced DNA damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16452482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000019265 OR RCV000496817 OR RCV001526335" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019265, RCV000496817, RCV001526335" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019265...</a>
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<p>In 2 unrelated European families with a history of breast cancer (<a href="/entry/604370">604370</a>), <a href="#158" class="mim-tip-reference" title="Tischkowitz, M., Hamel, N., Carvalho, M. A., Birrane, G., Soni, A., van Beers, E. H., Joosse, S. A., Wong, N., Novak, D., Quenneville, L. A., Grist, S. A., Nederlof, P. M., Goldgar, D. E., Tavtigian, S. V., Monteiro, A. N., Ladias, J. A. A., Foulkes, W. D. <strong>Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach.</strong> Europ. J. Hum. Genet. 16: 820-832, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18285836[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2008.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285836">Tischkowitz et al. (2008)</a> identified a met1775-to-lys (M1775K) substitution in the BRCA1 gene and demonstrated its pathogenicity. The authors showed that expression of the M1775K-mutant protein in yeast and mammalian cells resulted in markedly reduced transcriptional activity of BRCA1, indicating the pathogenicity of the variant. The M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCT domains, thereby inhibiting BRCA1 interaction with the proteins BRIP1 (<a href="/entry/605882">605882</a>) and CTIP (RBBP8; <a href="/entry/604128">604128</a>), which are involved in DNA damage-induced checkpoint control. These findings indicated that the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. <a href="#158" class="mim-tip-reference" title="Tischkowitz, M., Hamel, N., Carvalho, M. A., Birrane, G., Soni, A., van Beers, E. H., Joosse, S. A., Wong, N., Novak, D., Quenneville, L. A., Grist, S. A., Nederlof, P. M., Goldgar, D. E., Tavtigian, S. V., Monteiro, A. N., Ladias, J. A. A., Foulkes, W. D. <strong>Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach.</strong> Europ. J. Hum. Genet. 16: 820-832, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285836</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18285836[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2008.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285836">Tischkowitz et al. (2008)</a> used a combination of functional, structural, molecular, and evolutionary methods in their study. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a Scandinavian family (LUND488) segregating breast-ovarian cancer (<a href="/entry/604370">604370</a>), <a href="#159" class="mim-tip-reference" title="Vallon-Christersson, J., Cayanan, C., Haraldsson, K., Loman, N., Bergthorsson, J. T., Brondum-Nielsen, K., Gerdes, A.-M., Moller, P., Kristoffersson, U., Olsson, H., Borg, A., Monteiro, A. N. A. <strong>Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families.</strong> Hum. Molec. Genet. 10: 353-360, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11157798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/10.4.353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157798">Vallon-Christersson et al. (2001)</a> identified a G-to-A transition at nucleotide 5215 in exon 18 of the BRCA1 gene, resulting in an arg1699-to-gln (R1699Q) substitution. The R1699Q substitution lies within alpha helix-2 of the C-terminal BRCT-N transactivation domain. <a href="#159" class="mim-tip-reference" title="Vallon-Christersson, J., Cayanan, C., Haraldsson, K., Loman, N., Bergthorsson, J. T., Brondum-Nielsen, K., Gerdes, A.-M., Moller, P., Kristoffersson, U., Olsson, H., Borg, A., Monteiro, A. N. A. <strong>Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families.</strong> Hum. Molec. Genet. 10: 353-360, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11157798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/10.4.353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157798">Vallon-Christersson et al. (2001)</a> found that BRCA1 with this substitution had wildtype transactivation activity when studied in yeast, but decreased activation when studied in mammalian cells, consistent with a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using mouse embryonic stem cells, <a href="#23" class="mim-tip-reference" title="Chang, S., Wang, R.-H., Akagi, K., Kim, K.-A., Martin, B. K., Cavallone, L., Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Haines, D. C., Basik, M., Mai, P., Poggi, E., Isaacs, C., Looi, L. M., Mun, K. S., Greene, M. H., Byers, S. W., Teo, S. H., Deng, C.-X., Sharan, S. K. <strong>Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155.</strong> Nature Med. 17: 1275-1282, 2011. Note: Erratum: Nature Med. 17: 2 p following 1282, 2011. Erratum: Nature Med. 17: 1521 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21946536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21946536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21946536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21946536">Chang et al. (2011)</a> found that expression of human BRCA1 with the R1699Q substitution reduced embryonic stem cell survival and caused upregulation of microRNA-155 (MIR155; <a href="/entry/609337">609337</a>), which has a role in promoting cell growth and is upregulated in various human cancers. Wildtype BRCA1, but not BRCA1 with the R1699Q substitution, downregulated mouse Mir155 expression by recruiting Hdac2 (<a href="/entry/605164">605164</a>) to the Mir155 promoter, resulting in deacetylation of histones H2a (see <a href="/entry/142720">142720</a>) and H3 (see <a href="/entry/601128">601128</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21946536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs45553935 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs45553935;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs45553935" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs45553935" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000031229 OR RCV000048857 OR RCV000131291 OR RCV000195366 OR RCV000585878" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000031229, RCV000048857, RCV000131291, RCV000195366, RCV000585878" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000031229...</a>
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<p>In a 28-year-old woman with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; <a href="/entry/617883">617883</a>), <a href="#36" class="mim-tip-reference" title="Domchek, S. M., Tang, J., Stopfer, J., Lilli, D. R., Hamel, N., Tischkowitz, M., Monteiro, A. N. A., Messick, T. E., Powers, J., Yonker, A., Couch, F. J., Goldgar, D. E., Davidson, H. R., Nathanson, K. L., Foulkes, W. D., Greenberg, R. A. <strong>Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer.</strong> Cancer Discov. 3: 399-405, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23269703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23269703</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23269703[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1158/2159-8290.CD-12-0421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23269703">Domchek et al. (2012)</a> identified compound heterozygous mutations in the BRCA1 gene: a c.5207T-C transition, resulting in a val1736-to-ala (V1736A) substitution at a conserved residue, and a 1-bp deletion (c.2457delC; <a href="#0039">113705.0039</a>) in exon 11, predicted to result in a frameshift and premature termination (Asp821IlefsTer25). She also carried a heterozygous variant of unknown significance in the BRCA2 gene (c.971G-C, R324T). The patient's mother died of ovarian cancer at age 55; her DNA was not available. A maternal great-aunt with both breast and ovarian cancer (BROVCA1; 604370) carried a heterozygous V1736A mutation, and another maternal great-aunt with peritoneal cancer carried the V1736A mutation and the BRCA2 R324T variant. A heterozygous V1736A mutation was also found in 2 unaffected family members. Tumor tissue from some of the patients with a heterozygous V1736A mutation showed loss of heterozygosity for the wildtype BRCA1 allele, suggesting that the V1736A mutation is pathogenic. Eleven additional pedigrees with BROVCA1 or other types of cancer associated with the V1736A mutation were subsequently ascertained. Segregation analysis yielded a combined odds ratio (OR) of 234:1 in favor of V1736A being pathogenic. In vitro functional expression studies showed that the BRCA1 V1736A variant was a hypomorphic allele, with decreased localization to double-strand breaks and decreased interaction with RAP80 (UIMC1; <a href="/entry/609433">609433</a>) compared to wildtype. No studies of the BRCA2 variant were performed. The paternal line of the proband also had multiple cases of breast cancer, although genetic studies were not performed on most of these individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23269703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80357669 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357669;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs80357669?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357669" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357669" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the 1-bp deletion (c.2457delC) in the BRCA1 gene, predicted to result in a frameshift and premature termination (Asp821IlefsTer25), that was found in compound heterozygous state in a patient with Fanconi anemia complementation group S (FANCS; <a href="/entry/617883">617883</a>) by <a href="#36" class="mim-tip-reference" title="Domchek, S. M., Tang, J., Stopfer, J., Lilli, D. R., Hamel, N., Tischkowitz, M., Monteiro, A. N. A., Messick, T. E., Powers, J., Yonker, A., Couch, F. J., Goldgar, D. E., Davidson, H. R., Nathanson, K. L., Foulkes, W. D., Greenberg, R. A. <strong>Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer.</strong> Cancer Discov. 3: 399-405, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23269703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23269703</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23269703[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1158/2159-8290.CD-12-0421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23269703">Domchek et al. (2012)</a>, see <a href="#0038">113705.0038</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23269703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000048789 OR RCV000077595 OR RCV000131821 OR RCV000148390 OR RCV000159999 OR RCV000191041 OR RCV000239322 OR RCV000457515 OR RCV000585864 OR RCV001357133 OR RCV003128133 OR RCV004804015" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000048789, RCV000077595, RCV000131821, RCV000148390, RCV000159999, RCV000191041, RCV000239322, RCV000457515, RCV000585864, RCV001357133, RCV003128133, RCV004804015" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000048789...</a>
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<p>In a woman, born of unrelated Finnish parents, with Fanconi anemia complementation group S (FANCS; <a href="/entry/617883">617883</a>), <a href="#131" class="mim-tip-reference" title="Sawyer, S. L., Tian, L., Kahkonen, M., Schwartzentruber, J., Kircher, M., University of Washington Centre for Mendelian Genomics, FORGE Canada Consortium, Majewski, J., Dyment, D. A., Innes, A. M., Boycott, K. M., Moreau, L. A., Moilanen, J. S., Greenberg, R. A. <strong>Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype.</strong> Cancer Discov. 5: 135-142, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25472942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25472942</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25472942[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1158/2159-8290.CD-14-1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25472942">Sawyer et al. (2014)</a> identified compound heterozygous mutations in the BRCA1 gene: a c.5095C-T transition (c.5095C-T, NM_007294) in exon 18, resulting in an arg1699-to-trp (R1699W) substitution, and a 4-bp deletion (c.594_597del4; <a href="#0041">113705.0041</a>) in exon 10, predicted to result in a frameshift and premature termination (Ser198ArgfsTer35). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The patient's mother, who carried the 4-bp deletion, had ovarian cancer (BROVCA1; <a href="/entry/604370">604370</a>); her tumor tissue showed loss of heterozygosity (LOH) of the wildtype BRCA1 allele. There was a strong family history of cancer, including ovarian, endometrial, and stomach cancer. Patient lymphocytes showed increased chromosomal breakage and radial chromosome formation compared to controls. Fibroblasts from the proband showed reduced expression of full-length BRCA1 protein, suggesting that the R1699W mutation leads to misfolding and reduced proteolytic stability. RT-PCR analysis suggested that the c.594_597 deletion resulted in nonsense-mediated mRNA decay. Further studies of patient cells showed decreased BRCA1 and RAD51 (<a href="/entry/179617">179617</a>) foci in response to insult, suggesting impaired double-strand break repair function. Ectopic expression of wildtype BRCA1 restored these repair functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25472942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The R1699W mutation had previously been identified in heterozygous state in a Scandinavian family (LUND279) segregating breast and ovarian cancer by <a href="#159" class="mim-tip-reference" title="Vallon-Christersson, J., Cayanan, C., Haraldsson, K., Loman, N., Bergthorsson, J. T., Brondum-Nielsen, K., Gerdes, A.-M., Moller, P., Kristoffersson, U., Olsson, H., Borg, A., Monteiro, A. N. A. <strong>Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families.</strong> Hum. Molec. Genet. 10: 353-360, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11157798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/10.4.353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157798">Vallon-Christersson et al. (2001)</a>. <a href="#159" class="mim-tip-reference" title="Vallon-Christersson, J., Cayanan, C., Haraldsson, K., Loman, N., Bergthorsson, J. T., Brondum-Nielsen, K., Gerdes, A.-M., Moller, P., Kristoffersson, U., Olsson, H., Borg, A., Monteiro, A. N. A. <strong>Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families.</strong> Hum. Molec. Genet. 10: 353-360, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11157798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11157798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11157798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/10.4.353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11157798">Vallon-Christersson et al. (2001)</a> found that BRCA1 with this substitution had wildtype transactivation activity when studied in yeast, but decreased transactivation activity when studied in mammalian cells, consistent with a loss of function. Moreover, the mutant protein was expressed at similar levels as wildtype, ruling out increased instability of the protein as a cause for loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11157798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs797045175 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797045175;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs797045175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs797045175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000191042 OR RCV000258289 OR RCV000585825 OR RCV001024704" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191042, RCV000258289, RCV000585825, RCV001024704" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191042...</a>
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<p>For discussion of the 4-bp deletion (c.594_597del4, NM_007294) in the BRCA1 gene, predicted to result in a frameshift and premature termination (Ser198ArgfsTer35), that was found in compound heterozygous state in a patient with Fanconi anemia complementation group S (FANCS; <a href="/entry/617883">617883</a>) by <a href="#131" class="mim-tip-reference" title="Sawyer, S. L., Tian, L., Kahkonen, M., Schwartzentruber, J., Kircher, M., University of Washington Centre for Mendelian Genomics, FORGE Canada Consortium, Majewski, J., Dyment, D. A., Innes, A. M., Boycott, K. M., Moreau, L. A., Moilanen, J. S., Greenberg, R. A. <strong>Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype.</strong> Cancer Discov. 5: 135-142, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25472942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25472942</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25472942[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1158/2159-8290.CD-14-1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25472942">Sawyer et al. (2014)</a>, see <a href="#0040">113705.0040</a>. Heterozygous carriers of this mutation had increased susceptibility to breast-ovarian cancer (BROVCA1; <a href="/entry/604370">604370</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25472942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555589094 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555589094;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1555589094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1555589094" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000585811 OR RCV000585837 OR RCV001867901 OR RCV004948457" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000585811, RCV000585837, RCV001867901, RCV004948457" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000585811...</a>
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<p>In a 2.5-year-old girl, born of consanguineous Brazilian parents, with Fanconi anemia complementation group S (FANCS; <a href="/entry/617883">617883</a>), <a href="#51" class="mim-tip-reference" title="Freire, B. L., Homma, T. K., Funari, M. F. A., Lerario, A. M., Leal, A. M., Velloso, E. D. R. P., Malaquias, A. C., Jorge, A. A. L. <strong>Homozygous loss of function BRCA1 variant causing a Fanconi-anemia-like phenotype, a clinical report</strong> Europ. J. Med. Genet. 61: 130-133, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29133208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29133208</a>] [<a href="https://doi.org/10.1016/j.ejmg.2017.11.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29133208">Freire et al. (2018)</a> identified a homozygous c.2909T-A transversion (c.2709T-A, NM_007294.3) in exon 10 of the BRCA1 gene, resulting in a cys903-to-ter (C903X) substitution, predicted to result in a complete loss of protein function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in her parents. The variant was not found in the 1000 Genomes Project or gnomAD databases. Patient cells showed increased chromosomal breakage compared to controls. The patient's mother was subsequently screened and found to have breast cancer (BROVCA1; <a href="/entry/604370">604370</a>). There was additional family history of breast cancer on the maternal side. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29133208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#138" class="mim-tip-reference" title="Seo, A., Steinberg-Shemer, O., Unal, S., Casadei, S., Walsh, T., Gumruk, F., Shalev, S., Shimamura, A., Akarsu, N. A., Tamary, H., King, M.-C. <strong>Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1.</strong> Proc. Nat. Acad. Sci. 115: 5241-5246, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29712865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29712865</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29712865[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1801796115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29712865">Seo et al. (2018)</a> noted that the C903X variant occurs in exon 11 of the BRCA1 gene and lies 3-prime to the naturally occurring alternative splice donor in exon 11. Thus, the naturally occurring isoform lacks the C903X mutation, likely accounting for the viability of the patient who is homozygous for a nonsense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29712865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397508838 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397508838;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397508838?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397508838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397508838" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000241007 OR RCV000509759 OR RCV000767397 OR RCV001328427" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000241007, RCV000509759, RCV000767397, RCV001328427" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000241007...</a>
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<p>In 2 sibs, born of consanguineous Arab parents (family A), with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; <a href="/entry/617883">617883</a>), <a href="#138" class="mim-tip-reference" title="Seo, A., Steinberg-Shemer, O., Unal, S., Casadei, S., Walsh, T., Gumruk, F., Shalev, S., Shimamura, A., Akarsu, N. A., Tamary, H., King, M.-C. <strong>Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1.</strong> Proc. Nat. Acad. Sci. 115: 5241-5246, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29712865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29712865</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29712865[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1801796115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29712865">Seo et al. (2018)</a> identified a homozygous c.1115G-A transition (c.1115G-A, NM_007294.3) in exon 11 of the BRCA1 gene, resulting in a trp372-to-ter (W372X) substitution. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family and was demonstrated to be germline rather than somatic in the patients. Homozygosity for the nonsense mutation was viable in these patients due to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5-prime to the mutation and produces 2 short isoforms that lack the residues affected by the mutation. Patient fibroblasts showed no detectable full-length BRCA1 protein, but had protein levels corresponding to one of the normal isoforms that retain some capacity to repair DNA damage and can partially compensate for loss of the full-length protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29712865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80357346 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80357346;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs80357346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs80357346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000111583 OR RCV000767398 OR RCV002381345" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000111583, RCV000767398, RCV002381345" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000111583...</a>
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<p>In 2 sibs, born of consanguineous Turkish parents (family B), with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; <a href="/entry/617883">617883</a>), <a href="#138" class="mim-tip-reference" title="Seo, A., Steinberg-Shemer, O., Unal, S., Casadei, S., Walsh, T., Gumruk, F., Shalev, S., Shimamura, A., Akarsu, N. A., Tamary, H., King, M.-C. <strong>Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1.</strong> Proc. Nat. Acad. Sci. 115: 5241-5246, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29712865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29712865</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29712865[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1801796115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29712865">Seo et al. (2018)</a> identified a homozygous c.1292T-G transversion (c.1292T-G, NM_007294.3) in exon 11 of the BRCA1 gene, resulting in a leu431-to-ter (L431X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was demonstrated to be germline rather than somatic in the patients. Homozygosity for the nonsense mutation was viable in these patients due to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5-prime to the mutation and produces 2 short isoforms that lack the residues affected by the mutation. These alternative isoforms retain some capacity for DNA damage repair and partially compensate for loss of the full-length protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29712865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Albertsen1994" class="mim-tip-reference" title="Albertsen, H., Plaetke, R., Ballard, L., Fujimoto, E., Connolly, J., Lawrence, E., Rodriguez, P., Robertson, M., Bradley, P., Milner, B., Fuhrman, D., Marks, A., Sargent, R., Cartwright, P., Matsunami, N., White, R. <strong>Genetic mapping of the BRCA1 region on chromosome 17q21.</strong> Am. J. Hum. Genet. 54: 516-525, 1994.">Albertsen et al. (1994)</a>; <a href="#Piver1993" class="mim-tip-reference" title="Piver, M. S., Baker, T. R., Jishi, M. F., Sandecki, A. M., Tsukada, Y., Natarajan, N., Mettlin, C. J., Blake, C. A. <strong>Familial ovarian cancer: a report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry 1981-1991.</strong> Cancer 71: 582-588, 1993.">Piver et al. (1993)</a>; <a href="#Puget1999" class="mim-tip-reference" title="Puget, N., Stoppa-Lyonnet, D., Sinilnikova, O. M., Pages, S., Lynch, H. T., Lenoir, G. M., Mazoyer, S. <strong>Screening for germline rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions.</strong> Cancer Res. 59: 455-461, 1999.">Puget et al. (1999)</a>; <a href="#Simard1993" class="mim-tip-reference" title="Simard, J., Feunteun, J., Lenoir, G., Tonin, P., Normand, T., The, V. L., Vivier, A., Lasko, D., Morgan, K., Rouleau, G. A., Lynch, H., Labrie, F., Narod, S. A. <strong>Genetic mapping of the breast-ovarian cancer syndrome to a small interval on chromosome 17q12-21: exclusion of candidate genes EDH17B2 and RARA.</strong> Hum. Molec. Genet. 2: 1193-1199, 1993.">Simard et al. (1993)</a>; <a href="#Sobol1992" class="mim-tip-reference" title="Sobol, H., Mazoyer, S., Narod, S. A., Smith, S. A., Black, D. M., Kerbrat, P., Jamot, B., Solomon, E., Ponder, B. A. J., Guerin, D. <strong>Genetic heterogeneity of early-onset familial breast cancer.</strong> Hum. Genet. 89: 381-383, 1992.">Sobol et al. (1992)</a>; <a href="#Stratton1994" class="mim-tip-reference" title="Stratton, M. R., Ford, D., Neuhasen, S., Seal, S., Wooster, R., Friedman, L. S., King, M.-C., Egilsson, V., Devilee, P., McManus, R., Daly, P. A., Smyth, E., Ponder, B. A. J., Peto, J., Cannon-Albright, L., Easton, D. F., Goldgar, D. E. <strong>Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q.</strong> Nature Genet. 7: 103-107, 1994.">Stratton et al. (1994)</a>
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<strong>Haplotype analysis of a BRCA1:185delAG mutation in a Chilean family supports its Ashkenazi origins.</strong>
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[<a href="https://doi.org/10.1034/j.1399-0004.2002.620208.x" target="_blank">Full Text</a>]
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Al-Sukhni, W., Rothenmund, H., Eppel Borgida, A., Zogopoulos, G., O'Shea, A.-M., Pollett, A., Gallinger, S.
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<strong>Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.</strong>
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Hum. Genet. 124: 271-278, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18762988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18762988</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18762988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-008-0554-0" target="_blank">Full Text</a>]
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Albertsen, H. M., Smith, S. A., Mazoyer, S., Fujimoto, E., Stevens, J., Williams, B., Rodriguez, P., Cropp, C. S., Slijepcevic, P., Carlson, M., Robertson, M., Bradley, P., Lawrence, E., Harrington, T., Mei Sheng, Z., Hoopes, R., Sternberg, N., Brothman, A., Callahan, R., Ponder, B. A. J., White, R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951316</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7951316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0894-472" target="_blank">Full Text</a>]
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Albertsen, H., Plaetke, R., Ballard, L., Fujimoto, E., Connolly, J., Lawrence, E., Rodriguez, P., Robertson, M., Bradley, P., Milner, B., Fuhrman, D., Marks, A., Sargent, R., Cartwright, P., Matsunami, N., White, R.
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<strong>Genetic mapping of the BRCA1 region on chromosome 17q21.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8116621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8116621</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8116621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Andersen, T. I., Borresen, A.-L., Moller, P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755943</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8755943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Anderson, S. F., Schlegel, B. P., Nakajima, T., Wolpin, E. S., Parvin, J. D.
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<strong>BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A.</strong>
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Nature Genet. 19: 254-256, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662397</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662397" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/930" target="_blank">Full Text</a>]
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Arason, A., Barkardottir, R. B., Egilsson, V.
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<strong>Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8460636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8460636</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8460636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bandera, C. A., Muto, M. G., Schorge, J. O., Berkowitz, R. S., Rubin, S. C., Mok, S. C.
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<strong>BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum.</strong>
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Obstet. Gynec. 92: 596-600, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9764635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9764635</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9764635" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0029-7844(98)00223-3" target="_blank">Full Text</a>]
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Bar-Sade, R. B., Kruglikova, A., Modan, B., Gak, E., Hirsh-Yechezkel, G., Theodor, L., Novikov, I., Gershoni-Baruch, R., Risel, S., Papa, M. Z., Ben-Baruch, G., Friedman, E.
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<strong>The 185delAG BRCA1 mutation originated before the dispersion of Jews in the Diaspora and is not limited to Ashkenazim.</strong>
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Hum. Molec. Genet. 7: 801-805, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9536083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9536083</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9536083" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/7.5.801" target="_blank">Full Text</a>]
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Bar-Sade, R. B., Theodor, L., Gak, E., Kruglikova, A., Hirsch-Yechezkel, G., Modan, B., Kuperstein, G., Seligsohn, U., Rechavi, G., Friedman, E.
