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Entry
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- *600185 - BRCA2 DNA REPAIR-ASSOCIATED PROTEIN; BRCA2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600185</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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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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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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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="#biochemicalFeatures">Biochemical Features</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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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600185">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>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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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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</li>
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</ul>
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</nav>
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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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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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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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="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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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="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000139618;t=ENST00000380152" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=675" 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=600185" 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>
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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="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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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="mimDnaLinksFold" 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.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000139618;t=ENST00000380152" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000059,NM_001406719,NM_001406720,NM_001406721,NM_001406722,NM_001432077,NR_176251" 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_000059" 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=600185" 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>
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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="mimProtein">
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<span class="panel-title">
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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=02554&isoform_id=02554_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/BRCA2" 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/1161384,1177438,2315186,11276061,11276063,12034851,13540359,16116616,23506223,24431156,24431158,24431160,24431162,24431164,24431166,24431168,24431170,24431172,24431174,24431176,24431178,24431180,24431182,24431191,24431193,24431195,24431197,24431199,24431201,24431203,24431205,24431207,24431209,24431211,24431213,37675289,71064155,114432132,116256779,119628904,119628905,119628906,187233949,408773052,408773054,408773056,408773058,408773060,408773062,408773064,408773066,408773068,408773070,408773072,655203996,655204001,655204009,655204013,655204017,655204021,655204026,655204031,655204035,655204040,655204061,655204374,655204416,655204443,655204489,655204521,655204539,655204570,655204597,655204616,655204657,655204672,655205039,655205091,655205092,655205093,655205150,655205169,727705129,815932495,815932497,815932499,815932501,815932503,815932505,815932507,815932509,815932511,815932513,815932515,815932517,815932519,815932521,819327359,819327361,958168067,958168069,958168071,958168073,958168075,958168077,958168081,958168083,958168085,1147163652,1237408064,1238813711,1238813713,1238813715,1238813717,1238813719,1238813721,1238813723,1238813725,1238813727,1238813729,1238813731,1238813733,1388694386,1388694388,1388694390,1483525183,1483525185,1483525187,1483525189,1483525191,1483525193,1483525195,1483525197,1483525199,1483525201,1483525203,1483525205,1483525207,1483525209,1483525211,1483525213,1483525215,1483525217,1483525219,1483525221,1483525223,1483525225,1483525227,1483525229,1483525231,1483525233,1483525235,1483525237,1483525239,1483525241,1483525243,1483525245,1483525247,1483525249,1483525251,1483525266,1483525268,1483525270,1483525271,1483525273,1633439653,1633439655,1633439657,1633439659,1775781152,1775781154,1775781156,1775781158,1813836565,1821655617,1821655619,1889924844,1896049798,1896049800,1899341482,1899341484,2001548938,2001548973,2028478947,2029084601,2029084603,2029084605,2029084607,2029084609,2029084611,2029084613,2043420624,2043420691,2043420693,2043420695,2043420697,2043420699,2043420701,2043420703,2043420705,2043420707,2043420709,2043420711,2043420713,2043420715,2043420717,2043420719,2043420721,2043420723,2043420725,2043420727,2043420729,2043420731,2043420733,2043420735,2043420737,2043420739,2043420741,2043420743,2043420745,2043420747,2043420749,2043420751,2043420753,2043420755,2043420757,2043420759,2043420761,2043420828,2043420830,2043420897,2043420899,2094552266,2094552268,2094552274,2164862745,2164862753,2164862755,2164862805,2164862807,2164862809,2164862811,2164862813,2164862815,2164862817,2164862819,2165384314,2165384316,2178104973,2178104975,2178104977,2178105004,2178105244,2178105246,2178105248,2178105250,2178105577,2178105579,2178105581,2178105583,2178105585,2203400801,2218469244,2218469246,2218469248,2218469256,2218469260,2218469264,2218469270,2240897237,2240897241,2240897267,2240897269,2301582623,2301582625,2301582627,2301582629,2301582681,2301582683,2301582685,2301582687,2301582689,2301582691,2301582693,2301582695,2301582697,2301582699,2301582701,2396616330,2396616332,2396616405,2577097962,2607637286,2607637288,2703623460,2703623462,2703623464,2703623466,2703623468,2703623470,2703623472,2703623474,2703623476,2703623478,2703623480,2703623482,2703623484,2703623486,2703623488,2703623490,2778098788,2909903175" 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/P51587" 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 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=675" 