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<strong>Could the 185delAG BRCA1 mutation be an ancient Jewish mutation?</strong>
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Europ. J. Hum. Genet. 5: 413-416, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9450187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9450187</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9450187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Barker, D. F., Almeida, E. R. A., Casey, G., Fain, P. R., Liao, S. Y., Masunaka, I., Noble, B., Kurosaki, T., Anton-Culver, H.
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<strong>BRCA1 R841W: a strong candidate for a common mutation with moderate phenotype.</strong>
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Genet. Epidemiol. 13: 595-604, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968716</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-2272(1996)13:6<595::AID-GEPI5>3.0.CO;2-#" target="_blank">Full Text</a>]
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Bennett, L. M., Haugen-Strano, A., Cochran, C., Brownlee, H. A., Fiedorek, F. T., Jr., Wiseman, R. W.
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[<a href="https://doi.org/10.1006/geno.1995.9963" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)00030-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/jama.283.17.2260" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21901007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21901007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21901007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21901007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature10371" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Bao Lige - updated : 08/10/2020
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<div class="row collapse" id="mimCollapseContributors">
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Ada Hamosh - updated : 03/27/2020<br>Ada Hamosh - updated : 03/26/2020<br>Bao Lige - updated : 12/18/2019<br>Bao Lige - updated : 06/28/2019<br>Cassandra L. Kniffin - updated : 04/16/2019<br>Ada Hamosh - updated : 01/14/2019<br>Cassandra L. Kniffin - updated : 02/27/2018<br>Ada Hamosh - updated : 02/22/2018<br>Ada Hamosh - updated : 2/4/2016<br>Carol A. Bocchini - updated : 11/10/2015<br>Cassandra L. Kniffin - updated : 6/23/2015<br>Paul J. Converse - updated : 5/29/2015<br>Ada Hamosh - updated : 7/17/2014<br>Patricia A. Hartz - updated : 1/14/2014<br>George E. Tiller - updated : 9/5/2013<br>Patricia A. Hartz - updated : 9/11/2012<br>Patricia A. Hartz - updated : 2/28/2012<br>Ada Hamosh - updated : 11/29/2011<br>Patricia A. Hartz - updated : 10/26/2011<br>Ada Hamosh - updated : 9/21/2011<br>Ada Hamosh - updated : 1/6/2010<br>Ada Hamosh - updated : 8/17/2009<br>Cassandra L. Kniffin - updated : 6/5/2009<br>Patricia A. Hartz - updated : 4/24/2009<br>Patricia A. Hartz - updated : 4/14/2009<br>Cassandra L. Kniffin - updated : 3/30/2009<br>Cassandra L. Kniffin - updated : 2/11/2009<br>Cassandra L. Kniffin - updated : 1/30/2009<br>Cassandra L. Kniffin - updated : 1/22/2009<br>Patricia A. Hartz - updated : 11/24/2008<br>Patricia A. Hartz - updated : 6/5/2008<br>Cassandra L. Kniffin - updated : 5/20/2008<br>Cassandra L. Kniffin - updated : 4/28/2008<br>Cassandra L. Kniffin - updated : 1/8/2008<br>Ada Hamosh - updated : 11/28/2007<br>Cassandra L. Kniffin - updated : 8/27/2007<br>Patricia A. Hartz - updated : 7/6/2007<br>Ada Hamosh - updated : 6/20/2007<br>George E. Tiller - updated : 5/22/2007<br>Victor A. McKusick - updated : 2/21/2007<br>Ada Hamosh - updated : 2/6/2007<br>Stylianos E. Antonarakis - updated : 12/18/2006<br>Patricia A. Hartz - updated : 10/18/2006<br>George E. Tiller - updated : 9/20/2006<br>Marla J. F. O'Neill - updated : 7/6/2006<br>George E. Tiller - updated : 9/30/2005<br>Ada Hamosh - updated : 9/19/2005<br>Patricia A. Hartz - updated : 7/25/2005<br>Patricia A. Hartz - updated : 7/14/2005<br>George E. Tiller - updated : 3/3/2005<br>Patricia A. Hartz - updated : 2/11/2005<br>Ada Hamosh - updated : 1/14/2005<br>George E. Tiller - updated : 12/17/2004<br>Patricia A. Hartz - updated : 9/9/2004<br>George E. Tiller - updated : 4/1/2004<br>Victor A. McKusick - updated : 2/6/2004<br>George E. Tiller - updated : 2/3/2004<br>Ada Hamosh - updated : 11/11/2003<br>Patricia A. Hartz - updated : 10/27/2003<br>Victor A. McKusick - updated : 10/23/2003<br>Victor A. McKusick - updated : 10/1/2003<br>Victor A. McKusick - updated : 8/27/2003<br>Victor A. McKusick - updated : 6/4/2003<br>Victor A. McKusick - updated : 3/12/2003<br>George E. Tiller - updated : 2/20/2003<br>Stylianos E. Antonarakis - updated : 11/26/2002<br>Victor A. McKusick - updated : 11/25/2002<br>Victor A. McKusick - updated : 9/27/2002<br>Victor A. McKusick - updated : 9/17/2002<br>Victor A. McKusick - updated : 8/29/2002<br>Victor A. McKusick - updated : 7/1/2002<br>Victor A. McKusick - updated : 6/12/2002<br>Michael B. Petersen - updated : 4/29/2002<br>Victor A. McKusick - updated : 4/12/2002<br>Victor A. McKusick - updated : 4/12/2002<br>Victor A. McKusick - updated : 2/11/2002<br>Michael B. Petersen - updated : 11/19/2001<br>Victor A. McKusick - updated : 10/9/2001<br>Victor A. McKusick - updated : 8/3/2001<br>Victor A. McKusick - updated : 6/27/2001<br>Victor A. McKusick - updated : 6/25/2001<br>George E. Tiller - updated : 4/24/2001<br>Victor A. McKusick - updated : 3/16/2001<br>Victor A. McKusick - updated : 3/15/2001<br>Stylianos E. Antonarakis - updated : 3/9/2001<br>Victor A. McKusick - updated : 3/8/2001<br>Victor A. McKusick - updated : 3/2/2001<br>Victor A. McKusick - updated : 1/2/2001<br>Victor A. McKusick - updated : 12/19/2000<br>Stylianos E. Antonarakis - updated : 11/27/2000<br>Paul J. Converse - updated : 11/16/2000<br>Paul J. Converse - updated : 11/14/2000<br>Ada Hamosh - updated : 10/19/2000<br>Carol A. Bocchini - updated : 10/3/2000<br>Victor A. McKusick - updated : 9/11/2000<br>Ada Hamosh - updated : 8/18/2000<br>Stylianos E. Antonarakis - updated : 8/8/2000<br>Ada Hamosh - updated : 8/1/2000<br>Victor A. McKusick - updated : 7/26/2000<br>Ada Hamosh - updated : 7/20/2000<br>Ada Hamosh - updated : 7/12/2000<br>Ada Hamosh - updated : 5/31/2000<br>Ada Hamosh - updated : 4/18/2000<br>Michael J. Wright - updated : 3/22/2000<br>Victor A. McKusick - updated : 2/18/2000<br>Victor A. McKusick - updated : 1/11/2000<br>Stylianos E. Antonarakis - updated : 1/7/2000<br>Stylianos E. Antonarakis - updated : 11/19/1999<br>Victor A. McKusick - updated : 11/1/1999<br>Victor A. McKusick - updated : 9/24/1999<br>Ada Hamosh - updated : 9/15/1999<br>John F. Jackson - reorganized : 9/14/1999<br>Wilson H. Y. Lo - updated : 7/16/1999<br>Ada Hamosh - updated : 7/14/1999<br>Stylianos E. Antonarakis - updated : 6/24/1999<br>Stylianos E. Antonarakis - updated : 5/21/1999<br>Ada Hamosh - updated : 5/20/1999<br>Victor A. McKusick - updated : 5/17/1999<br>Ada Hamosh - updated : 3/5/1999<br>Victor A. McKusick - updated : 3/2/1999<br>Victor A. McKusick - updated : 12/7/1998<br>Stylianos E. Antonarakis - updated : 11/10/1998<br>Victor A. McKusick - updated : 10/23/1998<br>Victor A. McKusick - updated : 10/1/1998<br>Victor A. McKusick - updated : 8/21/1998<br>Victor A. McKusick - updated : 8/17/1998<br>Victor A. McKusick - updated : 7/20/1998<br>Victor A. McKusick - updated : 6/23/1998<br>Michael J. Wright - updated : 6/16/1998<br>Victor A. McKusick - updated : 5/22/1998<br>Victor A. McKusick - updated : 5/8/1998<br>Victor A. McKusick - updated : 2/17/1998<br>Victor A. McKusick - updated : 12/18/1997<br>Victor A. McKusick - updated : 10/28/1997<br>Victor A. McKusick - updated : 6/23/1997<br>Victor A. McKusick - updated : 6/16/1997<br>Victor A. McKusick - updated : 6/2/1997<br>Victor A. McKusick - updated : 4/21/1997<br>Victor A. McKusick - updated : 4/15/1997<br>Victor A. McKusick - updated : 4/8/1997<br>Moyra Smith - updated : 3/3/1997<br>Moyra Smith - updated : 12/20/1996<br>Moyra Smith - updated : 12/11/1996<br>Lori M. Kelman - updated : 11/8/1996<br>Moyra Smith - updated : 10/4/1996<br>Stylianos E. Antonarakis - updated : 7/15/1996
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Victor A. McKusick : 12/20/1990
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alopez : 04/17/2024
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carol : 06/08/2023<br>carol : 10/06/2021<br>mgross : 08/10/2020<br>alopez : 03/27/2020<br>alopez : 03/27/2020<br>alopez : 03/26/2020<br>mgross : 12/18/2019<br>mgross : 06/28/2019<br>carol : 04/17/2019<br>carol : 04/16/2019<br>ckniffin : 04/16/2019<br>alopez : 01/14/2019<br>carol : 08/17/2018<br>carol : 03/12/2018<br>carol : 03/08/2018<br>carol : 03/07/2018<br>ckniffin : 02/27/2018<br>carol : 02/23/2018<br>alopez : 02/22/2018<br>carol : 04/25/2017<br>carol : 06/23/2016<br>alopez : 2/4/2016<br>carol : 11/11/2015<br>carol : 11/10/2015<br>joanna : 11/10/2015<br>carol : 6/25/2015<br>carol : 6/24/2015<br>mcolton : 6/23/2015<br>ckniffin : 6/23/2015<br>mgross : 5/29/2015<br>alopez : 3/30/2015<br>carol : 2/18/2015<br>carol : 9/29/2014<br>joanna : 8/14/2014<br>alopez : 7/17/2014<br>mgross : 1/14/2014<br>alopez : 9/5/2013<br>carol : 8/7/2013<br>carol : 4/3/2013<br>mgross : 2/5/2013<br>mgross : 1/11/2013<br>terry : 12/21/2012<br>terry : 12/20/2012<br>terry : 11/28/2012<br>alopez : 11/27/2012<br>terry : 11/9/2012<br>terry : 10/10/2012<br>terry : 10/2/2012<br>mgross : 9/13/2012<br>terry : 9/11/2012<br>terry : 7/13/2012<br>carol : 7/6/2012<br>carol : 7/5/2012<br>mgross : 2/28/2012<br>alopez : 12/16/2011<br>alopez : 11/30/2011<br>terry : 11/29/2011<br>mgross : 10/31/2011<br>mgross : 10/31/2011<br>mgross : 10/31/2011<br>terry : 10/26/2011<br>alopez : 9/21/2011<br>terry : 9/21/2011<br>carol : 6/17/2011<br>wwang : 11/19/2010<br>mgross : 11/3/2010<br>alopez : 10/26/2010<br>terry : 10/4/2010<br>joanna : 7/27/2010<br>alopez : 5/12/2010<br>alopez : 4/9/2010<br>alopez : 1/15/2010<br>carol : 1/12/2010<br>terry : 1/6/2010<br>alopez : 8/19/2009<br>alopez : 8/19/2009<br>terry : 8/17/2009<br>wwang : 6/23/2009<br>wwang : 6/23/2009<br>ckniffin : 6/5/2009<br>terry : 6/3/2009<br>mgross : 4/27/2009<br>terry : 4/24/2009<br>mgross : 4/14/2009<br>wwang : 4/10/2009<br>ckniffin : 3/30/2009<br>wwang : 2/20/2009<br>ckniffin : 2/11/2009<br>carol : 2/9/2009<br>carol : 2/6/2009<br>ckniffin : 1/30/2009<br>ckniffin : 1/30/2009<br>wwang : 1/27/2009<br>ckniffin : 1/22/2009<br>mgross : 12/2/2008<br>terry : 11/24/2008<br>alopez : 6/26/2008<br>terry : 6/5/2008<br>wwang : 5/22/2008<br>ckniffin : 5/20/2008<br>wwang : 5/1/2008<br>ckniffin : 4/28/2008<br>ckniffin : 2/5/2008<br>wwang : 1/28/2008<br>ckniffin : 1/8/2008<br>terry : 12/17/2007<br>alopez : 12/7/2007<br>terry : 11/28/2007<br>ckniffin : 9/10/2007<br>carol : 9/6/2007<br>ckniffin : 8/27/2007<br>mgross : 7/9/2007<br>terry : 7/6/2007<br>alopez : 6/27/2007<br>terry : 6/20/2007<br>wwang : 5/30/2007<br>terry : 5/22/2007<br>alopez : 2/23/2007<br>terry : 2/21/2007<br>alopez : 2/8/2007<br>terry : 2/6/2007<br>mgross : 12/18/2006<br>wwang : 10/20/2006<br>terry : 10/18/2006<br>wwang : 10/16/2006<br>alopez : 9/20/2006<br>wwang : 7/6/2006<br>terry : 6/23/2006<br>alopez : 9/30/2005<br>alopez : 9/20/2005<br>terry : 9/19/2005<br>wwang : 7/28/2005<br>terry : 7/25/2005<br>mgross : 7/14/2005<br>mgross : 4/14/2005<br>terry : 3/16/2005<br>alopez : 3/3/2005<br>mgross : 2/11/2005<br>alopez : 1/18/2005<br>alopez : 1/18/2005<br>terry : 1/14/2005<br>tkritzer : 12/17/2004<br>mgross : 9/9/2004<br>terry : 4/1/2004<br>terry : 3/18/2004<br>carol : 3/17/2004<br>tkritzer : 2/6/2004<br>cwells : 2/3/2004<br>tkritzer : 1/13/2004<br>tkritzer : 11/13/2003<br>terry : 11/11/2003<br>carol : 11/7/2003<br>cwells : 10/31/2003<br>terry : 10/27/2003<br>carol : 10/24/2003<br>cwells : 10/24/2003<br>terry : 10/23/2003<br>tkritzer : 10/3/2003<br>tkritzer : 10/1/2003<br>carol : 10/1/2003<br>carol : 9/12/2003<br>cwells : 9/12/2003<br>terry : 8/27/2003<br>carol : 6/26/2003<br>cwells : 6/9/2003<br>terry : 6/4/2003<br>carol : 4/1/2003<br>tkritzer : 3/25/2003<br>terry : 3/12/2003<br>ckniffin : 3/11/2003<br>cwells : 2/20/2003<br>ckniffin : 1/24/2003<br>terry : 1/6/2003<br>mgross : 11/26/2002<br>mgross : 11/26/2002<br>cwells : 11/25/2002<br>terry : 11/20/2002<br>alopez : 10/1/2002<br>alopez : 9/27/2002<br>mgross : 9/17/2002<br>carol : 9/17/2002<br>tkritzer : 9/6/2002<br>tkritzer : 9/4/2002<br>terry : 8/29/2002<br>carol : 8/5/2002<br>terry : 8/2/2002<br>cwells : 7/23/2002<br>terry : 7/1/2002<br>terry : 6/26/2002<br>cwells : 6/24/2002<br>terry : 6/12/2002<br>cwells : 5/2/2002<br>cwells : 4/29/2002<br>alopez : 4/25/2002<br>cwells : 4/18/2002<br>terry : 4/12/2002<br>terry : 4/12/2002<br>mgross : 4/8/2002<br>alopez : 3/21/2002<br>alopez : 3/12/2002<br>alopez : 2/12/2002<br>terry : 2/12/2002<br>terry : 2/11/2002<br>alopez : 1/16/2002<br>cwells : 11/29/2001<br>cwells : 11/19/2001<br>carol : 11/13/2001<br>mcapotos : 10/24/2001<br>terry : 10/9/2001<br>carol : 9/10/2001<br>cwells : 8/10/2001<br>cwells : 8/7/2001<br>terry : 8/3/2001<br>mgross : 6/27/2001<br>terry : 6/27/2001<br>terry : 6/27/2001<br>terry : 6/25/2001<br>cwells : 6/20/2001<br>cwells : 5/1/2001<br>cwells : 4/24/2001<br>cwells : 4/24/2001<br>mcapotos : 3/27/2001<br>mcapotos : 3/26/2001<br>mcapotos : 3/23/2001<br>mcapotos : 3/23/2001<br>terry : 3/16/2001<br>terry : 3/15/2001<br>carol : 3/12/2001<br>mgross : 3/9/2001<br>cwells : 3/8/2001<br>cwells : 3/8/2001<br>terry : 3/8/2001<br>terry : 3/2/2001<br>mcapotos : 1/22/2001<br>joanna : 1/17/2001<br>carol : 1/2/2001<br>carol : 12/19/2000<br>terry : 12/19/2000<br>mgross : 11/27/2000<br>mgross : 11/16/2000<br>mgross : 11/14/2000<br>mgross : 11/14/2000<br>alopez : 10/19/2000<br>mcapotos : 10/3/2000<br>carol : 10/3/2000<br>mcapotos : 9/27/2000<br>mcapotos : 9/20/2000<br>terry : 9/11/2000<br>alopez : 8/18/2000<br>mgross : 8/8/2000<br>carol : 8/3/2000<br>alopez : 8/1/2000<br>mcapotos : 8/1/2000<br>mcapotos : 7/28/2000<br>mcapotos : 7/28/2000<br>terry : 7/26/2000<br>alopez : 7/24/2000<br>terry : 7/20/2000<br>alopez : 7/12/2000<br>alopez : 5/31/2000<br>alopez : 4/18/2000<br>alopez : 3/22/2000<br>mgross : 3/15/2000<br>terry : 2/18/2000<br>mgross : 2/15/2000<br>terry : 1/11/2000<br>mgross : 1/7/2000<br>terry : 12/2/1999<br>mgross : 11/19/1999<br>alopez : 11/15/1999<br>carol : 11/9/1999<br>terry : 11/1/1999<br>alopez : 10/26/1999<br>terry : 9/24/1999<br>carol : 9/15/1999<br>carol : 9/15/1999<br>carol : 9/14/1999<br>carol : 7/16/1999<br>carol : 7/14/1999<br>carol : 7/14/1999<br>mgross : 6/24/1999<br>mgross : 6/4/1999<br>mgross : 5/25/1999<br>mgross : 5/21/1999<br>mgross : 5/21/1999<br>alopez : 5/20/1999<br>terry : 5/17/1999<br>alopez : 3/5/1999<br>alopez : 3/5/1999<br>terry : 3/2/1999<br>alopez : 2/17/1999<br>carol : 12/11/1998<br>terry : 12/7/1998<br>carol : 11/10/1998<br>dkim : 11/6/1998<br>terry : 10/29/1998<br>terry : 10/29/1998<br>carol : 10/27/1998<br>terry : 10/27/1998<br>terry : 10/23/1998<br>dkim : 10/12/1998<br>carol : 10/6/1998<br>terry : 10/1/1998<br>alopez : 8/21/1998<br>carol : 8/20/1998<br>terry : 8/17/1998<br>dholmes : 7/22/1998<br>dholmes : 7/22/1998<br>terry : 7/20/1998<br>terry : 7/16/1998<br>terry : 7/9/1998<br>alopez : 6/29/1998<br>carol : 6/25/1998<br>terry : 6/23/1998<br>terry : 6/17/1998<br>terry : 6/16/1998<br>terry : 6/3/1998<br>terry : 5/22/1998<br>alopez : 5/14/1998<br>terry : 5/8/1998<br>mark : 3/2/1998<br>terry : 2/17/1998<br>mark : 2/11/1998<br>terry : 2/4/1998<br>mark : 1/10/1998<br>terry : 12/18/1997<br>alopez : 11/17/1997<br>jenny : 10/28/1997<br>terry : 10/28/1997<br>alopez : 8/8/1997<br>mark : 7/16/1997<br>mark : 7/16/1997<br>alopez : 7/10/1997<br>alopez : 7/8/1997<br>mark : 7/8/1997<br>alopez : 7/3/1997<br>alopez : 7/3/1997<br>mark : 7/2/1997<br>jenny : 6/23/1997<br>jenny : 6/23/1997<br>mark : 6/18/1997<br>terry : 6/16/1997<br>terry : 6/5/1997<br>mark : 6/2/1997<br>terry : 6/2/1997<br>mark : 5/16/1997<br>mark : 5/16/1997<br>mark : 4/21/1997<br>jenny : 4/15/1997<br>terry : 4/9/1997<br>jenny : 4/8/1997<br>terry : 4/4/1997<br>mark : 3/3/1997<br>terry : 1/17/1997<br>mark : 12/20/1996<br>terry : 12/16/1996<br>terry : 11/20/1996<br>jamie : 11/20/1996<br>jamie : 11/8/1996<br>mark : 11/7/1996<br>mark : 11/7/1996<br>mark : 10/24/1996<br>mark : 10/5/1996<br>mark : 10/4/1996<br>mark : 9/18/1996<br>mark : 9/10/1996<br>terry : 9/3/1996<br>terry : 8/22/1996<br>mark : 8/10/1996<br>terry : 8/9/1996<br>terry : 8/5/1996<br>carol : 7/15/1996<br>terry : 7/12/1996<br>terry : 7/12/1996<br>mark : 4/27/1996<br>mark : 4/25/1996<br>terry : 4/22/1996<br>mark : 4/19/1996<br>terry : 4/15/1996<br>mark : 3/6/1996<br>terry : 3/4/1996<br>mark : 2/29/1996<br>mark : 2/29/1996<br>terry : 2/26/1996<br>mark : 2/23/1996<br>mark : 2/23/1996<br>terry : 2/19/1996<br>mark : 2/16/1996<br>mark : 2/13/1996<br>mark : 1/25/1996<br>terry : 1/23/1996<br>mark : 12/15/1995<br>terry : 12/13/1995<br>mark : 12/7/1995<br>terry : 12/7/1995<br>terry : 12/7/1995<br>terry : 12/7/1995<br>mark : 11/17/1995<br>terry : 11/16/1995<br>jason : 6/7/1994<br>mimadm : 4/12/1994<br>pfoster : 3/25/1994<br>warfield : 3/23/1994
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<h3>
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<span class="mim-font">
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<strong>*</strong> 113705
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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BRCA1 DNA REPAIR-ASSOCIATED PROTEIN; BRCA1
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</span>
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<h4>
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<span class="mim-font">
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BREAST CANCER 1 GENE
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: BRCA1</em></strong>
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</span>
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</p>
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<p>
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<strong>
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<em>
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Cytogenetic location: 17q21.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 17:43,044,295-43,170,327 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<h4>
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<strong>Gene-Phenotype Relationships</strong>
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<th>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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<th>
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="3">
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<span class="mim-font">
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17q21.31
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<td>
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<span class="mim-font">
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{Breast-ovarian cancer, familial, 1}
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<td>
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<span class="mim-font">
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604370
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<td>
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<span class="mim-font">
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Autosomal dominant; Multifactorial
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</td>
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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{Pancreatic cancer, susceptibility to, 4}
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<span class="mim-font">
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614320
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<span class="mim-font">
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<span class="mim-font">
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3
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<span class="mim-font">
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Fanconi anemia, complementation group S
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</span>
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</td>
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<td>
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<span class="mim-font">
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617883
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</tbody>
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</table>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>BRCA1 plays critical roles in DNA repair, cell cycle checkpoint control, and maintenance of genomic stability. BRCA1 forms several distinct complexes through association with different adaptor proteins, and each complex forms in a mutually exclusive manner (Wang et al., 2009). </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Miki et al. (1994) identified cDNA sequences corresponding to the BRCA1 gene by positional cloning of the region on 17q21 implicated in familial breast-ovarian cancer syndrome (604370). The deduced 1,863-residue protein with zinc finger domains near the N terminus. A 7.8-kb mRNA transcript was identified in testes, thymus, breast and ovary. There appeared to be a complex pattern of alternative splicing. </p><p>Bennett et al. (1995) found that the mouse Brca1 gene shares 75% identity of the coding region with the human sequence at the nucleotide level, whereas the predicted amino acid identity was only 58%. </p><p>Jensen et al. (1996) demonstrated that BRCA1 encodes a 190-kD protein with sequence homology and biochemical analogy to members of the granin protein family, including chromogranin A (118910), chromogranin B (118920), and secretogranin II, also known as chromogranin C (118930). They noted that BRCA2 (600185) also includes a motif similar to the granin consensus at the C terminus of the protein. Both BRCA1 and the granins localize to secretory vesicles, are secreted by a regulated pathway, are posttranslationally glycosylated, and are responsive to hormones. The authors stated that as a regulated secretory protein, BRCA1 appears to function by a mechanism not previously described for tumor suppressor products. As reviewed by Steeg (1996), granins are a family of acidic proteins that bind calcium and aggregate in its presence. Known members of the granin family have been solely neuroendocrine or endocrine in origin; if BRCA1 is a granin it will necessarily expand the protein family boundaries. </p><p>ElShamy and Livingston (2004) identified a splice variant of BRCA1 that incorporates a unique 40-nucleotide first exon, exon 1c, that is located 24 Mb upstream of BRCA1 exons 1a and 1b. The 3-prime end of this cDNA extends 335 nucleotides into intron 11, prompting ElShamy and Livingston (2004) to designate it IRIS for 'in-frame reading of BRCA1 intron 11 splice variant.' The deduced BRCA1-IRIS protein contains 1,399 amino acids. In vitro transcription-translation resulted in a protein with an apparent molecular mass of about 150 kD. Northern blot analysis of fibroblast mRNA detected BRCA1-IRIS at about 4.5 kb. Semiquantitative PCR detected variable and developmentally regulated expression of BRCA1-IRIS and full-length BRCA1 in several adult and fetal human tissues. Unlike full-length BRCA1, BRCA1-IRIS was exclusively chromatin associated, failed to interact with BARD1 in vivo or in vitro, exhibited unique nuclear immunostaining, and coimmunoprecipitated with core DNA replication initiation sites and with replication initiation proteins. Suppression of BRCA1-IRIS hindered DNA replication, whereas overexpression stimulated DNA replication. ElShamy and Livingston (2004) concluded that endogenous BRCA1-IRIS positively influences the DNA replication initiation machinery. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Miki et al. (1994) determined that the BRCA1 gene contains 22 exons spanning about 110 kb of DNA. </p><p>Brown et al. (1996) determined the detailed structure of the BRCA1 genomic region. They showed that this region of chromosome 17 contains a tandem duplication of approximately 30 kb which results in 2 copies of BRCA1 exons 1 and 2, of exons 1 and 3 of the adjacent gene that Brown et al. (1994) designated 1A1-3B (M17S2; 166945), and of a previously reported 295-bp intergenic region. Sequence analysis of the duplicated exons of BRCA1, 1A1-3B, and flanking genomic DNA revealed to Brown et al. (1996) that there was maintenance of exon/intron structure and a high degree of nucleotide sequence identity, which suggested that these duplicated exons are nonprocessed pseudogenes. They noted that these findings could not only confound BRCA1 mutation analysis but have implications for the normal and abnormal regulation of BRCA1 transcription, translation, and function. </p><p>Smith et al. (1996) sequenced 117,143 bp from human chromosome 17 encompassing BRCA1. The 24 exons of BRCA1 spanned an 81-kb region that had an unusually high density of Alu repetitive DNA (41.5%), but a relatively low density (4.8%) of other repetitive sequences. BRCA1 intron lengths ranged in size from 403 bp to 9.2 kb and contained 3 intragenic microsatellite markers located in introns 12, 19, and 20. In addition to BRCA1, the contig contained 2 complete genes which they called RHO7 (601555) and VAT1. RHO7 is a member of the RHO family of GTP binding proteins and VAT1 is an abundant membrane protein of cholinergic synaptic vesicles. The order of genes on the chromosome was found to be: centromere-IFP35 (600735)-VAT1-RHO7-BRCA1-M17S2-telomere. Smith et al. (1996) suggested that these features may contribute to chromosomal instability or changes in transcription. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The BRCA1 gene maps to human chromosome 17q21 (Miki et al., 1994). Albertsen et al. (1994) used simple sequence repeat (SSR) markers to construct a high-resolution genetic map of a 40-cM region around 17q21. For 5 of the markers, genotypes were 'captured' by using an ABI sequencing instrument and stored in a locally developed database as a step toward automated genotyping. In a second report, Albertsen et al. (1994) described construction of a physical map of a 4-cM region containing the BRCA1 gene. The map comprised a contig of 137 overlapping YACs and P1 clones, onto which they had placed 112 PCR markers. They localized more than 20 genes on the map, 10 of which had not been mapped to the region previously, and isolated 30 cDNA clones representing partial sequences of as yet unidentified genes. They failed to find any deleterious mutations on sequencing of 2 genes that lie within a narrow region defined by meiotic breakpoints in BRCA1 patients. O'Connell et al. (1994) developed a radiation hybrid map of the BRCA1 region as the basis of YAC cloning and pulsed field gel electrophoretic mapping of the candidate region for the BRCA1 gene. </p><p>Xu et al. (1997) determined that the NBR2 gene (618708) is located between the BRCA1 gene and the pseudo-BRCA1 genes and is aligned in a head-to-head orientation with BRCA1. The transcriptional start sites of NBR2 and BRCA1 are separated by 218 bp. Suen et al. (2005) reported that the NBR2 and BRCA1 genes share a 56-bp segment between them as a bidirectional promoter. </p><p>By an intersubspecific backcross using a DNA sequence variant in the Brca1 locus, Bennett et al. (1995) mapped the Brca1 gene to distal mouse chromosome 11 in a region of extensive homology of synteny to human chromosome 17. </p><p>Schrock et al. (1996) mapped the Brca1 gene to mouse chromosome 11, specifically 11D. DeGregorio et al. (1996) mapped the gene to mouse chromosome 11. </p><p><strong><em>Pseudogene</em></strong></p><p>
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The 5-prime end of the BRCA1 gene lies within a duplicated region on chromosome 17q21. This region contains BRCA1 exons 1A, 1B, and 2 and their surrounding introns; as a result, a BRCA1 pseudogene lies upstream of BRCA1. Puget et al. (2002) found extensive homology between the tandemly situated BRCA1 and its pseudogene. Exon 1A of BRCA1 and of the pseudogene were 44.5 kb apart. Distinct homologous recombination events had occurred between intron 2 of BRCA1 and intron 2 of the BRCA1 pseudogene, leading to 37-kb deletions. These breakpoint junctions were found to be located at close but distinct sites within segments that are 98% identical. The mutant alleles lack the BRCA1 promoter and harbor a chimeric gene consisting of pseudogene exons 1A, 1B, and 2, which lacks the initiation codon, fused to BRCA1 exons 3-24. This represented a new mutational mechanism for the BRCA1 gene. The presence of a large region homologous to BRCA1 on the same chromosome appeared to constitute a hotspot for recombination. Brown et al. (2002) likewise identified a deletion consistent with recombination between BRCA1 and the BRCA1 pseudogene. In germline BRCA1, a promoter deletion was found in 1 of 60 familial breast cancer patients from the Australian population. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Thompson et al. (1995) found that BRCA1 mRNA levels were markedly decreased during the transition from carcinoma in situ to invasive cancer in sporadic breast cancer. Experimental inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells but had no effect on nonmammary epithelial cells. The results suggested that BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth and that this function is compromised in breast cancer either by direct mutation or by alterations in gene expression. </p><p>Chen et al. (1995) identified the BRCA1 gene product as a 220-kD nuclear phosphoprotein in normal cells, including breast ductal epithelial cells, and in 18 of 20 tumor cell lines derived from tissues other than breast and ovary. However, in 16 of 17 breast and ovarian cancer lines and in 17 of 17 samples of cells obtained from malignant effusions, BRCA1 localized mainly in the cytoplasm. Absence of BRCA1 or aberrant subcellular location was also observed to a variable extent in histologic sections of many breast cancer biopsies. The findings suggested to the authors that BRCA1 abnormalities may be involved in the pathogenesis of many breast cancers, sporadic as well as familial. Scully et al. (1996), however, reported results that did not support the hypothesis that wildtype BRCA1 is specifically excluded from the nucleus in sporadic breast and ovarian cancer. </p><p>Coene et al. (1997) reported a well-defined localization of BRCA1 in the perinuclear compartment of the endoplasmic reticulum-Golgi complex and in tubes invaginating the nucleus. The nuclear detection was fixation dependent, which helped to explain the controversial findings previously reported. The nuclear tubes were not seen in every cell, and therefore the authors suggested that an involvement in the cell cycle was possible. These tubes probably enhance nuclear-cytoplasmic interactions by increasing the surface area. </p><p>Chen et al. (1996) raised mouse polyclonal antibodies to 3 regions of the human BRCA1 protein and confirmed their earlier finding of a 220-kD nuclear phosphoprotein. They reported that expression and phosphorylation of the BRCA1 gene and protein are cell cycle dependent in a synchronized population of bladder carcinoma cells. The greatest levels of both expression and phosphorylation occurred in S and M phases. </p><p>Chen et al. (1998) used mammalian expression vectors to transfect cells with BRCA1 and BRCA2 as well as with several antibodies to recognize these proteins in order to study their subcellular localizations. They showed that BRCA1 and BRCA2 coexist in a biochemical complex and colocalize in subnuclear foci in somatic cells and on the axial elements of developing synaptonemal complexes. Like BRCA1 and RAD51 (179617), BRCA2 relocates to replication sites following exposure of S phase cells to hydroxyurea or UV irradiation. Thus, BRCA1 and BRCA2 participate together in a pathway (or pathways) associated with the activation of double-strand break repair and/or homologous recombination. Dysfunction of this pathway may be a general phenomenon in the majority of cases of hereditary breast and/or ovarian cancer. </p><p>Zhong et al. (1999) showed that BRCA1 interacts in vitro and in vivo with RAD50 (604040), which forms a complex with MRE11 (600814) and p95/nibrin (NBS1; 602667). Upon irradiation, BRCA1 was detected in the nucleus, in discrete foci which colocalize with RAD50. Formation of irradiation-induced foci positive for BRCA1, RAD50, MRE11, or p95 was dramatically reduced in HCC/1937 breast cancer cells carrying a homozygous mutation in BRCA1 but was restored by transfection of wildtype BRCA1. Ectopic expression of wildtype, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent methyl methanesulfonate. These data suggested to the authors that BRCA1 is important for the cellular responses to DNA damage that are mediated by the RAD50-MRE11-p95 complex. </p><p>Holt et al. (1996) demonstrated that retroviral transfer of the wildtype BRCA1 gene inhibits growth in vitro of all breast cancer and ovarian cancer cell lines tested, but not colon or lung cancer cells or fibroblasts. Mutant BRCA1, however, had no effect on growth of breast cancer cells; ovarian cancer cell growth was not affected by BRCA1 mutations in the 5-prime portion of the gene but was inhibited by 3-prime BRCA1 mutations. Development of MCF-7 tumors in nude mice was inhibited when MCF-7 cells were transfected with wildtype, but not mutant, BRCA1. Among mice with established MCF-7 tumors, peritoneal treatment with a retroviral vector expressing wildtype BRCA1 significantly inhibited tumor growth and increased survival. The results of Holt et al. (1996) were consistent with the previous observation that the site of BRCA1 mutation is associated with relative susceptibility to ovarian versus breast cancer. </p><p>To identify downstream target genes of BRCA1, Harkin et al. (1999) established cell lines with tightly regulated inducible expression of the BRCA1 gene. High-density oligonucleotide arrays were used to analyze gene expression profiles at various times following BRCA1 induction. A major target of BRCA1 is the DNA damage-inducible gene GADD45 (126335). Induction of BRCA1 triggers apoptosis through activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK; see 601158), a signaling pathway potentially linked to GADD45 gene family members. </p><p>Lorick et al. (1999) showed that like other RING finger proteins, the N-terminal 788 amino acids of BRCA1 expressed as a GST fusion protein facilitated E2-dependent ubiquitination. The authors noted that RING mutations in BRCA1 are associated with familial carcinomas. </p><p>In an effort to understand the function of BRCA1, Wu et al. (1996) used a yeast 2-hybrid system to identify proteins that associate with BRCA1 in vivo. This analysis led to the identification of BARD1 (601593), a novel protein that interacts with the N-terminal region of BRCA1. </p><p>By Western and immunofluorescence analyses in synchronized T24 bladder cancer cells, Jin et al. (1997) studied the expression patterns of the BARD1 and BRCA1 proteins. They found that the steady-state levels of BARD1, unlike those of BRCA1, remain relatively constant during cell cycle progression. However, immunostaining revealed that BARD1 resides within BRCA1 nuclear dots during S phase of the cell cycle, but not during the G1 phase. Nevertheless, BARD1 polypeptides are found exclusively in the nuclear fractions of both G1- and S-phase cells. Therefore, progression to S phase is accompanied by the aggregation of nuclear BARD1 polypeptides into BRCA1 nuclear dots. This cell cycle-dependent colocalization of BARD1 and BRCA1 indicates a role for BARD1 in BRCA1-mediated tumor suppression. </p><p>Scully et al. (1997) found that the BRCA1 gene product is a component of the RNA polymerase II holoenzyme (polII) by several criteria. BRCA1 was found to copurify with the holoenzyme over multiple chromatographic steps. Other tested transcription activators that could potentially contact the holoenzyme were not stably associated with the holoenzyme as determined by copurification. Antibody specific for the holoenzyme component SRB7 specifically purified BRCA1. (SRB proteins are a key component of the holoenzyme and were discovered in a yeast genetic screen as suppressors of RNA polymerase B mutations; hence, the designation SRB. A benign difference is that SRB proteins bind to the C-terminal domain of yeast polII and are found only in the polII holoenzyme.) Immunopurification of BRCA1 complexes also specifically purified transcriptionally active RNA polII and transcription factors TFIIF (see 189968), TFIIE (see 189962), and TFIIH (see 189972), which are known components of the holoenzyme. Moreover, a BRCA1 domain, which is deleted in about 90% of clinically relevant mutations, participated in binding to the holoenzyme complex in cells. These data were considered consistent with other data identifying transcription activation domains in the BRCA1 protein, and link the BRCA1 tumor suppressor protein with the transcription process as a holoenzyme-bound protein. </p><p>RNA helicase A, or RHA (140 kD), was identified by Lee and Hurwitz (1993) and Zhang and Grosse (1997) as a helicase of unknown function with homology to the Drosophila 'maleless' gene, which functions to increase expression of genes from the male X chromosome. Anderson et al. (1998) showed that RHA protein links BRCA1 to the holoenzyme complex. These results were the first to identify specific protein interaction with the BRCA1 C-terminal domain and were consistent with the model that BRCA1 functions as a transcriptional coactivator. </p><p>Association of the BRCA1 protein with the DNA repair gene RAD51 (179617) and changes in the phosphorylation and cellular localization of the protein after exposure to DNA-damaging agents are consistent with a role for BRCA1 in DNA repair. Although Gowen et al. (1998) reported that mouse embryonic stem cells deficient in BRCA1 are defective in the ability to carry out transcription-coupled repair of oxidative DNA damage and are hypersensitive to ionizing radiation and hydrogen peroxide, this article was later retracted because of the possibility of 'fabricated and falsified research findings' by one of the authors (Gowen et al., 2003). </p><p>Using transient transfection assays, Fan et al. (1999) demonstrated that BRCA1 inhibits signaling by the ligand-activated estrogen receptor ER-alpha (ESR1; 133430) through the estrogen-responsive enhancer element and blocks the C-terminal transcriptional activation function AF2 of ER-alpha. These results suggested that wildtype BRCA1 protein may function, in part, to suppress estrogen-dependent mammary epithelial proliferation by inhibiting ER-alpha mediated transcriptional pathways related to cell proliferation, and that loss of this ability may contribute to tumorigenesis. </p><p>Scully et al. (1999) found that retrovirally expressed wildtype BRCA1 decreased the gamma irradiation (IR) sensitivity and increased the efficiency of double-strand DNA break repair of the BRCA1 -/- human breast cancer line, HCC1937. It also reduced the susceptibility of the cells to double-strand DNA break generation by IR. In contrast, multiple clinically validated BRCA1 products with missense mutations were nonfunctional in these assays. These data constituted the basis for a BRCA1 functional assay and suggested that efficient repair of double-strand DNA breaks is linked to BRCA1 tumor suppression. </p><p>BRCA1 contains a C-terminal domain (BRCT) that is shared with several other proteins involved in maintaining genome integrity. In an effort to understand the function of BRCA1, Yarden and Brody (1999) sought to isolate proteins that interact with the BRCT domain. Purified BRCT polypeptide was used as a probe to screen a human placenta cDNA expression library by Far Western analysis. The authors reported that BRCA1 interacts in vivo and in vitro with the Rb-binding proteins RbAp46 (RBBP7; 300825) and RbAp48 (RBBP4; 602923), as well as with Rb (RB1; 614041). Moreover, the BRCT domain associated with the histone deacetylases HDAC1 (601241) and HDAC2 (605164). These results demonstrated that BRCA1 interacts with components of the histone deacetylase complex, and therefore may explain the involvement of BRCA1 in multiple processes such as transcription, DNA repair, and recombination. </p><p>Lee et al. (2000) reported that CHK2 (604373) regulates BRCA1 function after DNA damage by phosphorylating serine-988 of BRCA1. Lee et al. (2000) demonstrated that CHK2 and BRCA1 interact and colocalize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine-988 is required for the release of BRCA1 from CHK2. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937. However, BRCA1 phosphorylation may be complicated. For example, Cortez et al. (1999) demonstrated that ATM (607585) can phosphorylate serines at positions 1423 and 1524 of BRCA1 after a high dose of gamma radiation. In addition, Ruffner et al. (1999) demonstrated that CDK2 (116953) phosphorylated serine-1497 during the G1/S phase of cell cycle. Phosphorylation of the different serine residues is likely to have different effects on BRCA1 function. </p><p>Maor et al. (2000) cotransfected a luciferase reporter gene under the control of the insulin-like growth factor-1 receptor (IGF1R; 147370) promoter with a wildtype BRCA1-encoding expression vector into multiple cell lines. They observed a significant reduction in luciferase activity in all 3 cell lines tested, demonstrating suppression of promoter activity by BRCA1 in a dose-dependent manner. Functional interaction between BRCA1 and SP1 (189906) in the regulation of the IGF1R gene was studied in Schneider cells, a Drosophila cell line which lacks endogenous SP1. In these cells, BRCA1 suppressed 45% of the SP1-induced trans-activation of the IGF1R promoter. Maor et al. (2000) concluded that BRCA1 is capable of suppressing the IGF1R promoter in a number of cell lines, resulting in low levels of receptor mRNA protein. Maor et al. (2000) hypothesized that mutant versions of BRCA1 lacking trans-activational activity can potentially derepress the IGF1R promoter. Activation of the overexpressed receptor by locally produced or circulating IGFs may elicit a myogenic event which may be a key mechanism in the etiology of breast and ovarian cancer. </p><p>Li et al. (2000) demonstrated that the BRCA1-associated protein CTIP (604124) becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase ATM (see 607585). ATM phosphorylates CTIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CTIP, resulting in persistent repression of BRCA1-dependent induction of GADD45 upon ionizing radiation. Li et al. (2000) concluded that ATM, by phosphorylating CTIP upon ionizing radiation, may modulate BRCA1-mediated regulation of the DNA damage-response GADD45 gene, thus providing a potential link between ATM deficiency and breast cancer. </p><p>Using human and mouse expression plasmids in several protein interaction assays, Sum et al. (2002) identified CTIP and BRCA1 as LMO4 (603129)-binding proteins. The LMO4-BRCA1 interaction required the C-terminal BRCT domains of BRCA1. LDB1 (603451) also associated with a complex containing LMO4, CTIP, and BRCA1 in transfected human embryonic kidney cells. In functional assays, LMO4 repressed BRCA1-mediated transcriptional activation in both yeast and mammalian cells. </p><p>Huttley et al. (2000) used phylogeny-based maximum likelihood analysis of the BRCA1 sequences from primates and other animals and found that the ratios of replacement to silent nucleotide substitutions on the human and chimpanzee lineages were not different from one another but were different from those of other primate lineages, and were greater than 1. This is consistent with the historic occurrence of positive darwinian selection pressure on the BRCA1 protein in the human and chimpanzee lineages. Analysis of genetic variation in a sample of female Australians of northern European origin showed evidence for Hardy-Weinberg disequilibrium at polymorphic sites in BRCA1, consistent with the possibility that natural selection is affecting genotype frequencies in modern Europeans. The clustering of between-species variation in the region of the gene encoding the RAD51-interacting domain of BRCA1 suggests the maintenance of genomic integrity as a possible target of selection. </p><p>Using a combination of affinity- and conventional chromatographic techniques, Bochar et al. (2000) isolated a predominant form of a multiprotein BRCA1-containing complex from human cells displaying chromatin-remodeling activity. Mass spectrometric sequencing of components of this complex indicated that BRCA1 is associated with a SWI/SNF-related complex, and the authors showed that BRCA1 can directly interact with the BRG1 (SMARCA4; 603254) subunit of the SWI/SNF complex. Moreover, p53 (TP53; 191170)-mediated stimulation of transcription by BRCA1 was completely abrogated by either a dominant-negative mutant of BRG1 (Khavari et al., 1993) or the cancer-causing deletion of exon 11 of BRCA1 (Xu et al., 1999). These findings revealed a direct function for BRCA1 in transcriptional control through modulation of chromatin structure. </p><p>Ye et al. (2001) found that BRCA1 induced large-scale chromatin decondensation in Chinese hamster ovary cells. COBRA1 (611180) bound one of the chromatin-unfolding domains of BRCA1, and by itself COBRA1 induced large-scale chromatin decondensation. </p><p>Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM, BLM (604610), MSH2 (609309), MSH6 (600678), MLH1 (120436), the RAD50-MRE11-NBS1 complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Confocal microscopy demonstrated that BRCA1, BLM, and the RAD50-MRE11-NBS1 complex colocalize to large nuclear foci. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. </p><p>BRCA1 is implicated in the transcriptional regulation of DNA damage-inducible genes that function in cell cycle arrest. To explore the mechanistic basis for this regulation, Zheng et al. (2000) performed a yeast 2-hybrid screen for proteins associated with BRCA1 and isolated a cDNA encoding ZBRK1 (605422). ZBRK1 binds to a specific sequence, GGGxxxCAGxxxTTT, within GADD45 (126335) intron 3 that supports the assembly of a nuclear complex minimally containing both ZBRK1 and BRCA1. Through this recognition sequence, ZBRK1 represses transcription in a BRCA1-dependent manner. The results revealed a novel corepressor function for BRCA1 and provided a mechanistic basis for the biologic activity of BRCA1 through sequence-specific transcriptional regulation. </p><p>The nonsense-mediated mRNA decay pathway minimizes the potential damage caused by nonsense mutations. In-frame nonsense codons located at a minimum distance upstream of the last exon-exon junction are recognized as premature termination codons, targeting the mRNA for degradation. Some nonsense mutations cause skipping of one or more exons, presumably during pre-mRNA splicing in the nucleus; this phenomenon is termed nonsense-mediated altered splicing (NAS). By analyzing NAS in BRCA1, Liu et al. (2001) showed that inappropriate exon skipping can be reproduced in vitro and that it results from disruption of a splicing enhancer in the coding sequence. Enhancers can be disrupted by a single nonsense, missense, or translationally silent point mutation, without recognition of an open reading frame as such. These results argued against a nuclear reading-frame scanning mechanism for NAS. Coding region single-nucleotide polymorphisms within exonic splicing enhancers or silencers may affect the patterns or efficiency of mRNA splicing, which may in turn cause phenotypic variability and variable penetrance of mutations elsewhere in a gene. </p><p>Hedenfalk et al. (2001) used microarray technology to determine gene-expression profiles in BRCA1-positive breast cancers as contrasted with BRCA2-positive breast cancers. The suspicion that a difference might be found came from the fact that the 2 types of tumors are often histologically distinctive. Furthermore, tumors with BRCA1 mutations are generally negative for both estrogen and progesterone receptors, whereas most tumors with BRCA2 mutations are positive for these hormone receptors. RNA from samples of primary tumors from 7 carriers of the BRCA1 mutation and 7 carriers of the BRCA2 mutation was compared with a microarray of 6,512 cDNA clones of 5,361 genes. The authors found that significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. </p><p>Garcia-Higuera et al. (2001) showed that a nuclear complex containing the FANCA (607139), FANCC (227645), FANCF (603467), and FANCG (602956) proteins is required for the activation of the FANCD2 protein (613984) to a monoubiquitinated isoform. In normal cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots). Activated FANCD2 protein colocalizes with BRCA1 in ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. The authors concluded that the FANCD2 protein therefore provides the missing link between the Fanconi anemia (FA) protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all subtypes of Fanconi anemia (see 227650). </p><p>The Fanconi anemia nuclear complex (composed of the FA proteins A, C, G, and F) is essential for protection against chromosome breakage. It activates the downstream protein FANCD2 by monoubiquitylation; this then forges an association with the BRCA1 protein at sites of DNA damage. Pace et al. (2002) showed that the FANCE (600901) protein is part of this nuclear complex, binding both FANCC and FANCD2. Indeed, FANCE is required for the nuclear accumulation of FANCC and provides a critical bridge between the FA complex and FANCD2. Disease-associated FANCC mutants do not bind to FANCE, cannot accumulate in the nucleus and are unable to prevent chromosome breakage. </p><p>Paull et al. (2001) demonstrated that recombinant human BRCA1 protein binds strongly to DNA, an activity conferred by a domain in the center of the BRCA1 polypeptide. As a result of this binding, BRCA1 inhibits the nucleolytic activity of the MRE11/RAD50/NBS1 complex, an enzyme implicated in numerous aspects of double-strand break repair. BRCA1 displays a preference for branched DNA structures and forms protein-DNA complexes cooperatively between multiple DNA strands, but without DNA sequence specificity. </p><p>Mutations in the TP53 tumor suppressor gene (191170) are found in 70 to 80% of BRCA1-mutated breast cancers but only 30% of those with wildtype BRCA1 (Schuyer and Berns, 1999). The p53 protein regulates nucleotide excision repair (NER) through transcriptional regulation of genes involved in the recognition of adducts in genomic DNA. Loss of p53 function, as in Li-Fraumeni syndrome (151623), results in deficient global genomic repair (GGR), a subset of NER that targets and removes lesions from the whole genome (Ford and Hanawalt (1995, 1997)). Hartman and Ford (2002) showed that BRCA1 specifically enhances the GGR pathway, independent of p53, and can induce p53-independent expression of the NER genes XPC (613208), DDB2 (600811), and GADD45. Defects in the NER pathway in BRCA1-associated breast cancers may be causal in tumor development, suggesting a multistep model of carcinogenesis. </p><p>Yarden et al. (2002) showed that BRCA1 is essential for activating the Chk1 kinase (603078) that regulates DNA damage-induced G2/M arrest. BRCA1 controls the expression, phosphorylation, and cellular localization of Cdc25C (157680) and Cdc2/cyclin B kinase (116940)--proteins that are crucial for the G2/M transition. Since BRCA1 regulates key effectors that control the G2/M checkpoint, it is involved in regulating the onset of mitosis. </p><p>Ganesan et al. (2002) found that BRCA1 colocalized with markers of the inactive X chromosome (Xi) on Xi in female somatic cells and associated with XIST (314670) RNA, as detected by chromatin immunoprecipitation. Breast and ovarian carcinoma cells lacking BRCA1 showed evidence of defects