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=ENSG00000139618;t=ENST00000380152" 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=BRCA2" 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=BRCA2" 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+675" 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/BRCA2" 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:675" 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/675" 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=chr13&hgg_gene=ENST00000380152.8&hgg_start=32315077&hgg_end=32400268&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:1101" 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:1101" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600185[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=600185[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://gnomad.broadinstitute.org/gene/ENSG00000139618" 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=BRCA2" 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=BRCA2" 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=BRCA2" 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=BRCA2" title="LOVD - BReast CAncer 2 - literature unclassified variants (BRCA2)" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">LOVD - BReast CAncer 2 - l…</a></div><div style="margin-left: 0.5em;"><a href="http://databases.lovd.nl/genomed/home.php?select_db=BRCA2" title="Zhejiang University-Adinovo Center BRCA2 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.rockefeller.edu/fanconi/mutate/" title="Fanconi Anaemia Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Fanconi Anaemia Mutation D…</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=BRCA2&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/PA25412" 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:1101" 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:109337" 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/BRCA2#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:109337" 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/675/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=675" 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://zfin.org/ZDB-GENE-060510-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</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:600185" 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:675" 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=BRCA2&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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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1156923005, 25081006, 302849000, 399068003, 443333004<br />
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<strong>ICD10CM:</strong> C61<br />
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<strong>ICD9CM:</strong> 185<br />
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">ICD+</a>
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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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600185
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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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BRCA2 DNA REPAIR-ASSOCIATED PROTEIN; BRCA2
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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">
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BRCA2 GENE<br />
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FANCD1 GENE; FANCD1
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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=BRCA2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BRCA2</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>
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Cytogenetic location: <a href="/geneMap/13/83?start=-3&limit=10&highlight=83">13q13.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr13:32315077-32400268&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'})">13:32,315,077-32,400,268</a> </span>
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</em>
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</strong>
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<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>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<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>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
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<a href="/clinicalSynopsis/table?mimNumber=114480,612555,613029,155255,613347,176807,605724,194070" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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View Clinical Synopses
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</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>
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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>
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<tr>
|
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<td rowspan="8">
|
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<span class="mim-font">
|
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<a href="/geneMap/13/83?start=-3&limit=10&highlight=83">
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13q13.1
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
{Breast cancer, male, susceptibility to}
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|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/114480"> 114480 </a>
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|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
{Breast-ovarian cancer, familial, 2}
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/612555"> 612555 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
|
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</td>
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</tr>
|
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|
|
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Glioblastoma 3}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613029"> 613029 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
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</tr>
|
|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Medulloblastoma}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/155255"> 155255 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Pancreatic cancer 2}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613347"> 613347 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Prostate cancer}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/176807"> 176807 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Fanconi anemia, complementation group D1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/605724"> 605724 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Wilms tumor