in Xi chromatin structure. Reconstitution of BRCA1-deficient cells with wildtype BRCA1 led to the appearance of focal XIST RNA staining without altering XIST abundance. Inhibiting BRCA1 synthesis in a suitable reporter line led to increased expression of an otherwise silenced Xi-located GFP transgene. These observations suggested that loss of BRCA1 in female cells may lead to Xi perturbation and destabilization of its silenced state. </p><p>Folias et al. (2002) used yeast 2-hybrid analysis and coimmunoprecipitation methods to demonstrate a direct interaction between the FANCA and BRCA1 proteins. Direct interaction with other FANC proteins was not demonstrable. The amino terminal portion of FANCA and the central part (amino acids 740-1,083) of BRCA1 contained the sites of interaction. The interaction did not depend on DNA damage, suggesting that FANCA and BRCA1 may be constitutively interacting. </p><p>Yu et al. (2003) demonstrated that the BRCA1 BRCT domain directly interacts with phosphorylated BRCA1-associated carboxyl-terminal helicase (BACH1; 602751). The specific interaction between BRCA1 and phosphorylated BACH1 is cell cycle regulated and is required for DNA damage-induced checkpoint control during the transition from G2 to M phase of the cell cycle. Further, Yu et al. (2003) showed that 2 other BRCT domains interact with their respective physiologic partners in a phosphorylation-dependent manner. Thirteen additional BRCT domains also preferentially bind phosphopeptides rather than nonphosphorylated control peptides. Yu et al. (2003) concluded that their data implied that the BRCT domain is a phosphoprotein binding domain involved in cell cycle control. </p><p>Dong et al. (2003) isolated a holoenzyme complex containing BRCA1, BRCA2, BARD1 (601593), and RAD51 (179617), which they called the BRCA1- and BRCA2-containing complex (BRCC). The complex showed UBC5 (see UBE2D1; 602961)-dependent ubiquitin E3 ligase activity. Inclusion of BRE (610497) and BRCC3 (300617) enhanced ubiquitination by the complex, and cancer-associated truncations in BRCA1 reduced the association of BRE and BRCC3 with the complex. RNA interference of BRE and BRCC3 in HeLa cells increased cell sensitivity to ionizing radiation and resulted in a defect in G2/M checkpoint arrest. Dong et al. (2003) concluded that the BRCC is a ubiquitin E3 ligase that enhances cellular survival following DNA damage. </p><p>Deng and Wang (2003) discussed the functions of BRCA1 in DNA damage repair and cellular responses that link development and cancer. </p><p>Morris and Solomon (2004) demonstrated an association of cellular BRCA1 with conjugated ubiquitin. The association was apparent at DNA replication structures in S-phase, following treatment with hydroxyurea, and at sites of double-strand break repair after exposure to ionizing radiation. Downregulation of endogenous, cellular BRCA1:BARD1 using siRNA resulted in abrogation of ubiquitin conjugation in these structures, suggesting that heterodimer activity may be required for their formation. Conversely, ectopically expressed full-length BRCA1, but not BRCA1 bearing specific N-terminal amino acid substitutions, was able to cooperate with BARD1 to increase ubiquitin conjugation in cells. Conjugation of ubiquitin in foci was inhibited by the expression of ubiquitin bearing a lysine-6 mutation, suggesting that the ubiquitin polymers formed at these sites may be dependent on lysine-6 for linkage. The authors concluded that BRCA1-directed ligation of ubiquitin occurs during S-phase and in response to replication stress and DNA damage. </p><p>Furuta et al. (2005) found that reduction of BRCA1 by RNA interference enhanced proliferation and impaired acinus formation in a normal human mammary epithelial cell line. Depletion of BRCA1 upregulated the expression of genes involved in proliferation and downregulated genes involved in differentiation. The C-terminal BRCT domain of BRCA1 appeared to be necessary to induce differentiation. Growth medium that was conditioned by differentiating normal mammary epithelial cells could induce differentiation in breast cancer cells with reduced BRCA1 function. Furuta et al. (2005) concluded that BRCA1 is involved in secretion of certain paracrine/autocrine factors that induce mammary epithelial cell differentiation in response to extracellular matrix signals. </p><p>Farmer et al. (2005) showed that BRCA1 or BRCA2 (600185) dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP (173870) enzymatic activity, resulting in chromosomal instability, cell cycle arrest, and subsequent apoptosis. The authors suggested that this seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. Farmer et al. (2005) concluded that their results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer. </p><p>Joukov et al. (2006) found that the heterodimeric tumor suppressor complex BRCA1/BARD1 was required for mitotic spindle-pole assembly and for accumulation of TPX2 (605917), a major spindle organizer, on spindle poles in both HeLa cells and Xenopus egg extracts. This BRCA1/BARD1 function was centrosome independent, operated downstream of Ran GTPase (601179), and depended upon BRCA1/BARD1 E3 ubiquitin ligase activity. Joukov et al. (2006) concluded that BRCA1/BARD1 function in mitotic spindle assembly likely contributes to its role in chromosome stability control and tumor suppression. </p><p>The BRCT repeats of the breast and ovarian cancer predisposition protein BRCA1 are essential for tumor suppression. Using phosphopeptide affinity proteomic analysis, Wang et al. (2007) identified a protein, Abraxas (ABRA1; 611143), that directly binds to the BRCA1 BRCT repeats through a phospho-ser-X-X-phe motif. Abraxas binds BRCA1 to the mutual exclusion of BACH1 (602751) and CTIP (604124), forming a third type of BRCA1 complex. Abraxas recruits the ubiquitin-interacting motif (UIM)-containing protein RAP80 (609433) to BRCA1. Both Abraxas and RAP80 were required for DNA damage resistance, G2/M checkpoint control, and DNA repair. RAP80 was required for optimal accumulation of BRCA1 on damaged DNA (foci) in response to ionizing radiation, and the UIM domains alone were capable of foci formation. Wang et al. (2007) concluded that the RAP80-Abraxas complex may help recruit BRCA1 to DNA damage sites in part through recognition of ubiquitinated proteins. </p><p>Sobhian et al. (2007) reported the interaction of the BRCA1 BRCT domain with RAP80, a ubiquitin-binding protein. RAP80 targets a complex containing the BRCA1-BARD1 (601593) E3 ligase and the deubiquitinating enzyme BRCC36 (300617) to MDC1 (607593)-gamma-H2AX (601772)-dependent lys6- and lys63-linked ubiquitin polymers at double-strand breaks. Sobhian et al. (2007) stated that these events are required for cell cycle checkpoint and repair response to ionizing radiation, implicating ubiquitin chain recognition and turnover in the BRCA1-mediated repair of double-strand breaks. </p><p>Kim et al. (2007) independently reported the identification of RAP80 as a BRCA1-interacting protein in humans. RAP80 contains a tandem UIM domain, which is required for its binding with ubiquitin in vitro and its damage-induced foci formation in vivo. Moreover, Kim et al. (2007) showed that RAP80 specifically recruits BRCA1 to DNA damage sites and functions with BRCA1 in G2/M checkpoint control. Kim et al. (2007) concluded that taken together, their results suggested the existence of ubiquitination-dependent signaling pathway involved in the DNA damage response. </p><p>Wang et al. (2008) found lower expression of SIRT1 (604479) in mouse and human BRCA1-associated breast cancers compared with controls. Reduced Sirt1 expression in Brca1-mutant mice was associated with increased expression of survivin (BIRC5; 603352), and this expression pattern as reversed by induced expression of Brca1. Wang et al. (2008) showed that BRCA1 bound to the SIRT1 promoter and increased SIRT1 expression, which in turn inhibited survivin expression. Furthermore, inhibition of Brca1-mutant tumor growth by the anticancer agent resveratrol was associated with upregulation of Sirt1 activity, followed by reduction in survivin and apoptosis of the tumor cells. </p><p>Using gene conformation analysis with BRCA1 from human breast cancer cell lines and mouse mammary tissue, Tan-Wong et al. (2008) found that chromatin loops were imposed on the BRCA1 gene by the juxtaposition of the promoter and 3-prime terminator regions in addition to internal sequences. The repressed BRCA1 conformation was predicted to resemble a 4-leaf clover. The interaction between the BRCA1 promoter and terminator regions was lost upon estrogen stimulation and during lactation development in the mouse. This activated conformation was predicted to have 3 loops and a long 3-prime tail. Loop formation was transcription-dependent, and the terminator region suppressed estrogen-induced transcription. Tan-Wong et al. (2008) also found that BRCA1 promoter and terminator interactions varied in different breast cancer cell lines. The authors concluded that estrogen-induced release of the terminator region from the promoter allows BRCA1 transcription, and that defects in BRCA1 chromatin structure may contribute to dysregulated BRCA1 expression in breast tumors. </p><p>Yun and Hiom (2009) identified a role for CTIP in repair of DNA double-strand breaks (DSBs) in the avian B-cell line DT40. They established that CTIP is required not only for repair of DSBs by homologous recombination in S/G2 phase but also for microhomology-mediated end joining (MMEJ) in G1. The function of CTIP in homologous recombination, but not MMEJ, is dependent on the phosphorylation of serine residue 327 and recruitment of BRCA1. Cells expressing CTIP protein that cannot be phosphorylated at ser327 are specifically defective in homologous recombination and have a decreased level of single-stranded DNA after DNA damage, whereas MMEJ remains unaffected. Yun and Hiom (2009) concluded that their data support a model in which phosphorylation of ser327 of CTIP as cells enter S phase and the recruitment of BRCA1 functions as a molecular switch to shift the balance of DSB repair from error-prone DNA end joining to error-free homologous recombination. </p><p>Morris et al. (2009) reported that BRCA1 is modified by SUMO in response to genotoxic stress, and colocalizes at sites of DNA damage with SUMO1 (601912), SUMO2 (603042)/SUMO3 (602231), and the SUMO conjugating-enzyme Ubc9 (601661). PIAS SUMO E3 ligases (PIAS1; 603566 and PIAS4 605989) colocalize with and modulate SUMO modification of BRCA1, and are required for BRCA1 ubiquitin ligase activity in cells. In vitro, SUMO modification of the BRCA1/BARD1 (601593) heterodimer greatly increases its ligase activity, identifying it as a SUMO-regulated ubiquitin ligase. Furthermore, PIAS SUMO ligases are required for complete accumulation of double-stranded DNA damage repair proteins subsequent to RNF8 (611685) accrual, and for proficient double-strand break repair. Morris et al. (2009) concluded that the sumoylation pathway plays a significant role in mammalian DNA damage response. </p><p>Wu et al. (2010) found that the E3 ubiquitin ligase HERC2 (605837) countered the stabilizing effect of BARD1 on BRCA1 and caused BRCA1 degradation. The HECT domain of HERC2 interacted with and caused ubiquitination of an N-terminal degradation domain of BRCA1, targeting BRCA1 for degradation. The HERC2-BRCA1 interaction and BRCA1 degradation were maximal during S phase in synchronized HeLa cells and rapidly diminished as cells entered G2-M. Wu et al. (2010) concluded that HERC2 is an E3 ligase that counters the stabilizing effect of BARD1 and targets BRCA1 for degradation during S phase of the cell cycle. </p><p>Using yeast 2-hybrid, immunoprecipitation, and immunoblot analyses, Wu-Baer et al. (2010) showed that human UBXN1 (616378) interacted with the BRCA1/BARD1 heterodimer. UBXN1 could also interact with the N terminus of BRCA1 alone, but the presence of BARD1 enhanced the interaction. The C-terminal portion of UBXN1 was involved in interaction of UBXN1 with BRCA1, and the N-terminal UBA domain of UBXN1 bound lys6-linked polyubiquitin chains conjugated to BRCA1. UBXN1 inhibited the E3 ligase activity of BRCA1/BARD1, and this inhibition depended on the ubiquitin-binding activity of UBXN1. Wu-Baer et al. (2010) proposed that UBXN1 regulates the enzymatic function of BRCA1 in a ubiquitination status-dependent manner. </p><p>Using yeast 2-hybrid, coimmunoprecipitation, and microarray analyses, Harte et al. (2010) found that human BRD7 (618489) and BRCA1 interacted and cooperated in regulation of BRCA1-dependent transcription. Chromatin immunoprecipitation assays revealed that BRD7 was present on the ESR1 promoter and was responsible for recruitment of BRCA1 and OCT1 (POU2F1; 164175) to the ESR1 promoter. Depletion of either BRCA1 or BRD7 resulted in loss of ESR1 expression and resistance to antiestrogen treatment. </p><p>Zhu et al. (2011) showed that loss of BRCA1 in mice results in transcriptional derepression of the tandemly repeated satellite DNA. Brca1 deficiency is accompanied by a reduction of condensed DNA regions in the genome and loss of ubiquitylation of histone H2A (see 613499) at satellite repeats. BRCA1 binds to satellite DNA regions and ubiquitylates H2A in vivo. Ectopic expression of H2A fused to ubiquitin reverses the effects of BRCA1 loss, indicating that BRCA1 maintains heterochromatin structure via ubiquitylation of histone H2A. Satellite DNA derepression was also observed in mouse and human BRCA1-deficient breast cancers. Ectopic expression of satellite DNA can phenocopy BRCA1 loss in centrosome amplification, cell-cycle checkpoint defects, DNA damage, and genomic instability. Zhu et al. (2011) proposed that the role of BRCA1 in maintaining global heterochromatin integrity accounts for many of its tumor suppressor functions. </p><p>Using mouse embryonic stem cells, Chang et al. (2011) found that expression of human BRCA1 with the arg1699-to-gln (R1699Q; 113705.0037) mutation caused upregulation of microRNA-155 (MIR155; 609337) and reduced embryonic stem cell survival. R1699Q interfered with differentiation of stem cells into embryoid bodies with distinct cell layers, which was associated with apoptotic cell death. In situ hybridization revealed 40-fold upregulation of Mir155 in a subset of cells from R1699Q embryoid bodies. Northern blot and RT-PCR analyses revealed that MIR155 was upregulated in all cell lines and breast cancer tumors with BRCA1 deficiency examined. Wildtype BRCA1, but not BRCA1 with the R1699Q substitution, downregulated mouse Mir155 expression by recruiting Hdac2 (605164) to the Mir155 promoter, resulting in deacetylation of histones H2a (see 613499) and H3 (see 602810). Chang et al. (2011) concluded that BRCA1 has a role in the epigenetic control of MIR155. </p><p>To determine whether the E3 ubiquitin ligase activity of BRCA1 is required for tumor suppression, Shakya et al. (2011) generated mice that express an enzymatically defective Brca1. The enzymatically defective Brca1 prevented tumor formation to the same degree as did wildtype Brca1 in 3 different genetically engineered mouse models of cancer. In contrast, a mutation that ablated phosphoprotein recognition by the BRCA C terminus (BRCT) domains of BRCA1 elicited tumors in each of the 3 genetically engineered mouse models. Thus, Shakya et al. (2011) concluded that BRCT phosphoprotein recognition, but not the E3 ligase activity, is required for BRCA1 tumor suppression. </p><p>By expression screening, Lee et al. (2012) found that YY1 (600013) was a potent positive regulator of BRCA1. YY1 directly bound the proximal promoter region of BRCA1. Expression of Yy1 and Brca1 correlated positively during the mammary cycle in mouse mammary gland. Expression of YY1 and BRCA1 correlated positively in histologic examination of normal human and tumor breast tissue, with generally lower expression of both proteins in breast cancers. Overexpression of YY1 caused cell cycle arrest in transfected breast cancer cells and inhibited tumor formation following injection in nude mice. </p><p>Willis et al. (2014) reported that the E. coli Tus/Ter complex can be engineered to induce site-specific replication fork stalling and chromosomal homologous recombination (HR)/sister chromatid recombination (SCR) in mouse cells. Tus/Ter-induced HR entails processing of bidirectionally arrested forks. Willis et al. (2014) found that the Brca1 C-terminal tandem BRCT repeat and regions of Brca1 encoded by exon 11, 2 Brca1 elements implicated in tumor suppression, control Tus/Ter-induced HR. Inactivation of either Brca1 or Brca2 (600185) increases the absolute frequency of 'long-tract' gene conversions at Tus/Ter-stalled forks, an outcome not observed in response to a site-specific endonuclease-mediated chromosomal double-strand break. Therefore, HR at stalled forks is regulated differently from HR at double-strand breaks arising independently of a replication fork. Willis et al. (2014) proposed that aberrant long-tract HR at stalled replication forks contributes to genomic instability and breast/ovarian cancer predisposition in BRCA mutant cells. </p><p>Orthwein et al. (2015) reported that the cell cycle controls the interaction of BRCA1 with PALB2 (610355)-BRCA2 to constrain BRCA2 function to the S/G2 phases in human cells. Orthwein et al. (2015) found that the BRCA1-interaction site on PALB2 is targeted by an E3 ubiquitin ligase composed of KEAP1 (606016), a PALB2-interacting protein, in complex with cullin-3 (603136)-RBX1 (603814). PALB2 ubiquitylation suppresses its interaction with BRCA1 and is counteracted by the deubiquitylase USP11 (300050), which is itself under cell-cycle control. Restoration of the BRCA1-PALB2 interaction combined with the activation of DNA-end resection is sufficient to induce homologous recombination in G1, as measured by RAD51 (179617) recruitment, unscheduled DNA synthesis, and a CRISPR-Cas9-based gene-targeting assay. Orthwein et al. (2015) concluded that the mechanism prohibiting homologous recombination in G1 minimally consists of the suppression of DNA-end resection coupled with a multistep block of the recruitment of BRCA2 to DNA damage sites that involves the inhibition of BRCA1-PALB2-BRCA2 complex assembly. </p><p>Small, approximately 10-kilobase microhomology-mediated tandem duplications are abundant in the genomes of BRCA1-linked but not BRCA2-linked breast cancer. Willis et al. (2017) defined the mechanism underlying this rearrangement signature by showing that in primary mammalian cells, BRCA1, but not BRCA2, suppresses the formation of tandem duplications at a site-specific chromosomal replication fork barrier imposed by the binding of Tus proteins to an array of Ter sites. BRCA1 has no equivalent role at chromosomal double-stranded DNA breaks, indicating that tandem duplications form specifically at stalled forks. Tandem duplications in BRCA1 mutant cells arise by a replication restart-bypass mechanism terminated by end joining or by microhomology-mediated template switching, the latter forming complex tandem duplication breakpoints. Solitary DNA ends form directly at Tus-Ter, implicating misrepair of these lesions in tandem duplication formation. Willis et al. (2017) noted that BRCA1 inactivation is strongly associated with approximately 10-kilobase tandem duplications in ovarian cancer. This tandem duplicator phenotype may be a general signature of BRCA1-deficient cancer. </p><p>By examining purified wildtype and mutant BRCA1-BARD1 (601593), Zhao et al. (2017) showed that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1-BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. Zhao et al. (2017) provided evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1-BARD1 mutants with weakened RAD51 interactions showed compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells. </p><p>Panda et al. (2018) found that the centrosome-associated proteins Cep112 (618980) and Brca1 interacted in mouse cells. Both Cep112 and Brca1 also interacted with Ginir, a long intergenic noncoding RNA (lincRNA). When high levels of Ginir RNA were present in mouse cells, Ginir disrupted interaction between Cep112 and Brca1 and affected their expression levels and cellular localizations. Interference of Cep112-Brca1 interaction by Ginir resulted in replicative stress and mitotic dysregulation, causing genomic instability and propelling cells towards malignant transformation. </p><p>Daza-Martin et al. (2019) showed that BRCA1 in complex with BARD1, and not the canonical BRCA1-PALB2 interaction, is required for fork protection. BRCA1-BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1 (601052). PIN1 activity enhances BRCA1-BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. Daza-Martin et al. (2019) identified genetic variants of BRCA1-BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1-BARD1 that are required for fork protection and associated with cancer development. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Familial Breast-Ovarian Cancer Susceptibility 1</em></strong></p><p>
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In affected members of 5 of 8 kindreds with hereditary breast-ovarian cancer linked to chromosome 17q (BROVCA1; 604370), Miki et al. (1994) identified 5 different heterozygous pathogenic mutations in the BRCA1 gene (see, e.g., 113705.0035). The mutations included an 11-bp deletion, a 1-bp insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. </p><p>Castilla et al. (1994) found 8 putative disease-causing mutations in the BRCA1 gene (see, e.g., 113705.0001; 113705.0006; 113705.0013; 113705.0014) in 50 probands with a family history of breast and/or ovarian cancer. The authors used single-strand conformation polymorphism (SSCP) analysis on PCR-amplified genomic DNA. The data were considered consistent with a tumor suppressor model. The heterogeneity of mutations, coupled with the large size of the gene, indicated that clinical application of BRCA1 mutation testing would be technically challenging. </p><p>In 10 families with breast-ovarian cancer, Friedman et al. (1994) used SSCP analysis and direct sequencing to identify 9 different heterozygous BRCA1 mutations (see, e.g., 113705.0004; 113705.0007-113705.0009). The mutations in 7 instances led to protein truncation at sites throughout the gene. A missense mutation, which occurred independently in 2 families, led to loss of a cysteine in the zinc-binding domain. An intronic single basepair substitution destroyed an acceptor site and activated a cryptic splice site, leading to a 59-bp insertion and chain termination. In 4 families with both breast and ovarian cancer, chain termination mutations were found in the N-terminal half of the protein. </p><p>Simard et al. (1994) identified mutations in the BRCA1 gene in 12 of 30 Canadian families with breast-ovarian cancer syndrome (see, e.g., 113705.0003). Six frameshift mutations accounted for all 12 mutant alleles, including nucleotide insertions (2 mutations) and deletions (4 mutations). The same 1-bp insertion mutation in codon 1,755 was found in 4 independent families, whereas 4 other families shared a 2-bp deletion mutation in codons 22 to 23. These families were not known to be related, but haplotype analysis suggested that the carriers of each of these mutations had common ancestors. </p><p>Futreal et al. (1994) demonstrated allelic loss at the BRCA1 locus in primary breast and ovarian tumors. Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all 4 mutations were germline alterations and occurred in cancers of early-onset type. These results were interpreted as indicating that mutation in the BRCA1 gene may not be critical to the development of most breast and ovarian cancers that arise in the absence of a mutant germline allele. This situation is unlike that in the APC gene (611731), which is involved in both hereditary polyposis coli and sporadic colorectal cancer, and that of some other genes involved in both familial and sporadic cancer. </p><p>In 4 of 47 sporadic ovarian cancers, Merajver et al. (1995) examined tumor DNAs by SSCP and found 4 somatic mutations in the BRCA1 gene; all 4 had loss of heterozygosity (LOH) at a BRCA1 intragenic marker. The findings supported a tumor-suppressor mechanism for BRCA1; somatic mutation on one chromosome and LOH on the other may result in inactivation of BRCA1 in some sporadic ovarian cancers. </p><p>Since more than 75% of the reported mutations in the BRCA1 gene result in truncated proteins, Hogervorst et al. (1995) used the protein truncation test (PTT) to screen for mutations in exon 11 which encodes 61% of the BRCA1 protein. In 45 patients from breast and/or ovarian cancer families, they found 6 novel mutations: 2 single nucleotide insertions, 3 small deletions (of 1-5 bp), and a nonsense mutation identified in 2 unrelated families. Furthermore, they were able to amplify the remaining coding region by RT-PCR using lymphocyte RNA. Combined with the protein truncation test, they detected aberrantly spliced products affecting exons 5 and 6 in 1 of 2 BRCA1-linked families examined. </p><p>Serova et al. (1996) identified mutations in the BRCA1 gene in 16 of 20 families with breast-ovarian cancer, including 1 family with a case of male breast cancer. Nine of these mutations had not been reported previously. Most mutations generated a premature stop codon leading to the formation of a truncated BRCA1 protein of 2 to 88% of the expected normal length. The RING-finger domain was altered by 2 of the mutations. A reduced quantity of BRCA1 transcript was associated with 8 of the mutations. Of the 4 families with no detectable BRCA1 mutation, only 1 was clearly linked to the BRCA1 locus. </p><p>Dunning et al. (1997) examined the frequency of 4 polymorphisms in the BRCA1 gene in a large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, the 4 sites generated only 3 haplotypes with a frequency more than 1.3%. The 2 most common haplotypes had frequencies of 0.57 and 0.32, respectively, and these frequencies did not differ significantly between patient and control groups. Dunning et al. (1997) concluded that the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, the data suggested that a gln356-to-arg (Q356R) allele may have a different genotype distribution in breast cancer patients than that in controls; arg356 homozygotes were more frequent in the control group (p = 0.01), indicating that it may be protective against breast cancer. </p><p>Langston et al. (1996) found germline BRCA1 mutations in 6 of 80 women in whom breast cancer was diagnosed before the age of 35 and who were not selected on the basis of family history. Four additional rare sequence variants of unknown functional significance were also identified. Two of the mutations and 3 of the rare sequence variants were found among the 39 women who reported no family history of breast or ovarian cancer. None of the mutations and only 1 of the rare variants was identified in a reference population of 73 unrelated subjects. </p><p>FitzGerald et al. (1996) obtained similar results in a study of 30 women with breast cancer before the age of 30: 4 (13%) had chain-terminating mutations and 1 had a missense mutation in the BRCA1 gene. Two of the 4 Jewish women in this cohort had the 185delAG mutation (113705.0003). Among 39 Jewish women with breast cancer before the age of 40, FitzGerald et al. (1996) found that 8 (21%) carried the 185delAG mutation (95% CI, 9-36%). FitzGerald et al. (1996) concluded that germline BRCA1 mutations can be present in young women with breast cancer who do not belong to families with multiple affected members. </p><p>Gayther et al. (1996) stated that more than 65 distinct mutations scattered throughout the coding region of BRCA1 had been detected. </p><p>Couch et al. (1996) reported a total of 254 BRCA1 mutations, 132 (52%) of which were unique. These represented mutations entered into a database established by the Breast Cancer Information Core (BIC). A total of 221 (87%) of all mutations or 107 (81%) of the unique mutations are small deletions, insertions, nonsense point mutations, splice variants, and regulatory mutations that result in truncation or absence of the BRCA1 protein. A total of 11 disease-associated missense mutations (5 unique) and 21 variants (19 unique) as yet unclassified as missense mutations or polymorphisms had been detected. Thirty-five independent benign polymorphisms had been described. The most common mutations were 185delAG (113705.0003) and 5382insC (113705.0018), which accounted for 30 (11.7%) and 26 (10.1%), respectively, of all the mutations. </p><p>Stoppa-Lyonnet et al. (1996) described 2 independent BRCA1 mutations in a single family. A woman with breast cancer diagnosed at age 25 inherited a deleterious allele from her father. Her mother had ovarian and breast cancer caused by a separate mutation, which was the basis of breast cancer in 5 or more of her relatives. The authors pointed out that the segregation of 2 BRCA1 mutations resulted in the failure to demonstrate linkage to either chromosome 17 or chromosome 13 and could lead to the erroneous hypothesis of the involvement of a third locus in familial breast cancer. Narod et al. (1995) suggested that the fraction of familial breast cancer that is not accounted for by BRCA1 or BRCA2 may be small. </p><p>In a screening of Hungarian breast/ovarian cancer families for germline mutations in BRCA1 and BRCA2, Ramus et al. (1997) found 1 individual who carried the 185delAG mutation (113705.0003) in BRCA1, as well as the 6174delT mutation (600185.0009) in BRCA2. Each mutation had been shown to have a frequency of approximately 1% in the Ashkenazi Jewish population. Although the patient was not recorded as having a Jewish origin, haplotype analysis suggested that both mutations were of the Ashkenazi type. There was a maternal family history of breast cancer and the paternal family history was unknown. The patient was found to have breast cancer at age 48 and ovarian cancer at age 50 years. The ages at diagnosis and the tumor types were not different from those of patients with either BRCA1 or BRCA2 mutations. Both mutations were present in 3 different samples from the patient: breast tumor, ovarian tumor, and lymphocyte DNA. There was no evidence of LOH on either chromosome 13 or chromosome 17. </p><p>Liede et al. (1998) found mutations of both BRCA1 and BRCA2 in a breast cancer patient of Scottish descent. Grade II adenocarcinoma of the breast was diagnosed at the age of 35 years. Simultaneous screening by protein truncation tests of both BRCA genes detected a 2508G-T mutation of the BRCA1 gene (113705.0023) and a 3295insA mutation of BRCA2 (600185.0011). The patient had both a maternal and a paternal history of breast cancer. The maternal side contained cases of postmenopausal breast cancer; the paternal side contained cases of premenopausal breast cancer. The mother, however, did not have either mutation, suggesting that both BRCA1 and BRCA2 germline mutations originated from the father of the proband. </p><p>Using a comprehensive screen of the entire BRCA1 coding region, Janezic et al. (1999) determined the prevalence of BRCA1 alterations in a population-based series of 107 consecutive ovarian cancer cases diagnosed in Orange County, California, between March 1, 1994 and February 28, 1995. The participation rate was 82%. BRCA1 alterations were sought using the RNase mismatch cleavage assay followed by direct sequencing. Two truncating mutations, 962del4 (113705.0024) and 3600del11 (113705.0025), were identified. Both patients had a family history of breast or ovarian cancer. Several novel as well as previously reported uncharacterized variants were also identified, some of which were associated with a family history of cancer. Using allele-specific amplification, Janezic et al. (1999) determined the frequency distribution of common polymorphisms in the 91 Caucasian cancer cases in this series and 24 sister controls. The rare form of the Q356R polymorphism was significantly (p = 0.03) associated with a family history of ovarian cancer, suggesting that this polymorphism may influence ovarian cancer risk. </p><p>Vallon-Christersson et al. (2001) characterized the effect of C-terminal germline variants identified in Scandinavian breast and ovarian cancer families. Seven familial missense mutations, a truncating mutation, 4 missense variants, and 1 in-frame deletion were studied using 2 separate reporter genes. The authors concluded that transactivation activity may reflect a tumor-suppressing function of BRCA1 and further support the role of BRCA1 missense mutations in disease predisposition. A discrepancy was noted between results from yeast- and mammalian-based assays, indicating that it may not be possible to unambiguously characterize variants with the yeast assay alone. </p><p>Perrin-Vidoz et al. (2002) assessed the relative amount of transcripts encoded by BRCA1 alleles harboring 30 different truncating mutations in lymphoblastoid cell lines established from carriers from breast/ovarian cancer families. The authors observed that nonsense-mediated decay (NMD) was triggered by 80% of alleles containing a premature termination codon (PTC) and resulted in a 1.5- to 5-fold reduction in mRNA abundance. All truncating mutations located in the 3.4-kb long central exon were subject to NMD, irrespective of their distance to the downstream exon-exon junction. PTCs not leading to NMD were either located in the last exon or very close to the translation initiation codon. Perrin-Vidoz et al. (2002) hypothesized that reinitiation could explain why transcripts carrying early PTCs escape NMD. </p><p>Rostagno et al. (2003) performed mutation analysis of the BRCA1 gene in 140 families from the southeast of France with a history of breast and/or ovarian cancer. As expected, BRCA1 gene alteration, including missense mutations of unknown biologic significance, were more frequent in families with a history of breast-ovarian cancer (32%) than in breast-cancer-only families (12%). </p><p>The Scottish/Northern Irish BRCA1/BRCA2 Consortium (2003) identified 107 families in Scotland or Northern Ireland with mutations in the BRCA1 or BRCA2 genes: 59 had BRCA1 mutations and 46 had BRCA2 mutations. Two families had mutations in both genes. The most common mutations were the BRCA1 2800delAA mutation (113705.0008) in 11 families and the BRCA2 6503delTT mutation (600185.0002) in 12 families. Prevalence of breast cancer was similar for BRCA1 and BRCA2 mutation families (average 3.7 and 3.6 per family, respectively), but those with BRCA1 mutations had a much greater risk of ovarian cancer (average 1.5 and 0.6 per family, respectively). Mutations within the 5-prime two-thirds of BRCA1 carried a significantly higher relative risk of ovarian cancer, and the same was true for mutations within the central portion of BRCA2 (the 'OCCR'). </p><p>Among 349 Belgian families with breast-ovarian cancer, Claes et al. (2004) found that 49 had BRCA1 mutations and 26 had BRCA2 mutations. Male breast cancer was significantly indicative of a BRCA2 mutation. Mutations in the 5-prime ends of BRCA1 and BRCA2 were associated with a significantly increased risk of ovarian cancer relative to the center portion of the gene. </p><p>In 64 Chilean families with breast-ovarian cancer, Jara et al. (2006) found that 7 (10.9%) carried mutations in the BRCA1 gene and 3 (4.7%) carried mutations in the BRCA2 gene. Only 2 families had the same BRCA1 mutation, indicating heterogeneity in the spectrum of BRCA mutations in this population. </p><p>Among 300 US probands from high-risk families who tested negative for BRCA1 or BRCA2 gene mutations by conventional testing, Walsh et al. (2006) identified 31 with genomic rearrangements of BRCA1 and 4 with genomic rearrangements of BRCA2, totaling 35 (12%) of 300. Inherited rearrangements of BRCA1 or BRCA2 were found in a larger proportion of families with ovarian and/or male breast cancer (18%) than in those with only female breast cancer (4.2%). Fourteen probands (4%) had mutations in the CHEK2 gene (604373), and 3 (1%) had mutations in p53 (191170). </p><p>By analysis of BRCA1 mutations in the BIC database, Pavlicek et al. (2004) showed that distribution of reported missense mutations, but not frameshift and nonsense mutations, was positively correlated with BRCA1 protein conservation. Based on protein sequence conservation, they identified missense changes that are likely to compromise BRCA1 function. </p><p>Easton et al. (2007) undertook a systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer predisposition genes. Easton et al. (2007) identified 43 sequence variants with odds greater than 20 to 1 in favor of causality of breast cancer in BRCA1 and 17 in BRCA2. A total of 133 variants of unknown clinical significance had odds of at least 100 to 1 in favor of neutrality with respect to risk. Those with evidence in favor of causality were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. </p><p>Wang et al. (2010) genotyped 3,451 BRCA1 and 2,006 BRCA2 mutation carriers at 350 SNPs identified as candidate breast cancer risk factors in 2 breast cancer genomewide association studies (GWAS). Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk. The minor alleles of rs6138178 in SNRPB (182282) and rs6602595 in CAMK1D (607957) displayed the strongest associations in BRCA1 carriers (p(trend) = 3.6 x 10(-4), 95% CI 0.69-0.90 and p(trend) = 4.2 x 10(-4), 95% CI 1.10-1.41, respectively). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. </p><p><strong><em>Fanconi Anemia, Complementation Group S</em></strong></p><p>
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In a 28-year-old woman with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; 617883), Domchek et al. (2012) identified 2 mutations in the BRCA1 gene (V1736A, 113705.0038 and c.2457delC, 113705.0039), as well as a variant of unknown significance in the BRCA2 gene (c.971G-C, R324T). In vitro functional expression studies showed that the BRCA1 V1736A variant was a hypomorphic allele, with decreased localization to double-strand breaks and decreased interaction with RAP80 (UIMC1; 609433) compared to wildtype. No studies of the BRCA2 variant were performed. The patient's mother died of ovarian cancer at age 55; her DNA was not available. A maternal great-aunt with both breast and ovarian cancer (BROVCA1; 604370) carried a heterozygous V1736A mutation, and another maternal great-aunt with peritoneal cancer carried the V1736A mutation and the BRCA2 R324T variant. A heterozygous V1736A mutation was also found in 2 unaffected family members. </p><p>Sawyer et al. (2014) reported a woman with FANCS who was compound heterozygous for mutations in the BRCA1 gene (R1699W, 113705.0040 and c.594_597del4, 113705.0041). Patient lymphocytes showed increased chromosomal breakage and radial chromosome formation compared to controls. The patient's mother, who was heterozygous for the 4-bp deletion, had ovarian cancer. There was a strong family history of cancer, including ovarian, endometrial, and stomach cancer. Fibroblasts from the proband showed reduced expression of full-length BRCA1 protein, suggesting that the R1699W mutation leads to misfolding and reduced proteolytic stability. RT-PCR analysis suggested that the c.594_597 deletion resulted in nonsense-mediated mRNA decay. Further studies of patient cells showed decreased BRCA1 and RAD51 (179617) foci in response to insult, suggesting impaired double-strand break repair function. Ectopic expression of wildtype BRCA1 restored these repair functions. The R1699W mutation had previously been identified in heterozygous state in a Scandinavian family (LUND279) segregating breast and ovarian cancer by Vallon-Christersson et al. (2001). </p><p>In a 2.5-year-old girl, born of consanguineous Brazilian parents, with FANCS, Freire et al. (2018) identified a homozygous nonsense mutation in the BRCA1 gene (C903X; 113705.0042). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in her parents. Patient cells showed increased chromosomal breakage compared to controls. The patient's mother was subsequently screened and found to have breast cancer; there was additional family history of breast cancer on the maternal side. </p><p>In 4 patients from 2 unrelated consanguineous Middle Eastern families with a complex phenotype consistent with FANCS, Seo et al. (2018) identified homozygous nonsense mutations in the BRCA1 gene (W372X, 113705.0043 and L431X, 113705.0044). Both mutations, as well as the previously reported C903X mutation (Freire et al., 2018), occurred in exon 11. Complete loss of BRCA1 was thought to be embryonic lethal; however, homozygosity for these nonsense mutations was viable in these patients due to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5-prime to the mutations and produces 2 short isoforms that lack the residues affected by the mutations. Fibroblasts derived from 1 patient showed no detectable full-length BRCA1 protein, but had protein levels corresponding to one of the normal isoforms that retain some capacity to repair DNA damage and can partially compensate for loss of the full-length protein. </p><p><strong><em>Prostate Cancer</em></strong></p><p>
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In Icelandic studies, Arason et al. (1993) suggested that male carriers of the BRCA1 gene may have an increased risk of prostate cancer. Langston et al. (1996) studied the BRCA1 gene in 61 men who met one or more of these criteria: (1) under 53 years of age at diagnosis prostate cancer; (2) a family history of breast cancer in a first-degree female relative diagnosed under 51 years of age; or (3) a family history of prostate cancer in 2 or more male relatives, with at least 1 relative diagnosed at less than 56 years of age. They found 1 germline mutation, 185delAG (113705.0003), in 1 subject and 5 different rare sequence variants (1 of which was detected in 2 unrelated men). None of the rare variants were found in population-based controls. Isaacs et al. (1995) failed to identify a significantly increased risk of breast cancer among relatives of prostate cancer probands. The findings of Langston et al. (1996) are not necessarily in conflict, since the contribution of germline BRCA1 mutations to the overall incidence of prostate cancer appears to be small, at most, and may be limited to specific subgroups of patients. </p><p>Nastiuk et al. (1999) set out to determine whether the common germline mutations of BRCA1 (113705.0003) or BRCA2 (600185.0009), which are frequent in the Ashkenazi Jewish population, predispose Ashkenazi Jewish men to prostate cancer. They found that each of these germline mutations occurred at an incidence in prostate cancer patients that closely matched that in the general Ashkenazi Jewish population. They suggested that unlike cases of breast and ovarian cancers, mutations in BRCA1 or BRCA2 do not significantly predispose men to prostate cancer. Vazina et al. (2000) also concluded that BRCA1 and BRCA2 germline mutations that are common in Jewish populations probably contribute little to the occurrence of cancer of the prostate, to inherited predisposition, or to early-onset disease in Jewish individuals. </p><p>In 940 Ashkenazi Israelis with prostate cancer, Giusti et al. (2003) tested DNA obtained from paraffin sections for the 3 Jewish founder mutations: 185delAG (113705.0003) and 5382insC (113705.0018) in BRCA1 and 6174delT (600185.0009) in BRCA2. They estimated that there is a 2-fold increase in BRCA mutation-related prostate cancer among Ashkenazi Israelis. No differences were noted between the histopathologic features of cases with or without founder mutations, and no difference was found in the mean age at diagnosis between cases with or without a founder mutation. </p><p><strong><em>Other Cancers</em></strong></p><p>
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Al-Sukhni et al. (2008) found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer (see 614320) who carried a heterozygous germline BRCA1 mutation (see, e.g., 113705.0003 and 113705.0018). Pancreatic tumor DNA was available for sequencing in 4 cases, and 3 demonstrated loss of the wildtype allele. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. Al-Sukhni et al. (2008) concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs. </p><p>Jonsson et al. (2019) analyzed the germline, blood, and matched tumor tissue of 17,152 patients with cancer diagnosed with 1 of 55 cancer types in whom prospective clinical sequencing of up to 468 cancer-associated genes was performed to guide treatment decisions for advanced and metastatic disease. Jonsson et al. (2019) defined somatic loss-of-function alterations in the BRCA1 and BRCA2 genes, and identified germline pathogenic and probable pathogenic variants in BRCA1 and BRCA2. Jonsson et al. (2019) showed that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1 or BRCA2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP (173870) inhibition were observed only in tumor types associated with increased heritable cancer risk in BRCA1/2 carriers. Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumor pathogenesis that was independent of mutant BRCA1 or BRCA2. Overall, mutant BRCA is an indispensable founding event for some tumors, but in a considerable proportion of other cancers, it appears to be biologically neutral, a difference predominantly conditioned by tumor lineage, with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making. </p><p><strong><em>Mutation Detection Methodology</em></strong></p><p>
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Hacia et al. (1996) noted that all of the then-current methods used to detect BRCA1 mutations began with PCR amplification and required gel electrophoresis, which seriously complicated the challenge of scale-up, automation, and cost reduction. They demonstrated the feasibility of using oligonucleotide arrays in a DNA chip-based assay to screen for a wide range of heterozygous mutations in the 3.45-kb exon 11 of the BRCA1 gene. They concluded that DNA chip-based assays provided a valuable new technology for high throughput, cost-efficient detection of genetic alterations. </p><p>The detection of inactivating mutations in tumor suppressor genes is critical to their characterization, as well as to the development of diagnostic testing. Most approaches for mutational screening of germline specimens are complicated by the fact that mutations are heterozygous and that missense mutations are difficult to interpret in the absence of information about protein function. Ishioka et al. (1997) described a novel method using Saccharomyces cerevisiae for detecting protein-truncating mutations in any gene of interest. In their procedure, the PCR-amplified coding sequence of the gene is inserted by homologous recombination into a yeast URA3 fusion protein, and transformants are assayed for growth in the absence of uracil. The high efficiency of homologous recombination in yeast ensures that both alleles are represented among transformants and achieves separation of alleles, which facilitates subsequent nucleotide sequencing of the mutated transcript. The specificity of translational initiation of the URA3 gene leads to minimal enzymatic activity in transformants harboring an inserted stop codon, and hence to reliable distinction between specimens with wildtype alleles and those with a heterozygous truncating mutation. This yeast-based codon assay accurately detected heterozygous truncating mutations in the BRCA1 gene in patients with early onset of breast cancer and in the APC gene (611731) in patients with familial adenomatous polyposis. </p><p>Petrij-Bosch et al. (1997) reported that the mutation spectrum of BRCA1 available at that time had been biased by PCR-based mutation-screening methods, such as SSCP, the protein truncation test (PPT), and direct sequencing, using genomic DNA as template. Three large genomic deletions that were not detectable by those approaches comprised 36% of all BRCA1 mutations found in Dutch breast cancer families up to that time. A 510-bp Alu-mediated deletion comprising exon 22 was found in 8 of 170 breast cancer families recruited for research purposes and in 6 of 49 probands referred to the Amsterdam Family Cancer Clinic for genetic counseling. In addition, a 3,835-bp Alu-mediated deletion encompassing exon 13 was detected in 4 of the 170 research families, while a deletion of approximately 14 kb was detected in a single family. Haplotype analyses indicated that each recurrent mutation had a single common ancestor. </p><p>Van Orsouw et al. (1999) reported an inexpensive system for mutation analysis based on a combination of multiplex PCR amplification and 2-dimensional electrophoresis. In a panel of 60 samples, 14 mutations were confirmed, and an additional 5 mutations were found. Fifteen different polymorphic variants were also identified. </p><p>Montagna et al. (2003) applied multiplex ligation-dependent probe amplification (MLPA) methodology to 37 hereditary breast-ovarian cancer families. All had a high prior probability of BRCA1 mutation, and 15 were previously shown to carry a mutation in either the BRCA2 gene (5 families) or the BRCA1 gene (10 families, including 1 genomic rearrangement). The application of BRCA1 MLPA to the remaining 22 uninformative families allowed the identification of 5 additional genomic rearrangements. Loss of constitutive heterozygosity of polymorphic markers in linkage disequilibrium was predictive of such BRCA1 alterations. BRCA1 genomic deletions accounted for more than one-third (6 of 15) of the pathogenic BRCA1 mutations in this series. </p><p>Using a method that combines sequence alignment with calculation of Grantham variation and deviation (A-GVGD), Tavtigian et al. (2006) analyzed most of the missense substitutions observed in BRCA1 and resolved known neutral and deleterious missense substitutions into distinct sets. In addition, 8 previously unclassified BRCA1 missense substitutions observed in trans with 1 or more deleterious mutations, and within the cross-species range of variation observed at their position in the protein, were classified as neutral. Tavtigian et al. (2006) stated that these combined methods can classify as neutral about 50% of missense substitutions that have been observed with 2 or more clearly deleterious mutations. </p><p>Findlay et al. (2018) used saturation genome editing to assay 96.5% of all possible single-nucleotide variants (SNVs) in 13 exons that encode functionally critical domains of BRCA1. Functional effects for nearly 4,000 SNVs were bimodally distributed and almost perfectly concordant with established assessments of pathogenicity. Over 400 nonfunctional missense SNVs were identified as well as 300 SNVs that disrupt expression. Findlay et al. (2018) concluded that these results will be useful for clinical interpretation of BRCA1 variants, and noted that their approach can be applied to other genes. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gayther et al. (1995) analyzed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. In 32 families (53%), a total of 22 different mutations were detected, of which 14 were previously unreported. They observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within the family. The data suggested to the authors a transition in risk such that mutations in the 3-prime third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supported previous data suggesting that some BRCA1 mutation carriers have common ancestors; however, Gayther et al. (1995) found at least 2 examples where recurrent mutations appeared to have arisen independently, judging from the different haplotype background. </p><p>Studies of a number of diseases have indicated that fine-structure haplotype analysis can provide insight into the 'genetic history' of a particular mutation (or presumed mutation for rare diseases where the disease gene is not yet identified). To address both the question of mutation origin and the relationship between mutation and phenotype, Neuhausen et al. (1996) constructed a haplotype of 9 polymorphic STR markers within or immediately flanking the BRCA1 locus in a set of 61 families (selected to contain 1 of 6 BRCA1 mutations that had been identified a minimum of 4 times). The mutation appeared to have an effect on the relative proportion of cases of breast and ovarian cancer: 57% of women presumed affected because of the 1294del40 mutation (113705.0006) had ovarian cancer, compared with 14% of affected women with the splice site mutation in intron 5 of BRCA1 (113705.0034). A high degree of haplotype conservation across the region was observed. Any haplotype differences found were most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. One mutation, 4184del4 (113705.0015), had the same ancestral haplotype in two-thirds of the families studied. Neuhausen et al. (1996) estimated that this mutation had arisen 170 generations ago. </p><p>To determine whether hereditary ovarian cancers have distinct clinical and pathologic features compared with sporadic (nonhereditary) ovarian cancers, Boyd et al. (2000) performed a retrospective cohort study of a consecutive series of 933 ovarian cancers diagnosed and treated at the Sloan-Kettering Cancer Center. This study was restricted to patients of Jewish origin because of the ease of BRCA1 and BRCA2 genotyping in this ethnic group. Of the 189 patients who identified themselves as Jewish, 88 hereditary cases were identified with the presence of a germline founder mutation in BRCA1 or BRCA2. The remaining 101 cases from the same series not associated with a BRCA mutation, and 2 additional groups with ovarian cancer from clinical trials (for survival analysis), were included for comparison. Hereditary cancers were rarely diagnosed before age 40 years and were common after age 60 years, with mean age at diagnosis being significantly younger for BRCA1- versus BRCA2-linked patients (54 vs 62 years). Histology, grade, stage, and success of cytoreductive surgery were similar for hereditary and sporadic cases. The hereditary group had a longer disease-free interval following primary chemotherapy in comparison with the nonhereditary group, with a median time to recurrence of 14 months and 7 months, respectively (p less than 0.001). Those with hereditary cancers had improved survival compared with the nonhereditary group. Boyd et al. (2000) concluded that although BRCA-associated hereditary ovarian cancers in this population have surgical and pathologic characteristics similar to those of sporadic cancers, advanced-stage hereditary cancer patients survive longer than nonhereditary cancer patients. Age penetrance is greater for BRCA1-linked than for BRCA2-linked cancers in this population. </p><p>Hohenstein and Fodde (2003) reviewed genotype/phenotype correlations at the BRCA1 locus in humans and mice. </p><p>Basal-like breast cancer is a subtype of breast cancer that is highly proliferative, poorly differentiated, and has a poor prognosis. These tumor cells express cytokeratin markers typical of basally oriented epithelial cells of the normal mammary gland. Saal et al. (2008) found that loss of PTEN (601728) protein expression was significantly associated with the basal-like cancer subtype in both nonhereditary breast cancer and hereditary BRCA1-deficient breast cancer. Loss of PTEN in the BRCA1-deficient basal-like breast cancer tumors was associated with frequent gross PTEN mutations, including intragenic chromosome breaks, inversions, deletions, and micro copy number alterations, consistent with a mechanism involving inappropriate repair of double-strand DNA breaks. The findings indicated a specific and recurrent oncogenic consequence of BRCA1-dependent dysfunction in DNA repair and implied that the PTEN pathway is directly involved in transformation of basal-like progenitor cells. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To establish the role of missense changes in the BRCA1 gene in breast cancer susceptibility, Fleming et al. (2003) used comparative evolutionary methods to identify potential functionally important amino acid sites in exon 11. By aligning sequences from 57 eutherian mammals and categorizing amino acid sites by degree of conservation, they identified 41 missense mutations in exon 11 (38 in conserved and 3 in rapidly evolving regions) likely to influence gene function and thereby contribute to breast cancer susceptibility. They used Bayesian phylogenetic analyses to determine relationships among orthologs and identify codons evolving under positive selection. Most conserved residues occurred in a region with the highest concentration of protein-interacting domains. Rapidly evolving residues were concentrated in the RAD51-interacting domain, suggesting that selection is acting most strongly on the role of BRCA1 in DNA repair. </p><p>Pavlicek et al. (2004) isolated and characterized full-size BRCA1 homologs from rhesus macaque, orangutan, gorilla, and chimpanzee. Analysis of human and nonhuman primate BRCA1 sequence revealed an unusually high proportion of insertion/deletions in noncoding DNA that were associated with Alu repeats. Most Alu elements involved in genomic rearrangement in humans were retained in nonhuman primates, indicating that structural instability of this locus may be intrinsic in anthropoids. Analysis of the nonsynonymous/synonymous mutation ratio in BRCA1 coding sequence showed that most of the internal sequence is variable between primates and evolved under positive selection. In contrast, the terminal regions of BRCA1, which encode the RING finger and BRCT domains, experienced negative selection and are almost identical between the compared primates. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Gowen et al. (1996) described homozygous mice lacking the mouse Brca1 gene. The mice, possessing a deletion of the large exon 11, died between days 10 and 13 of embryonic development, suffering from a variety of neuroepithelial defects. Hakem et al. (1996) described another strain of homozygous mice for a putative Brca1-null mutation produced by targeted deletion of exons 5 and 6. These mutant mice were more severely affected, dying at about embryonic day 7.5 with no signs of mesoderm formation and exhibiting reduced cell proliferation. There were also strong signs of disruptive cell cycle regulation via altered expression levels of cyclin E (123837), mdm2 (164785) and p21 (116899). Hakem et al. (1996) speculated that the death of mutant embryos was due to failure of the proliferative burst required for germ layer development. Hakem et al. (1996) reported that after about 1 year of age, Brca1 heterozygous female mice showed no evidence of cancer. Gowen et al. (1996) also had been unable to detect tumors in 1-year-old heterozygotes. </p><p>To study mechanisms underlying BRCA1-related tumorigenesis, Xu et al. (1999) derived mouse embryonic fibroblast cells carrying a targeted deletion of exon 11 of the Brca1 gene. The mutant cells maintained an intact G1-S cell cycle checkpoint and proliferated poorly. However, a defective G2-M checkpoint in these cells was accompanied by extensive chromosomal abnormalities. Mutant fibroblasts contained multiple functional centrosomes, leading to unequal chromosome segregation, abnormal nuclear division, and aneuploidy. These data uncovered an essential role for BRCA1 in maintaining genetic stability through the regulation of centrosome duplication and the G2-M checkpoint. </p><p>Moynahan et al. (1999) reported that Brca1-deficient mouse embryonic stem cells had impaired repair of chromosomal double-strand breaks by homologous recombination. The relative frequencies of homologous and nonhomologous DNA integration and double-strand break repair were also altered. The results demonstrated a caretaker role for BRCA1 in preserving genomic integrity by promoting homologous recombination and limiting mutagenic nonhomologous repair processes. </p><p>Hakem et al. (1997) generated mice double mutant for Brca1(5-6) and p53, or Brca1(5-6) and p21. Mutation in either p53 or p21 prolonged the survival of Brca1(5-6) mutant embryos from embryonic day 7.5 to embryonic day 9.5. The development of most Brca1(5-6)/p21 double-mutant embryos was comparable to that of their wildtype littermates, although no mutant survived past embryonic day 10.5. Because mutation of neither p53 nor p21 completely rescued Brca1(5-6) embryos, the authors suggested that the lethality of the embryos is likely due to a multifactorial process. </p><p>Ludwig et al. (1997) created mice deficient for Brca1 by targeted disruption, resulting in deletion of exon 2. They also disrupted Brca2 by replacing a segment of exon 11. Heterozygotes were indistinguishable from wildtype littermates. Nullizygous embryos became developmentally retarded and disorganized, and died early in development. In Brca1 mutants, the onset of abnormalities was earlier by 1 day and their phenotypic features and time of death were highly variable, whereas the phenotype of Brca2-null embryos was more uniform, and they survived for at least 8.5 embryonic days. Brca1/Brca2 double mutants were similar to Brca1-null mutants. Ludwig et al. (1997) reported that the impact of Brca1- or Brca2-null mutation was less severe in a p53-null background. </p><p>Xu et al. (2001) found that mouse embryos homozygous for deletion of exon 11 of the Brca1 gene died late in gestation because of widespread apoptosis. Elimination of 1 p53 allele completely rescued this embryonic lethality and restored normal mammary gland development. However, most female mice homozygous for the Brca1 exon 11 deletion and heterozygous for loss of the p53 gene developed mammary tumors with loss of the remaining p53 allele within 6 to 12 months. Lymphomas and ovarian tumors also occurred at lower frequencies. Heterozygous mutation of the p53 gene decreased p53 and resulted in attenuated apoptosis and G1-S checkpoint control, allowing the homozygous Brca1 exon 11-deleted cells to proliferate. The p53 protein regulates Brca1 transcription both in vitro and in vivo, and Brca1 participates in p53 accumulation after gamma irradiation. These findings provided a mechanism for BRCA1-associated breast carcinogenesis. </p><p>McCarthy et al. (2003) determined that mouse embryos with double mutant Bard1 -/- ; Brca1 -/- genotype were phenotypically indistinguishable from either single Bard1 or single Brca1 homozygous mutants. Embryos that carried at least 1 wildtype allele of both Bard1 and Brca1 were normal and had 20 to 25 somites, while each embryo that was null for either Bard1 or Brca1 exhibited the characteristic phenotype of severe growth retardation, degeneration, and embryonic lethality. The similarity of phenotypes indicated to McCarthy et al. (2003) that the developmental functions of Brca1 and Bard1 are mediated by the Brca1/Bard1 heterodimer. </p><p>Mouse embryonic fibroblasts carrying targeted deletion of exon 11 of the Brca1 gene or a Gadd45a null mutation suffer centrosome amplification. Wang et al. (2004) found that mouse embryos carrying both mutations were exencephalic and exhibited a high incidence of apoptosis accompanied by altered levels of Bax (600040), Bcl2 (151430), and p53. They concluded that BRCA1 and GADD45A have a synergistic role in regulating centrosome duplication and maintaining genome integrity. </p><p>Poole et al. (2006) demonstrated that mammary glands of nulliparous Brca1/p53-deficient mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype that occurs only during pregnancy in wildtype mice. Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway. Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis. Poole et al. (2006) concluded that their findings revealed a tissue-specific function for the BRCA1 protein and raised the possibility that antiprogesterone treatment may be useful for breast cancer prevention in individuals with BRCA1 mutations. </p><p>Shakya et al. (2008) found that conditional inactivation of Bard1 in mouse mammary epithelial cells induced basal-like mammary carcinomas with a frequency, latency, and histopathology indistinguishable from those developed in conditional Brca1-mutant mice and in double conditional Bard1/Brca1-mutant mice. Reminiscent of human breast carcinomas due to BRCA1 mutation, the mouse tumors were triple negative for estrogen receptor (see 133430) and progesterone receptor (PGR; 607311) expression and Her2/neu (ERBB2; 164870) amplification. They also expressed basal cytokeratins Ck5 (KRT5; 148040) and Ck14 (KRT14; 148066), had elevated frequency of p53 lesions, and displayed high levels of chromosomal instability. Shakya et al. (2008) concluded that the tumor suppressor activities of both BARD1 and BRCA1 are mediated through the BRCA1/BARD1 heterodimer. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>44 Selected Examples):</strong>
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</span>
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</h4>
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<p />
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</div>
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<h4>
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<span class="mim-font">
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<strong>.0001 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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BRCA1, CYS64GLY
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<br />
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SNP: rs80357064,
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gnomAD: rs80357064,
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ClinVar: RCV000019228, RCV000047634, RCV000129894, RCV000235121, RCV000496255
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</span>
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<span class="mim-text-font">
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<p>In a kindred in which 8 members had breast cancer and 5 members had ovarian cancer (604370), Castilla et al. (1994) found a TGT-to-GGT transversion in codon 64 of the BRCA1 gene, leading to substitution of glycine for cysteine (C64G). Analysis of tumor DNA in 2 affected members of this kindred showed that the wildtype allele had been lost and only the C64G mutant allele remained, thus supporting the tumor suppressor model. </p>
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</span>
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</div>
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<div>
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<br />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, CYS61GLY
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<br />
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SNP: rs28897672,
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gnomAD: rs28897672,
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ClinVar: RCV000019229, RCV000047597, RCV000131902, RCV000159935, RCV000239114, RCV000412714, RCV000415051, RCV000785199, RCV001270967, RCV004802937, RCV005003390
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</span>
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<span class="mim-text-font">
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<p>Gorski et al. (2000) identified a cys61-to-gly (C61G) mutation in the BRCA1 gene to be a founder mutation in Polish families with breast-ovarian cancer (604370), accounting for 20% of identified mutations. They studied 66 families in which at least 3 related females were affected with breast or ovarian cancer and at least 1 of these 3 had been diagnosed with cancer before the age of 50. Mutations were identified in 35 (53%) of the 66 families. </p><p>Merajver et al. (1995) analyzed genomic DNA of tumor and normal fractions of 47 ovarian cancers for mutations in BRCA1 using the SSCP technique. Somatic mutations in the BRCA1 gene were identified in 4 tumors, all of which also had loss of heterozygosity at a BRCA1 intragenic marker. One of these, found in an endometrioid ovarian carcinoma in a 53-year-old woman, was a C61G substitution in the zinc finger motif. The data supported a tumor-suppressor mechanism for BRCA1. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PANCREATIC CANCER, SUSCEPTIBILITY TO, 4, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, 2-BP DEL, 185AG
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<br />
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SNP: rs80357914,
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ClinVar: RCV000019230, RCV000019231, RCV000034761, RCV000056295, RCV000131394, RCV000213650, RCV000735481, RCV000785197, RCV001353942, RCV001836711, RCV003128128, RCV003225925, RCV004554604, RCV004566751, RCV005003391
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Breast-Ovarian Cancer Susceptibility</em></strong></p><p>
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Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 2-bp (AG185) deletion in the normal sequence TTA GAG of codons 22-23 in exon 3. The AGAG presumably predisposed to the deletion. This mutation changes the reading frame of the mRNA and causes a premature termination codon at position 39. This mutation was detected in index cases from 4 families that were not known to be related and originated from different areas in Canada. In these 4 families there were a total of 12 cases of breast cancer and 11 cases of ovarian cancer. </p><p>Struewing et al. (1995) pointed out that all 10 published families with the 185delAG mutation (also called 187delAG) were Ashkenazi Jewish (of Eastern European origin). They knew of an eleventh Ashkenazi breast/ovarian cancer family with the 185delAG mutation; furthermore, only 1 Ashkenazi Jewish family was known to have a BRCA1 mutation other than 185delAG. In addition, Ashkenazi families with the 185delAG mutation appeared to share a common haplotype. In a study of 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, they observed the 185delAG mutation in 0.9% (95% confidence limit, 0.4%-1.8%), and in 815 reference individuals not selected for ethnic origin, none had the mutation. </p><p>Roa et al. (1996) found the 185delAG mutation in 1.09% of approximately 3,000 Ashkenazi Jewish individuals and found the 5382insC mutation (113705.0018) in 0.13%. BRCA2 analysis on 3,085 individuals from the same population showed a carrier frequency of 1.52% for the 6174delT mutation (600185.0009). The expanded population-based study confirmed that the BRCA1 185delAG mutation and the BRCA2 6174delT mutation constituted the 2 most frequent mutant alleles predisposing to hereditary breast cancer among Ashkenazim and suggested a relatively lower penetrance for the 6174delT mutation in BRCA2. </p><p>Bar-Sade et al. (1997) examined 639 unrelated healthy Jews of Iraqi extraction, a presumed low-risk group for the 185delAG mutation which occurs predominantly in Ashkenazim. Three individuals were identified as 185delAG mutation carriers, and haplotype analysis of the Iraqi mutation carriers showed that 2 of the Iraqis shared a haplotype in common with 6 Ashkenazi mutation carriers, and a third had a haplotype that differed by a single marker. This suggested to Bar-Sade et al. (1997) that the BRCA1 185delAG mutation may have arisen before the dispersion of the Jewish people in the Diaspora, at least at the time of Christ. </p><p>Bar-Sade et al. (1998) extended their analyses to other non-Ashkenazi subsets: 354 of Moroccan origin, 200 Yemenites, and 150 Iranian Jews. Four of Moroccan origin (1.1%) and none of the Yemenites or Iranians were carriers of the 185delAG mutation. BRCA1 allelic patterns (haplotypes) were determined for 4 of these individuals and for 12 additional non-Ashkenazi 185delAG mutation carriers who had breast/ovarian cancer. The common 'Ashkenazi haplotype' was shared by 6 non-Ashkenazi individuals; 4 had a closely related pattern, and the rest (n = 6) displayed a distinct BRCA1 allelic pattern. The authors concluded that the 185delAG BRCA1 mutation occurs in some non-Ashkenazi populations at rates comparable with that of Ashkenazim. The majority of Jewish 185delAG mutation carriers have the same haplotype, supporting the founder effect notion, but dating the mutation's origin to an earlier date than previously estimated. The different allelic pattern at the BRCA1 locus in some Jewish mutation carriers might suggest that the mutation arose independently. </p><p>Bandera et al. (1998) demonstrated the 185delAG mutation in 2 women with a personal or family history of breast cancer and papillary serous carcinoma of the peritoneum (PSCP). PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma and it may develop years after oophorectomy. Schorge et al. (1998) demonstrated that the tumors were multifocal in these cases, indicating that patients with germline BRCA1 mutations may develop PSCP in addition to breast and ovarian carcinomas. </p><p>Ah Mew et al. (2002) reported the 185delAG mutation in a non-Jewish Chilean family with no reported Jewish ancestry. The linked haplotype present in this family was identical to that identified in the Ashkenazi Jewish population. </p><p>Buisson et al. (2006) found that BRCA1 transcripts bearing the 185delAG mutation are not degraded by nonsense-mediated mRNA decay. Using Western blot analysis, they examined HeLa cells transfected with minigenes for this transcript and another with a premature termination codon at position 36 and found that translation from these transcripts was reinitiated at codon 128. </p><p><strong><em>Pancreatic Cancer Susceptibility</em></strong></p><p>
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|
Al-Sukhni et al. (2008) found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer (PNCA4; 614320) who carried a heterozygous germline BRCA1 mutation. Three patients carried the 185delAG mutation. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. Al-Sukhni et al. (2008) concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, 59-BP INS
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<br />
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SNP: rs80358061,
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gnomAD: rs80358061,
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ClinVar: RCV000031030, RCV000047725, RCV000074570, RCV000131898, RCV000469831, RCV000735531, RCV004758603, RCV004802959
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (604370). They identified a T-to-G transversion at nucleotide 332 in exon 5 of the BRCA1 gene, leading to a premature termination codon at position 75 and a truncated protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, 1-BP INS
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<br />
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SNP: rs80357569,
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gnomAD: rs80357569,
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|
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ClinVar: RCV000047310, RCV000074359, RCV000129421, RCV000190459, RCV000735524, RCV000785394, RCV004803951
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp (A) insertion in the normal sequence GAA AAA AAG of codons 337-339 in exon 11, changing the reading frame of the mRNA and causing a premature termination codon at position 345. This mutation was detected in the index case of a Canadian family with a total of 4 cases of breast cancer and 3 cases of ovarian cancer, bringing the probability of linkage to BRCA1 to 98.3%. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, 40-BP DEL, NT1294
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<br />
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SNP: rs80359874,
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gnomAD: rs80359874,
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|
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ClinVar: RCV000019234, RCV000047372, RCV000131965, RCV000159899, RCV000238898, RCV001353523, RCV001798011, RCV004802938
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They both identified a 40-bp deletion from position 1294 to 1333, which led to a premature termination codon that was 5 codons distal to the deletion and predicted a truncated BRCA1 protein of 396 amino acids. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0007 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, SER766TER
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<br />
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|
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SNP: rs80357780,
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gnomAD: rs80357780,
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|
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ClinVar: RCV000019235, RCV000214000, RCV000496882, RCV000759504, RCV001170823
|
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|
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (604370). They identified a 2-bp (AG) deletion at nucleotide 2415 in exon 11 of the BRCA1 gene, leading to a premature termination codon in place of serine-766 and a truncated protein. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
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BRCA1, 2-BP DEL, 2800AA
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<br />
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|
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SNP: rs80357971,
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|
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ClinVar: RCV000019236, RCV000047927, RCV000074575, RCV000131876, RCV000735499
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|
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|
|
|
</span>
|
|
</div>
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|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (604370). They identified a 2-bp (AA) deletion at nucleotide 2800 in exon 11 of the BRCA1 gene, leading to a premature termination codon at position 901 and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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<div>
|
|
<br />
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</div>
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</div>
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|
<div>
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, SER915TER
|
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|
|
<br />
|
|
|
|
SNP: rs80357540,
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|
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|
|
|
|
|
ClinVar: RCV000047955, RCV000132272, RCV000167766
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (604370). They identified a 2-bp (TC) deletion at nucleotide 2863 in exon 11 of the BRCA1 gene, leading to a premature termination codon in place of serine-915 and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
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|
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<div>
|
|
<br />
|
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</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 1-BP DEL, 3121A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357601,
|
|
|
|
|
|
gnomAD: rs80357601,
|
|
|
|
|
|
ClinVar: RCV000019238, RCV000048039, RCV000159912, RCV000163096
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp deletion (3121delA) in the normal sequence GAA AAC of codons 1001-1002 in exon 11, changing the reading frame of the mRNA and causing a premature termination codon at position 1023. This mutation was detected in the index case of a Canadian family with a total of 5 cases of breast cancer and 1 case of ovarian cancer (604370), bringing the probability of linkage to BRCA1 to 90%. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, SER1040ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs4986852,
|
|
|
|
|
|
gnomAD: rs4986852,
|
|
|
|
|
|
ClinVar: RCV000019239, RCV000034739, RCV000048074, RCV000120293, RCV000128951, RCV000456692, RCV002476991
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, has been reclassified based on the findings of Millot et al. (2012). </p><p>Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (604370). They identified a G-to-A transition at nucleotide 3238 in exon 11 of the BRCA1 gene, changing serine to asparagine at position 1040 (S1040N). </p><p>Functional assays used to assess the impact of the S1040N variant indicated that S1040N is a class 1 variant (not pathogenic or of no clinical significance), according to the International Agency for Research on Cancer (IARC) class system (Millot et al., 2012). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, ARG1203TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs62625308,
|
|
|
|
|
|
gnomAD: rs62625308,
|
|
|
|
|
|
ClinVar: RCV000019240, RCV000048251, RCV000131818, RCV000148389, RCV000159978, RCV000239343, RCV000677815, RCV000735444, RCV000785373, RCV001642230, RCV003162256, RCV003332084, RCV004554605, RCV004802939, RCV004808551, RCV005016279
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (604370). They identified a C-to-T substitution in exon 11 at position 3726 of the BRCA1 gene, leading to a premature termination codon in place of arginine-1203 and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, GLU1250TER
|
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|
|
|
|
<br />
|
|
|
|
SNP: rs28897686,
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|
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gnomAD: rs28897686,
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|
|
|
|
|
ClinVar: RCV000019241, RCV000048311, RCV000074586, RCV000131811, RCV000465125, RCV000506391, RCV004802940
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a G-to-T substitution in exon 11 at position 3867, leading to a premature termination codon in place of glutamic acid-1250 and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 4-BP DEL, NT3875
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357868,
|
|
|
|
|
|
gnomAD: rs80357868,
|
|
|
|
|
|
ClinVar: RCV000019242, RCV000048314, RCV000131810, RCV000167859, RCV000239051, RCV000735506, RCV000782127, RCV000785410, RCV004758594
|
|
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 4-bp deletion at position 3875, leading to a premature termination codon at position 1252 and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 4-BP DEL, 4185TCAA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357508,
|
|
|
|
|
|
gnomAD: rs80357508,
|
|
|
|
|
|
ClinVar: RCV000019243, RCV000048431, RCV000131887, RCV000159924, RCV000238776, RCV000476410, RCV000735453, RCV001353670, RCV004802941, RCV004808552, RCV005003392
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (604370). Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. In both studies, a 4-bp (TCAA) deletion in exon 11 at position 4184, leading to a premature termination codon at position 1364 and a truncated protein, was identified. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, ARG1443TER
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|
|
|
|
<br />
|
|
|
|
SNP: rs41293455,
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|
|
|
|
|
gnomAD: rs41293455,
|
|
|
|
|
|
ClinVar: RCV000019244, RCV000048523, RCV000131880, RCV000159989, RCV000235131, RCV000239083, RCV000735445, RCV000763000, RCV001353404, RCV004802942
|
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|
|
|
|
</span>
|
|
</div>
|
|
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a C-to-T substitution at position 4446 of the BRCA1 gene, leading to a premature termination codon in place of arginine-1443 and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, ARG1443GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs41293455,
|
|
|
|
|
|
gnomAD: rs41293455,
|
|
|
|
|
|
ClinVar: RCV000019245, RCV000048522, RCV000129043, RCV000427206, RCV000588512, RCV004554606
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a C-to-G transition at position 4446, changing arginine-1443 to glycine. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
PANCREATIC CANCER, SUSCEPTIBILITY TO, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 1-BP INS, 5382C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357906,
|
|
|
|
|
|
gnomAD: rs80357906,
|
|
|
|
|
|
ClinVar: RCV000019246, RCV000019247, RCV000056287, RCV000119097, RCV000131328, RCV000258962, RCV000412924, RCV000415060, RCV000495973, RCV000735471, RCV001353680, RCV003128129, RCV004554607, RCV004802943, RCV005003393
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Breast-Ovarian Cancer Susceptibility</em></strong></p><p>
|
|
Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp (C) insertion at position 5382 in exon 20, changing the reading frame of the mRNA and causing a premature termination codon at position 1829 in exon 24. This mutation was detected in the index case of 4 Canadian families. In 1 of these families, 10 cases of cancer appeared in a single large sibship, including 3 cases of breast cancer, 2 ovarian cancers, 2 leukemias, 2 pancreatic cancers, and 1 prostate cancer. A case of leukemia and a case of Hodgkin disease were seen in more recent generations. In the 4 families with the 5382insC mutation, there were 14 cases of breast cancer and 5 cases of ovarian cancer. </p><p>Gayther et al. (1997) found that the 5382insC and 4153delA (113705.0030) mutations in the BRCA1 gene may account for 86% of cases of familial ovarian cancer in Russia. </p><p>Gorski et al. (2000) found that 5382insC is a founder mutation in Polish families with breast-ovarian cancer, accounting for 51% of identified mutations. They studied 66 families in which at least 3 related females were affected with breast or ovarian cancer and at least 1 of these 3 had been diagnosed with cancer before the age of 50. Mutations were found in 35 (53%) of the 66 families; 18 of the families carried the 5382insC mutation. De Los Rios et al. (2001) reported findings in Canadian families suggesting that most of the mutation-carrying families of Polish ancestry have the BRCA1 5382insC mutation. </p><p>Porhanova et al. (2008) reported a 52-year-old Russian woman with ovarian cancer who was found to be compound heterozygous for the 5382inC mutation and a common Slavic mutation in the NBN gene (602667.0001). Investigation of the ovarian cancer tissue showed somatic loss of heterozygosity for NBN, but retention of heterozygosity for BRCA1. The patient did not have a particularly severe cancer-prone phenotype, and her parents did not have cancer, although 3 sibs developed cancer as adults. Porhanova et al. (2008) commented that haploinsufficiency of the BRCA1 gene may contribute to cancer progression without somatic changes. </p><p><strong><em>Pancreatic Cancer Susceptibility</em></strong></p><p>
|
|
Al-Sukhni et al. (2008) found loss of heterozygosity at the BRCA1 locus in pancreatic tumor DNA from 5 (71%) of 7 patients with pancreatic cancer (PNCA4; 614320) who carried a heterozygous germline BRCA1 mutation. Three patients carried the 5382insC mutation. In contrast, only 1 (11%) of 9 patients with sporadic pancreatic cancer and no germline BRCA1 mutations showed LOH at the BRCA1 locus. Al-Sukhni et al. (2008) concluded that BRCA1 germline mutations likely predispose to the development of pancreatic cancer, and suggested that individuals with these mutations be considered for pancreatic cancer-screening programs. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, TYR1853TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357629,
|
|
|
|
|
|
|
|
ClinVar: RCV000049050, RCV000074357, RCV000163976, RCV000265181
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21 (604370). They identified a 1-bp (A) insertion at nucleotide 5677 in exon 24 of the BRCA1 gene, leading to a premature termination codon in place of tyrosine-1853 and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 19-BP DEL, NT5085
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80359884,
|
|
|
|
|
|
|
|
ClinVar: RCV000019249
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 19-bp deletion between basepairs 5085 and 5103, leading to a termination codon at position 1656 and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 1-BP INS, 5438C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357823,
|
|
|
|
|
|
|
|
ClinVar: RCV000048927, RCV000074358, RCV000131363, RCV000478417, RCV000735454, RCV004804021
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer (604370) for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp (C) insertion at nucleotide 5438, leading to a termination codon at position 1773 and a truncated protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, ARG841TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1800709,
|
|
|
|
|
|
gnomAD: rs1800709,
|
|
|
|
|
|
ClinVar: RCV000019251, RCV000034733, RCV000047867, RCV000120283, RCV000162566, RCV000457953, RCV001170820, RCV002490393
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, has been reclassified based on the findings of Millot et al. (2012). </p><p>Barker et al. (1996) reported an arg841-to-trp (R814W) mutation in the BRCA1 gene as a common mutation identified in patients with breast-ovarian cancer (604370). </p><p>Functional assays used to assess the impact of the R814W variant indicated that R814W is a class 1 variant (not pathogenic or of no clinical significance), according to the International Agency for Research on Cancer (IARC) class system (Millot et al., 2012). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 2508G-T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs62625306,
|
|
|
|
|
|
gnomAD: rs62625306,
|
|
|
|
|
|
ClinVar: RCV000019252, RCV000162856, RCV000212169, RCV000496416, RCV000769717
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient of Scottish descent with breast cancer (604370), Liede et al. (1998) found double heterozygosity for 2 high-penetrance mutations: a 2508G-T transversion in BRCA1, resulting in a conversion of glutamic acid to a stop codon, and a 3295insA mutation (600185.0011) in BRCA2. Both mutations were thought to have come from the father. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 4-BP DEL, 962CTCA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357919,
|
|
|
|
|
|
|
|
ClinVar: RCV000019253, RCV000049168, RCV000131872, RCV000412670, RCV000735511, RCV002496415, RCV003992160
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Caucasian patient with a positive family history of breast or ovarian cancer (604370) in a first-degree relative, Janezic et al. (1999) identified a 962delCTCA mutation in the BRCA1 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 11-BP DEL, NT3600
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357877,
|
|
|
|
|
|
|
|
ClinVar: RCV000019254, RCV000048211, RCV000131815, RCV000159917, RCV000785408, RCV001271012, RCV004760336, RCV004802944
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Caucasian patient with a positive family history of breast or ovarian cancer (604370) in a first-degree relative, Janezic et al. (1999) identified a 3600del11 mutation in the BRCA1 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 1-BP DEL, 1675A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357662,
|
|
|
|
|
|
|
|
ClinVar: RCV000019255, RCV000129703, RCV000235933, RCV000496710
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Two BRCA1 founder mutations had been identified in the Norwegian population: 1675delA (Dorum et al., 1997) and 1135insA (113705.0027) (Andersen et al., 1996). Both result in a frameshift and a stop in exon 11. Dorum et al. (1999) ascertained 20 patients with breast-ovarian cancer (604370) with the BRCA1 1675delA mutation and 10 with the 1135insA mutation. Their relatives were described with respect to absence/presence of breast and/or ovarian cancer. Of 133 living female relatives, 83 (62%) were tested for the presence of a mutation. No difference in penetrance or expression between the 2 mutations was found, whereas differences according to method of ascertainment were seen. The overall findings were that disease started to occur at age 30 years and that by age 50 years 48% of the mutation-carrying women had experienced breast and/or ovarian cancer. More ovarian cancers than breast cancers were recorded. Both penetrance and expression (breast cancer vs ovarian cancer) were different from those in reports of the Ashkenazi founder mutations. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>.0027 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, 1-BP INS, 1135A
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<br />
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|
|
|
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ClinVar: RCV000047310, RCV000074359, RCV000129421, RCV000190459, RCV000735524, RCV000785394, RCV004803951
|
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|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>See 113705.0026 and Dorum et al. (1999). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0028 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, 2-BP DEL, 3888GA
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<br />
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SNP: rs80357579,
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|
ClinVar: RCV000031127, RCV000048325, RCV000131814, RCV000235232, RCV000677799, RCV000785411, RCV001391223, RCV001554258, RCV004758609, RCV004802973, RCV005016307
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Tesoriero et al. (1999) identified a woman who developed high-grade breast cancer with axillary nodal metastases before the age of 40 years (604370). Her father developed prostate cancer during his early fifties. Her mother had no cancer. The patient was found to have a de novo 2-bp deletion (GA) at nucleotide 3888 in exon 11 of the BRCA1 gene (3888delGA), and a 1-bp deletion (T) at nucleotide 6174 in exon 11 of the BRCA2 gene (600185.0009), which had been inherited from the father. Studies of a heterozygous polymorphism indicated that the 3888delGA mutation of BRCA1 originated from the father. The authors noted that despite the large number of variants identified in the BRCA1 and BRCA2 (600185) genes, there appeared to be no earlier published report of a de novo mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0029 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, 10-BP INS, NT943
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<br />
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SNP: rs387906563,
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|
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gnomAD: rs387906563,
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ClinVar: RCV000019258, RCV000049156, RCV000074602, RCV000129599, RCV000468976, RCV000735513, RCV002496721
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|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>Mefford et al. (1999) suggested that a 10-bp insertion at nucleotide 943 of the BRCA1 gene represents a founder mutation of African origin in patients with breast-ovarian cancer (604370). </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, 1-BP DEL, 4153A
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<br />
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SNP: rs80357711,
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|
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|
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gnomAD: rs80357711,
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|
|
ClinVar: RCV000031141, RCV000048413, RCV000074587, RCV000130638, RCV000239274, RCV001271017, RCV004758610, RCV004772833, RCV004802977
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|
|
</span>
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|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>By mutation analysis of the BRCA1 gene in families with breast-ovarian cancer (604370) in Russia, Gayther et al. (1997) identified a novel 4153delA mutation. They stated that this mutation and the 5382insC (113705.0018) mutation in the BRCA1 gene may account for 86% of cases of familial ovarian cancer in Russia. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
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<span class="mim-text-font">
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|
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|
BRCA1, 6-KB DUP, EX13
|
|
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|
|
<br />
|
|
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|
|
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ClinVar: RCV000019260
|
|
|
|
|
|
</span>
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|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>Puget et al. (1999) described a 6-kb duplication of exon 13 of the BRCA1 gene that created a frameshift in the coding sequence in 3 unrelated U.S. families of European ancestry and 1 Portuguese family with breast-ovarian cancer (604370). To estimate the frequency and geographic diversity of carriers of this duplication, the BRCA1 Exon 13 Duplication Screening Group (2000) studied 3,580 unrelated individuals with a family history of breast cancer and 934 early-onset breast and/or ovarian cancer cases ascertained through 39 institutions in 19 countries. A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2). Haplotyping showed that they were likely to have derived from a common ancestor, possibly of northern British origin. The screening group suggested that BRCA1 screening protocols, either in English-speaking countries or in countries with historic links with Great Britain, should include the PCR-based assay described in their report. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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</div>
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|
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</div>
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<div>
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|
|
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 1-BP DEL, 3744T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357571,
|
|
|
|
|
|
gnomAD: rs80357571,
|
|
|
|
|
|
ClinVar: RCV000112140, RCV000574479, RCV001269640, RCV002298457
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Sarantaus et al. (2000) performed haplotype analysis of 26 Finnish patients with breast-ovarian cancer (604370) carrying a 3744delT mutation in exon 11 of the BRCA1 gene. They estimated that the mutation could be traced back 23 to 36 generations (500-700 years). The mutation was observed in Swedish families also. Most of the Finnish families had lived in Central Ostrobothnia for at least 300 years, whereas the Swedish families came from the opposite side of the Gulf of Bothnia. Thus, the mutation could have been brought across the sea from Sweden to Finland with Swedish settlers. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, 5-BP INS, NT3171
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357856,
|
|
|
|
|
|
gnomAD: rs80357856,
|
|
|
|
|
|
ClinVar: RCV000019262, RCV000048059, RCV000131332, RCV000159913, RCV001353931
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Bergman et al. (2001) stated that the 3171ins5 mutation in the BRCA1 gene (originally reported by Johannsson et al. (1996) as 3166insTGAGA), is the most recurrent germline BRCA1/BRCA2 mutation in Sweden. Bergman et al. (2001) constructed haplotypes with polymorphic microsatellite markers within and flanking the BRCA1 gene in 18 apparently unrelated families with hereditary breast and/or ovarian cancer (604370) with a confirmed 3171ins5 mutation. All affected families originated from the same geographic area along the west coast of Sweden. The microsatellite markers spanned a region of 17.3 cM, and all of the analyzed families shared a common 3.7 cM haplotype in the 3171ins5 carriers spanning over 4 markers located within or very close to the BRCA1 gene. This haplotype was not present in any of the 116 control chromosomes, and the 3171ins5 mutation was likely to be identical by descent, i.e., a true founder. The estimated age of the mutation was calculated to be approximately 50 generations, or a first appearance some time around the 6th century (Bergman et al., 2001). No obvious correlation between the geographic origin and genotype was observed. This is probably a reflection of how the population of western Sweden historically has been a migrating people along the west coast, with limited migration beyond this distinct geographic area. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, ARG71GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357382,
|
|
|
|
|
|
gnomAD: rs80357382,
|
|
|
|
|
|
ClinVar: RCV000019263, RCV000047713, RCV000131899, RCV000195359, RCV000469732, RCV000508177, RCV000763009, RCV004758595, RCV004802945
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Vega et al. (2002) studied 30 Spanish breast and breast/ovarian cancer (604370) families for mutations in the BRCA1 and BRCA2 genes. Mutations were found in 8 of the 30 families (26.66%). All mutations were in the BRCA1 gene. The 330A-G transition in the BRCA1 gene, which resulted in an arg71-to-gly (R71G) substitution, was found in 4 unrelated families and accounted for 50% of all identified mutations. It had been described as a founder Spanish mutation, leading to aberrant splicing (Vega et al., 2001). The proband in 1 family had bilateral breast cancer at 27 and 30 years of age. Her mother, who also had the mutation, was diagnosed as having ovarian cancer at the age of 50. </p><p>Diez et al. (2003) stated that the 330A-G mutation affected the splice donor site in intron 5; it caused aberrant splicing which resulted in a deletion of 22 nucleotides in exon 5 and a stop at codon 64 (C64X). Diez et al. (2003) observed this mutation in 7 families, most of them of known Galician origin. As reported in the BRCA1 database, the 330A-G mutation had been observed in families with probable Spanish origin in diverse geographic locations in Europe other than Spain (France and the United Kingdom), and in Caribbean and South American families. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, MET1775ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs41293463,
|
|
|
|
|
|
gnomAD: rs41293463,
|
|
|
|
|
|
ClinVar: RCV000019264, RCV000048931, RCV000131375, RCV000167787, RCV001170589, RCV004554608, RCV004802946
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with breast-ovarian cancer (604370), Miki et al. (1994) identified a heterozygous T-to-G transversion in exon 21 of the BRCA1 gene, resulting in a met1775-to-arg (M1775R) substitution. </p><p>In the germline of patients with breast or ovarian cancer, Monteiro et al. (1996) identified the M1775R mutation in the BRCA1 gene. This mutation has impaired transcriptional activity on BRCA1. Williams and Glover (2003) performed structural studies on the effect of this mutation. The mutated side chain is extruded from the protein hydrophobic core, thereby altering the protein surface. Charge-charge repulsion, rearrangement of the hydrophobic core, and disruption of the native hydrogen bonding network at the interface between the 2 BRCT repeats contribute to the conformational instability of the mutant protein. Williams and Glover (2003) concluded that destabilization and global unfolding of the mutated BRCT domain at physiologic temperatures explained the pleiotropic molecular and genetic defects associated with the mutant protein. </p><p>Aglipay et al. (2006) showed that the M1775R mutation abrogated interaction of BRCA1 with BRAT1 (614506), which is required for activation of ATM (607585) following ionizing radiation-induced DNA damage. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