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/194070"> 194070 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
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|
</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/600185" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/600185" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<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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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
|
<a id="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
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</h4>
|
|
|
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<div>
|
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<a id="cloning" class="mim-anchor"></a>
|
|
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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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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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
|
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<p><a href="#96" class="mim-tip-reference" title="Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., and 29 others. <strong>Identification of the breast cancer susceptibility gene BRCA2.</strong> Nature 378: 789-792, 1995. Note: Erratum: Nature 379: 749 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524414</a>] [<a href="https://doi.org/10.1038/378789a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8524414">Wooster et al. (1995)</a> identified the BRCA2 gene by positional cloning of a region on chromosome 13q12-q13 implicated in Icelandic families with breast cancer (<a href="/entry/612555">612555</a>). The candidate disease gene was likely to be located in a 600-kb interval centered around D13S171. Using yeast artificial chromosome and P1 artificial chromosome contigs to identify trapped exons within that region, <a href="#96" class="mim-tip-reference" title="Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., and 29 others. <strong>Identification of the breast cancer susceptibility gene BRCA2.</strong> Nature 378: 789-792, 1995. Note: Erratum: Nature 379: 749 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524414</a>] [<a href="https://doi.org/10.1038/378789a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8524414">Wooster et al. (1995)</a> screened human fetal brain, placental, monocyte, and breast cancer cDNA libraries. They identified a cDNA encoding a 2,329-amino acid protein, but suggested that it may not represent the entire gene. Northern blot analysis demonstrated expression in normal breast epithelial cells, placenta, and a breast cancer cell line (MCF7). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8524414" 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="#78" class="mim-tip-reference" title="Tavtigian, S. V., Simard, J., Rommens, J., Couch, F., Shattuck-Eidens, D., Neuhausen, S., Merajver, S., Thorlacius, S., Offit, K., Stoppa-Lyonnet, D., Belanger, C., Bell, R., and 37 others. <strong>The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.</strong> Nature Genet. 12: 333-337, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589730</a>] [<a href="https://doi.org/10.1038/ng0396-333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589730">Tavtigian et al. (1996)</a> determined the complete coding sequence and exonic structure of BRCA2 and examined its pattern of expression. The composite BRCA2 cDNA sequence assembled consisted of 11,385 bp, but did not include the polyadenylation signal or poly(A) tail. Conceptual translation of the cDNA revealed an ORF beginning at nucleotide 229 and encoding a protein of 3,418 amino acids. There was no signal sequence at the end of terminus, and there were no obvious membrane-spanning regions. The highest levels of expression were observed in breast and thymus, with slightly lower levels in lung, ovary, and spleen. <a href="#78" class="mim-tip-reference" title="Tavtigian, S. V., Simard, J., Rommens, J., Couch, F., Shattuck-Eidens, D., Neuhausen, S., Merajver, S., Thorlacius, S., Offit, K., Stoppa-Lyonnet, D., Belanger, C., Bell, R., and 37 others. <strong>The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.</strong> Nature Genet. 12: 333-337, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589730</a>] [<a href="https://doi.org/10.1038/ng0396-333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589730">Tavtigian et al. (1996)</a> noted that the BRCA2 protein, like the BRCA1 protein (<a href="/entry/113705">113705</a>), is highly charged; roughly one-quarter of the residues are acidic or basic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589730" 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="Connor, F., Smith, A., Wooster, R., Stratton, M., Dixon, A., Campbell, E., Tait, T.-M., Freeman, T., Ashworth, A. <strong>Cloning, chromosomal mapping and expression pattern of the mouse Brca2 gene.</strong> Hum. Molec. Genet. 6: 291-300, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063750</a>] [<a href="https://doi.org/10.1093/hmg/6.2.291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063750">Connor et al. (1997)</a> described the mouse Brca2 gene. They sequenced cDNA for the entire 3,329-amino acid Brca2 protein and found that, like Brca1, Brca2 is relatively poorly conserved between humans and mice (approximately 60%). Brca2 was transcribed in a diverse range of mouse tissues, especially the testis, ovary, and midgestation embryo. Brca2 was also expressed in the mammary gland and was apparently induced upon pregnancy. The pattern of expression was strikingly similar to that of Brca1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9063750" 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="Warren, M., Smith, A., Partridge, N., Masabanda, J., Griffin, D., Ashworth, A. <strong>Structural analysis of the chicken BRCA2 gene facilitates identification of functional domains and disease causing mutations.</strong> Hum. Molec. Genet. 11: 841-851, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11929857/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11929857</a>] [<a href="https://doi.org/10.1093/hmg/11.7.841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11929857">Warren et al. (2002)</a> cloned and characterized the chicken Brca2 gene. The gene is organized similarly to the human BRCA2 gene, but is more compact. The chicken gene encodes a protein of 3,399 amino acids, which is poorly conserved with mammalian BRCA2 proteins, having only 37% overall amino acid sequence identity with human BRCA2. However, certain domains are much more highly conserved, indicating functional significance. The authors speculated that knowledge of the evolutionarily divergent chicken Brca2 sequence may be useful in distinguishing sequence variants from mutations in the human BRCA2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11929857" 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="#78" class="mim-tip-reference" title="Tavtigian, S. V., Simard, J., Rommens, J., Couch, F., Shattuck-Eidens, D., Neuhausen, S., Merajver, S., Thorlacius, S., Offit, K., Stoppa-Lyonnet, D., Belanger, C., Bell, R., and 37 others. <strong>The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.</strong> Nature Genet. 12: 333-337, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589730</a>] [<a href="https://doi.org/10.1038/ng0396-333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589730">Tavtigian et al. (1996)</a> determined that the human BRCA2 gene contains 27 exons. They noted that both the BRCA1 and BRCA2 genes have a large exon 11, translational start sites in exon 2, and coding sequences that are AT-rich; both span approximately 70 kb of genomic DNA and are expressed at high levels in testis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589730" 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="#97" class="mim-tip-reference" title="Wooster, R., Neuhausen, S. L., Mangion, J., Quirk, Y., Ford, D., Collins, N., Nguyen, K., Seal, S., Tran, T., Averill, D., Fields, P., Marshall, G., and 19 others. <strong>Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13.</strong> Science 265: 2088-2090, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8091231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8091231</a>] [<a href="https://doi.org/10.1126/science.8091231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8091231">Wooster et al. (1994)</a> mapped the BRCA2 gene to chromosome 13q12-q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8091231" 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="Couch, F. J., Rommens, J. M., Neuhausen, S. L., Belanger, C., Dumont, M., Abel, K., Bell, R., Berry, S., Bogden, R., Cannon-Albright, L., Farid, L., Frye, C., and 30 others. <strong>Generation of an integrated transcription map of the BRCA2 region on chromosome 13q12-q13.</strong> Genomics 36: 86-99, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8812419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8812419</a>] [<a href="https://doi.org/10.1006/geno.1996.0428" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8812419">Couch et al. (1996)</a> generated a detailed transcription map of the 1.0-Mb region on 13q12-q13 containing the BRCA2 gene. Evidence for 7 genes, 2 putative pseudogenes, and 9 additional putative transcription units was obtained. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8812419" 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="Connor, F., Smith, A., Wooster, R., Stratton, M., Dixon, A., Campbell, E., Tait, T.-M., Freeman, T., Ashworth, A. <strong>Cloning, chromosomal mapping and expression pattern of the mouse Brca2 gene.</strong> Hum. Molec. Genet. 6: 291-300, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063750</a>] [<a href="https://doi.org/10.1093/hmg/6.2.291" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063750">Connor et al. (1997)</a> found that the mouse Brca2 gene maps to mouse chromosome 5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9063750" 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="#100" class="mim-tip-reference" title="Yang, H., Jeffrey, P. D., Miller, J., Kinnucan, E., Sun, Y., Thoma, N. H., Zheng, N., Chen, P.-L., Lee, W.-H., Pavletich, N. P. <strong>BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.</strong> Science 297: 1837-1848, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12228710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12228710</a>] [<a href="https://doi.org/10.1126/science.297.5588.1837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12228710">Yang et al. (2002)</a> determined the 3.1-angstrom crystal structure of an approximately 90-kD BRCA2 domain bound to DSS1 (<a href="/entry/601285">601285</a>), which revealed 3 oligonucleotide-binding folds and a helix-turn-helix motif. <a href="#100" class="mim-tip-reference" title="Yang, H., Jeffrey, P. D., Miller, J., Kinnucan, E., Sun, Y., Thoma, N. H., Zheng, N., Chen, P.-L., Lee, W.-H., Pavletich, N. P. <strong>BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.</strong> Science 297: 1837-1848, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12228710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12228710</a>] [<a href="https://doi.org/10.1126/science.297.5588.1837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12228710">Yang et al. (2002)</a> also demonstrated that this BRCA2 domain binds single-stranded DNA, presented its 3.5-angstrom structure bound to oligo(dT)9, provided data that implicate the helix-turn-helix motif in double-stranded DNA binding, and showed that BRCA2 stimulates RAD51 (<a href="/entry/179617">179617</a>)-mediated recombination in vitro. <a href="#100" class="mim-tip-reference" title="Yang, H., Jeffrey, P. D., Miller, J., Kinnucan, E., Sun, Y., Thoma, N. H., Zheng, N., Chen, P.-L., Lee, W.-H., Pavletich, N. P. <strong>BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.</strong> Science 297: 1837-1848, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12228710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12228710</a>] [<a href="https://doi.org/10.1126/science.297.5588.1837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12228710">Yang et al. (2002)</a> concluded that BRCA2 functions directly in homologous recombination and provided a structural and biochemical basis for understanding the loss of recombination-mediated double-strand break repair in BRCA2-associated cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12228710" 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="#64" class="mim-tip-reference" title="Pellegrini, L., Yu, D. S., Lo, T., Anand, S., Lee, M., Blundell, T. L., Venkitaraman, A. R. <strong>Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.