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|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, MET1775LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs41293463,
|
|
|
|
|
|
gnomAD: rs41293463,
|
|
|
|
|
|
ClinVar: RCV000019265, RCV000496817, RCV001526335
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated European families with a history of breast cancer (604370), Tischkowitz et al. (2008) identified a met1775-to-lys (M1775K) substitution in the BRCA1 gene and demonstrated its pathogenicity. The authors showed that expression of the M1775K-mutant protein in yeast and mammalian cells resulted in markedly reduced transcriptional activity of BRCA1, indicating the pathogenicity of the variant. The M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCT domains, thereby inhibiting BRCA1 interaction with the proteins BRIP1 (605882) and CTIP (RBBP8; 604128), which are involved in DNA damage-induced checkpoint control. These findings indicated that the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Tischkowitz et al. (2008) used a combination of functional, structural, molecular, and evolutionary methods in their study. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0037 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, ARG1699GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs41293459,
|
|
|
|
|
|
gnomAD: rs41293459,
|
|
|
|
|
|
ClinVar: RCV000031217, RCV000048790, RCV000131564, RCV000195350, RCV000735446, RCV000785422, RCV002250479, RCV002496477, RCV003162265, RCV004554634, RCV004802991
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Scandinavian family (LUND488) segregating breast-ovarian cancer (604370), Vallon-Christersson et al. (2001) identified a G-to-A transition at nucleotide 5215 in exon 18 of the BRCA1 gene, resulting in an arg1699-to-gln (R1699Q) substitution. The R1699Q substitution lies within alpha helix-2 of the C-terminal BRCT-N transactivation domain. Vallon-Christersson et al. (2001) found that BRCA1 with this substitution had wildtype transactivation activity when studied in yeast, but decreased activation when studied in mammalian cells, consistent with a loss of function. </p><p>Using mouse embryonic stem cells, Chang et al. (2011) found that expression of human BRCA1 with the R1699Q substitution reduced embryonic stem cell survival and caused upregulation of microRNA-155 (MIR155; 609337), which has a role in promoting cell growth and is upregulated in various human cancers. Wildtype BRCA1, but not BRCA1 with the R1699Q substitution, downregulated mouse Mir155 expression by recruiting Hdac2 (605164) to the Mir155 promoter, resulting in deacetylation of histones H2a (see 142720) and H3 (see 601128). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
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<div>
|
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<div>
|
|
<h4>
|
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<span class="mim-font">
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<strong>.0038 FANCONI ANEMIA, COMPLEMENTATION GROUP S</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, VAL1736ALA
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<br />
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SNP: rs45553935,
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ClinVar: RCV000031229, RCV000048857, RCV000131291, RCV000195366, RCV000585878
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 28-year-old woman with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; 617883), Domchek et al. (2012) identified compound heterozygous mutations in the BRCA1 gene: a c.5207T-C transition, resulting in a val1736-to-ala (V1736A) substitution at a conserved residue, and a 1-bp deletion (c.2457delC; 113705.0039) in exon 11, predicted to result in a frameshift and premature termination (Asp821IlefsTer25). She also carried a heterozygous variant of unknown significance in the BRCA2 gene (c.971G-C, R324T). The patient's mother died of ovarian cancer at age 55; her DNA was not available. A maternal great-aunt with both breast and ovarian cancer (BROVCA1; 604370) carried a heterozygous V1736A mutation, and another maternal great-aunt with peritoneal cancer carried the V1736A mutation and the BRCA2 R324T variant. A heterozygous V1736A mutation was also found in 2 unaffected family members. Tumor tissue from some of the patients with a heterozygous V1736A mutation showed loss of heterozygosity for the wildtype BRCA1 allele, suggesting that the V1736A mutation is pathogenic. Eleven additional pedigrees with BROVCA1 or other types of cancer associated with the V1736A mutation were subsequently ascertained. Segregation analysis yielded a combined odds ratio (OR) of 234:1 in favor of V1736A being pathogenic. In vitro functional expression studies showed that the BRCA1 V1736A variant was a hypomorphic allele, with decreased localization to double-strand breaks and decreased interaction with RAP80 (UIMC1; 609433) compared to wildtype. No studies of the BRCA2 variant were performed. The paternal line of the proband also had multiple cases of breast cancer, although genetic studies were not performed on most of these individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0039 FANCONI ANEMIA, COMPLEMENTATION GROUP S</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, 1-BP DEL, 2457C
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<br />
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SNP: rs80357669,
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gnomAD: rs80357669,
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ClinVar: RCV000031052, RCV000047845, RCV000131356, RCV000167767, RCV000585855, RCV002482927, RCV004758606, RCV004802965
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the 1-bp deletion (c.2457delC) in the BRCA1 gene, predicted to result in a frameshift and premature termination (Asp821IlefsTer25), that was found in compound heterozygous state in a patient with Fanconi anemia complementation group S (FANCS; 617883) by Domchek et al. (2012), see 113705.0038. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0040 FANCONI ANEMIA, COMPLEMENTATION GROUP S</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
|
|
BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, INCLUDED
|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, ARG1699TRP
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<br />
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SNP: rs55770810,
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gnomAD: rs55770810,
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ClinVar: RCV000048789, RCV000077595, RCV000131821, RCV000148390, RCV000159999, RCV000191041, RCV000239322, RCV000457515, RCV000585864, RCV001357133, RCV003128133, RCV004804015
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a woman, born of unrelated Finnish parents, with Fanconi anemia complementation group S (FANCS; 617883), Sawyer et al. (2014) identified compound heterozygous mutations in the BRCA1 gene: a c.5095C-T transition (c.5095C-T, NM_007294) in exon 18, resulting in an arg1699-to-trp (R1699W) substitution, and a 4-bp deletion (c.594_597del4; 113705.0041) in exon 10, predicted to result in a frameshift and premature termination (Ser198ArgfsTer35). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The patient's mother, who carried the 4-bp deletion, had ovarian cancer (BROVCA1; 604370); her tumor tissue showed loss of heterozygosity (LOH) of the wildtype BRCA1 allele. There was a strong family history of cancer, including ovarian, endometrial, and stomach cancer. Patient lymphocytes showed increased chromosomal breakage and radial chromosome formation compared to controls. Fibroblasts from the proband showed reduced expression of full-length BRCA1 protein, suggesting that the R1699W mutation leads to misfolding and reduced proteolytic stability. RT-PCR analysis suggested that the c.594_597 deletion resulted in nonsense-mediated mRNA decay. Further studies of patient cells showed decreased BRCA1 and RAD51 (179617) foci in response to insult, suggesting impaired double-strand break repair function. Ectopic expression of wildtype BRCA1 restored these repair functions. </p><p>The R1699W mutation had previously been identified in heterozygous state in a Scandinavian family (LUND279) segregating breast and ovarian cancer by Vallon-Christersson et al. (2001). Vallon-Christersson et al. (2001) found that BRCA1 with this substitution had wildtype transactivation activity when studied in yeast, but decreased transactivation activity when studied in mammalian cells, consistent with a loss of function. Moreover, the mutant protein was expressed at similar levels as wildtype, ruling out increased instability of the protein as a cause for loss of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0041 FANCONI ANEMIA, COMPLEMENTATION GROUP S</strong>
|
|
</span>
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, INCLUDED
|
|
</span>
|
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</div>
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<div>
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<span class="mim-text-font">
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BRCA1, 4-BP DEL, NT594
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<br />
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SNP: rs797045175,
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ClinVar: RCV000191042, RCV000258289, RCV000585825, RCV001024704
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</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>For discussion of the 4-bp deletion (c.594_597del4, NM_007294) in the BRCA1 gene, predicted to result in a frameshift and premature termination (Ser198ArgfsTer35), that was found in compound heterozygous state in a patient with Fanconi anemia complementation group S (FANCS; 617883) by Sawyer et al. (2014), see 113705.0040. Heterozygous carriers of this mutation had increased susceptibility to breast-ovarian cancer (BROVCA1; 604370). </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0042 FANCONI ANEMIA, COMPLEMENTATION GROUP S</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, INCLUDED
|
|
</span>
|
|
</div>
|
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<div>
|
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<span class="mim-text-font">
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BRCA1, CYS903TER
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<br />
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|
|
SNP: rs1555589094,
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|
|
ClinVar: RCV000585811, RCV000585837, RCV001867901, RCV004948457
|
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|
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 2.5-year-old girl, born of consanguineous Brazilian parents, with Fanconi anemia complementation group S (FANCS; 617883), Freire et al. (2018) identified a homozygous c.2909T-A transversion (c.2709T-A, NM_007294.3) in exon 10 of the BRCA1 gene, resulting in a cys903-to-ter (C903X) substitution, predicted to result in a complete loss of protein function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in her parents. The variant was not found in the 1000 Genomes Project or gnomAD databases. Patient cells showed increased chromosomal breakage compared to controls. The patient's mother was subsequently screened and found to have breast cancer (BROVCA1; 604370). There was additional family history of breast cancer on the maternal side. </p><p>Seo et al. (2018) noted that the C903X variant occurs in exon 11 of the BRCA1 gene and lies 3-prime to the naturally occurring alternative splice donor in exon 11. Thus, the naturally occurring isoform lacks the C903X mutation, likely accounting for the viability of the patient who is homozygous for a nonsense mutation. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
|
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|
|
</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0043 FANCONI ANEMIA, COMPLEMENTATION GROUP S</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, TRP372TER
|
|
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|
|
<br />
|
|
|
|
SNP: rs397508838,
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|
|
|
gnomAD: rs397508838,
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|
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|
|
|
ClinVar: RCV000241007, RCV000509759, RCV000767397, RCV001328427
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, born of consanguineous Arab parents (family A), with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; 617883), Seo et al. (2018) identified a homozygous c.1115G-A transition (c.1115G-A, NM_007294.3) in exon 11 of the BRCA1 gene, resulting in a trp372-to-ter (W372X) substitution. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family and was demonstrated to be germline rather than somatic in the patients. Homozygosity for the nonsense mutation was viable in these patients due to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5-prime to the mutation and produces 2 short isoforms that lack the residues affected by the mutation. Patient fibroblasts showed no detectable full-length BRCA1 protein, but had protein levels corresponding to one of the normal isoforms that retain some capacity to repair DNA damage and can partially compensate for loss of the full-length protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0044 FANCONI ANEMIA, COMPLEMENTATION GROUP S</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA1, LEU431TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80357346,
|
|
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|
|
|
|
|
ClinVar: RCV000111583, RCV000767398, RCV002381345
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, born of consanguineous Turkish parents (family B), with a complex phenotype consistent with Fanconi anemia complementation group S (FANCS; 617883), Seo et al. (2018) identified a homozygous c.1292T-G transversion (c.1292T-G, NM_007294.3) in exon 11 of the BRCA1 gene, resulting in a leu431-to-ter (L431X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was demonstrated to be germline rather than somatic in the patients. Homozygosity for the nonsense mutation was viable in these patients due to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5-prime to the mutation and produces 2 short isoforms that lack the residues affected by the mutation. These alternative isoforms retain some capacity for DNA damage repair and partially compensate for loss of the full-length protein. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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</div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Albertsen et al. (1994); Piver et al. (1993); Puget et al. (1999);
|
|
Simard et al. (1993); Sobol et al. (1992); Stratton et al. (1994)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Aglipay, J. A., Martin, S. A., Tawara, H., Lee, S. W., Ouchi, T.
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|
<strong>ATM activation by ionizing radiation requires BRCA1-associated BAAT1.</strong>
|
|
J. Biol. Chem. 281: 9710-9718, 2006.
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[PubMed: 16452482]
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[Full Text: https://doi.org/10.1074/jbc.M510332200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ah Mew, N., Hamel, N., Galvez, M., Al-Saffar, M., Foulkes, W. D.
|
|
<strong>Haplotype analysis of a BRCA1:185delAG mutation in a Chilean family supports its Ashkenazi origins.</strong>
|
|
Clin. Genet. 62: 151-156, 2002.
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[PubMed: 12220453]
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[Full Text: https://doi.org/10.1034/j.1399-0004.2002.620208.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Al-Sukhni, W., Rothenmund, H., Eppel Borgida, A., Zogopoulos, G., O'Shea, A.-M., Pollett, A., Gallinger, S.
|
|
<strong>Germline BRCA1 mutations predispose to pancreatic adenocarcinoma.</strong>
|
|
Hum. Genet. 124: 271-278, 2008.
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[PubMed: 18762988]
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[Full Text: https://doi.org/10.1007/s00439-008-0554-0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Albertsen, H. M., Smith, S. A., Mazoyer, S., Fujimoto, E., Stevens, J., Williams, B., Rodriguez, P., Cropp, C. S., Slijepcevic, P., Carlson, M., Robertson, M., Bradley, P., Lawrence, E., Harrington, T., Mei Sheng, Z., Hoopes, R., Sternberg, N., Brothman, A., Callahan, R., Ponder, B. A. J., White, R.
|
|
<strong>A physical map and candidate genes in the BRCA1 region on chromosome 17q12-21.</strong>
|
|
Nature Genet. 7: 472-479, 1994.
|
|
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|
[PubMed: 7951316]
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[Full Text: https://doi.org/10.1038/ng0894-472]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Albertsen, H., Plaetke, R., Ballard, L., Fujimoto, E., Connolly, J., Lawrence, E., Rodriguez, P., Robertson, M., Bradley, P., Milner, B., Fuhrman, D., Marks, A., Sargent, R., Cartwright, P., Matsunami, N., White, R.
|
|
<strong>Genetic mapping of the BRCA1 region on chromosome 17q21.</strong>
|
|
Am. J. Hum. Genet. 54: 516-525, 1994.
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|
[PubMed: 8116621]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Andersen, T. I., Borresen, A.-L., Moller, P.
|
|
<strong>A common BRCA1 mutation in Norwegian breast and ovarian cancer families?</strong>
|
|
Am. J. Hum. Genet. 59: 486-487, 1996.
|
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[PubMed: 8755943]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Anderson, S. F., Schlegel, B. P., Nakajima, T., Wolpin, E. S., Parvin, J. D.
|
|
<strong>BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A.</strong>
|
|
Nature Genet. 19: 254-256, 1998.
|
|
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|
|
[PubMed: 9662397]
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[Full Text: https://doi.org/10.1038/930]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Arason, A., Barkardottir, R. B., Egilsson, V.
|
|
<strong>Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer.</strong>
|
|
Am. J. Hum. Genet. 52: 711-717, 1993.
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[PubMed: 8460636]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bandera, C. A., Muto, M. G., Schorge, J. O., Berkowitz, R. S., Rubin, S. C., Mok, S. C.
|
|
<strong>BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum.</strong>
|
|
Obstet. Gynec. 92: 596-600, 1998.
|
|
|
|
|
|
[PubMed: 9764635]
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 08/10/2020<br>Ada Hamosh - updated : 03/27/2020<br>Ada Hamosh - updated : 03/26/2020<br>Bao Lige - updated : 12/18/2019<br>Bao Lige - updated : 06/28/2019<br>Cassandra L. Kniffin - updated : 04/16/2019<br>Ada Hamosh - updated : 01/14/2019<br>Cassandra L. Kniffin - updated : 02/27/2018<br>Ada Hamosh - updated : 02/22/2018<br>Ada Hamosh - updated : 2/4/2016<br>Carol A. Bocchini - updated : 11/10/2015<br>Cassandra L. Kniffin - updated : 6/23/2015<br>Paul J. Converse - updated : 5/29/2015<br>Ada Hamosh - updated : 7/17/2014<br>Patricia A. Hartz - updated : 1/14/2014<br>George E. Tiller - updated : 9/5/2013<br>Patricia A. Hartz - updated : 9/11/2012<br>Patricia A. Hartz - updated : 2/28/2012<br>Ada Hamosh - updated : 11/29/2011<br>Patricia A. Hartz - updated : 10/26/2011<br>Ada Hamosh - updated : 9/21/2011<br>Ada Hamosh - updated : 1/6/2010<br>Ada Hamosh - updated : 8/17/2009<br>Cassandra L. Kniffin - updated : 6/5/2009<br>Patricia A. Hartz - updated : 4/24/2009<br>Patricia A. Hartz - updated : 4/14/2009<br>Cassandra L. Kniffin - updated : 3/30/2009<br>Cassandra L. Kniffin - updated : 2/11/2009<br>Cassandra L. Kniffin - updated : 1/30/2009<br>Cassandra L. Kniffin - updated : 1/22/2009<br>Patricia A. Hartz - updated : 11/24/2008<br>Patricia A. Hartz - updated : 6/5/2008<br>Cassandra L. Kniffin - updated : 5/20/2008<br>Cassandra L. Kniffin - updated : 4/28/2008<br>Cassandra L. Kniffin - updated : 1/8/2008<br>Ada Hamosh - updated : 11/28/2007<br>Cassandra L. Kniffin - updated : 8/27/2007<br>Patricia A. Hartz - updated : 7/6/2007<br>Ada Hamosh - updated : 6/20/2007<br>George E. Tiller - updated : 5/22/2007<br>Victor A. McKusick - updated : 2/21/2007<br>Ada Hamosh - updated : 2/6/2007<br>Stylianos E. Antonarakis - updated : 12/18/2006<br>Patricia A. Hartz - updated : 10/18/2006<br>George E. Tiller - updated : 9/20/2006<br>Marla J. F. O'Neill - updated : 7/6/2006<br>George E. Tiller - updated : 9/30/2005<br>Ada Hamosh - updated : 9/19/2005<br>Patricia A. Hartz - updated : 7/25/2005<br>Patricia A. Hartz - updated : 7/14/2005<br>George E. Tiller - updated : 3/3/2005<br>Patricia A. Hartz - updated : 2/11/2005<br>Ada Hamosh - updated : 1/14/2005<br>George E. Tiller - updated : 12/17/2004<br>Patricia A. Hartz - updated : 9/9/2004<br>George E. Tiller - updated : 4/1/2004<br>Victor A. McKusick - updated : 2/6/2004<br>George E. Tiller - updated : 2/3/2004<br>Ada Hamosh - updated : 11/11/2003<br>Patricia A. Hartz - updated : 10/27/2003<br>Victor A. McKusick - updated : 10/23/2003<br>Victor A. McKusick - updated : 10/1/2003<br>Victor A. McKusick - updated : 8/27/2003<br>Victor A. McKusick - updated : 6/4/2003<br>Victor A. McKusick - updated : 3/12/2003<br>George E. Tiller - updated : 2/20/2003<br>Stylianos E. Antonarakis - updated : 11/26/2002<br>Victor A. McKusick - updated : 11/25/2002<br>Victor A. McKusick - updated : 9/27/2002<br>Victor A. McKusick - updated : 9/17/2002<br>Victor A. McKusick - updated : 8/29/2002<br>Victor A. McKusick - updated : 7/1/2002<br>Victor A. McKusick - updated : 6/12/2002<br>Michael B. Petersen - updated : 4/29/2002<br>Victor A. McKusick - updated : 4/12/2002<br>Victor A. McKusick - updated : 4/12/2002<br>Victor A. McKusick - updated : 2/11/2002<br>Michael B. Petersen - updated : 11/19/2001<br>Victor A. McKusick - updated : 10/9/2001<br>Victor A. McKusick - updated : 8/3/2001<br>Victor A. McKusick - updated : 6/27/2001<br>Victor A. McKusick - updated : 6/25/2001<br>George E. Tiller - updated : 4/24/2001<br>Victor A. McKusick - updated : 3/16/2001<br>Victor A. McKusick - updated : 3/15/2001<br>Stylianos E. Antonarakis - updated : 3/9/2001<br>Victor A. McKusick - updated : 3/8/2001<br>Victor A. McKusick - updated : 3/2/2001<br>Victor A. McKusick - updated : 1/2/2001<br>Victor A. McKusick - updated : 12/19/2000<br>Stylianos E. Antonarakis - updated : 11/27/2000<br>Paul J. Converse - updated : 11/16/2000<br>Paul J. Converse - updated : 11/14/2000<br>Ada Hamosh - updated : 10/19/2000<br>Carol A. Bocchini - updated : 10/3/2000<br>Victor A. McKusick - updated : 9/11/2000<br>Ada Hamosh - updated : 8/18/2000<br>Stylianos E. Antonarakis - updated : 8/8/2000<br>Ada Hamosh - updated : 8/1/2000<br>Victor A. McKusick - updated : 7/26/2000<br>Ada Hamosh - updated : 7/20/2000<br>Ada Hamosh - updated : 7/12/2000<br>Ada Hamosh - updated : 5/31/2000<br>Ada Hamosh - updated : 4/18/2000<br>Michael J. Wright - updated : 3/22/2000<br>Victor A. McKusick - updated : 2/18/2000<br>Victor A. McKusick - updated : 1/11/2000<br>Stylianos E. Antonarakis - updated : 1/7/2000<br>Stylianos E. Antonarakis - updated : 11/19/1999<br>Victor A. McKusick - updated : 11/1/1999<br>Victor A. McKusick - updated : 9/24/1999<br>Ada Hamosh - updated : 9/15/1999<br>John F. Jackson - reorganized : 9/14/1999<br>Wilson H. Y. Lo - updated : 7/16/1999<br>Ada Hamosh - updated : 7/14/1999<br>Stylianos E. Antonarakis - updated : 6/24/1999<br>Stylianos E. Antonarakis - updated : 5/21/1999<br>Ada Hamosh - updated : 5/20/1999<br>Victor A. McKusick - updated : 5/17/1999<br>Ada Hamosh - updated : 3/5/1999<br>Victor A. McKusick - updated : 3/2/1999<br>Victor A. McKusick - updated : 12/7/1998<br>Stylianos E. Antonarakis - updated : 11/10/1998<br>Victor A. McKusick - updated : 10/23/1998<br>Victor A. McKusick - updated : 10/1/1998<br>Victor A. McKusick - updated : 8/21/1998<br>Victor A. McKusick - updated : 8/17/1998<br>Victor A. McKusick - updated : 7/20/1998<br>Victor A. McKusick - updated : 6/23/1998<br>Michael J. Wright - updated : 6/16/1998<br>Victor A. McKusick - updated : 5/22/1998<br>Victor A. McKusick - updated : 5/8/1998<br>Victor A. McKusick - updated : 2/17/1998<br>Victor A. McKusick - updated : 12/18/1997<br>Victor A. McKusick - updated : 10/28/1997<br>Victor A. McKusick - updated : 6/23/1997<br>Victor A. McKusick - updated : 6/16/1997<br>Victor A. McKusick - updated : 6/2/1997<br>Victor A. McKusick - updated : 4/21/1997<br>Victor A. McKusick - updated : 4/15/1997<br>Victor A. McKusick - updated : 4/8/1997<br>Moyra Smith - updated : 3/3/1997<br>Moyra Smith - updated : 12/20/1996<br>Moyra Smith - updated : 12/11/1996<br>Lori M. Kelman - updated : 11/8/1996<br>Moyra Smith - updated : 10/4/1996<br>Stylianos E. Antonarakis - updated : 7/15/1996
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<span class="mim-text-font">
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Victor A. McKusick : 12/20/1990
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</span>
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9/10/1996<br>terry : 9/3/1996<br>terry : 8/22/1996<br>mark : 8/10/1996<br>terry : 8/9/1996<br>terry : 8/5/1996<br>carol : 7/15/1996<br>terry : 7/12/1996<br>terry : 7/12/1996<br>mark : 4/27/1996<br>mark : 4/25/1996<br>terry : 4/22/1996<br>mark : 4/19/1996<br>terry : 4/15/1996<br>mark : 3/6/1996<br>terry : 3/4/1996<br>mark : 2/29/1996<br>mark : 2/29/1996<br>terry : 2/26/1996<br>mark : 2/23/1996<br>mark : 2/23/1996<br>terry : 2/19/1996<br>mark : 2/16/1996<br>mark : 2/13/1996<br>mark : 1/25/1996<br>terry : 1/23/1996<br>mark : 12/15/1995<br>terry : 12/13/1995<br>mark : 12/7/1995<br>terry : 12/7/1995<br>terry : 12/7/1995<br>terry : 12/7/1995<br>mark : 11/17/1995<br>terry : 11/16/1995<br>jason : 6/7/1994<br>mimadm : 4/12/1994<br>pfoster : 3/25/1994<br>warfield : 3/23/1994
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