</strong> Nature 420: 287-293, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12442171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12442171</a>] [<a href="https://doi.org/10.1038/nature01230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12442171">Pellegrini et al. (2002)</a> reported the structure of a complex between an evolutionarily conserved sequence in BRCA2 (the BRC repeat) and the RecA-homology domain of RAD51. The BRC repeat mimics a motif in RAD51 that serves as an interface for oligomerization between individual RAD51 monomers, thus enabling BRCA2 to control the assembly of the RAD51 nucleoprotein filament, which is essential for strand-pairing reactions during DNA recombination. The RAD51 oligomerization motif is highly conserved among RecA-like recombinases, highlighting a common evolutionary origin for the mechanism of nucleoprotein filament formation, mirrored in the BRC repeat. <a href="#64" class="mim-tip-reference" title="Pellegrini, L., Yu, D. S., Lo, T., Anand, S., Lee, M., Blundell, T. L., Venkitaraman, A. R. <strong>Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.</strong> Nature 420: 287-293, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12442171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12442171</a>] [<a href="https://doi.org/10.1038/nature01230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12442171">Pellegrini et al. (2002)</a> showed that cancer-associated mutations that affect the BRC repeat disrupt its predicted interaction with RAD51, yielding structural insight into mechanisms for cancer susceptibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12442171" 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="#34" 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> noted that BRCA2 includes a motif similar to the granin consensus at the C terminus of the protein. BRCA1 also has sequence homology and biochemical analogy to the granin protein family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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>Studying the expression of Brca2 in murine mammary epithelial cells as a function of proliferation and differentiation, <a href="#66" class="mim-tip-reference" title="Rajan, J. V., Wang, M., Marquis, S. T., Chodosh, L. A. <strong>Brca2 is coordinately regulated with Brca1 during proliferation and differentiation in mammary epithelial cells.</strong> Proc. Nat. Acad. Sci. 93: 13078-13083, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8917547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8917547</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=8917547[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.93.23.13078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8917547">Rajan et al. (1996)</a> demonstrated that Brca2 mRNA expression is tightly regulated during mammary epithelial proliferation and differentiation, and appears to be coordinately regulated with Brca1 expression. Both genes showed mRNA expression that was upregulated in rapidly proliferating cells; was downregulated in response to serum deprivation; was expressed in a cell cycle-dependent manner, peaking at the G1/S boundary; and was upregulated in the differentiating mammary epithelial cells in response to glucocorticoids. The results suggested that these genes are induced by, and may function in, overlapping regulatory pathways involved in the control of cell proliferation and differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8917547" 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="Milner, J., Ponder, B., Hughes-Davies, L., Seltmann, M., Kouzarides, T. <strong>Transcriptional activation functions in BRCA2. (Letter)</strong> Nature 386: 772-773, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126734</a>] [<a href="https://doi.org/10.1038/386772a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126734">Milner et al. (1997)</a> showed that the portion of human BRCA2 encoded by its third exon shares homology with a known transcription factor and is capable of activating transcription, thus indicating a potential function of BRCA2. The exon 3 sequence at the N terminus of BRCA2 (within a region highly conserved between human and mouse) showed sequence similarity to the activation domain of JUN (<a href="/entry/165160">165160</a>). They found that the activation potential within exon 3 is under negative control of inhibitory regions (IR1 and IR2) present immediately on either side of exon 3. The finding that BRCA2, like BRCA1, has transcriptional activation potential provides functional evidence of a relationship between the 2 proteins. Indeed, the fact that mutations found naturally in breast cancers disrupt the activation potential of both BRCA1 and BRCA2, indicates that compromising this activity may be an important step in the generation of a subset of familial breast cancers. Mutations found outside these activation domains may affect other functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9126734" 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="Daniels, M. J., Wang, Y., Lee, M., Venkitaraman, A. R. <strong>Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2.</strong> Science 306: 876-879, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15375219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15375219</a>] [<a href="https://doi.org/10.1126/science.1102574" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15375219">Daniels et al. (2004)</a> showed that BRCA2 deficiency impairs the completion of cell division by cytokinesis. Brca2 inactivation in mouse embryo fibroblasts (MEFs) and HeLa cells by targeted gene disruption or RNA interference delayed and prevented cell cleavage. Impeded cell separation was accompanied by abnormalities in myosin II organization during the late stages in cytokinesis. <a href="#12" class="mim-tip-reference" title="Daniels, M. J., Wang, Y., Lee, M., Venkitaraman, A. R. <strong>Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2.</strong> Science 306: 876-879, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15375219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15375219</a>] [<a href="https://doi.org/10.1126/science.1102574" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15375219">Daniels et al. (2004)</a> suggested that BRCA2 may have a role in regulating these events, as it localizes to the cytokinetic midbody. The authors concluded that their findings linked cytokinetic abnormalities to a hereditary cancer syndrome characterized by chromosomal instability and may help to explain why BRCA2-deficient tumors are frequently aneuploid. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15375219" 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>Role in DNA Repair</em></strong></p><p>
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<a href="#40" class="mim-tip-reference" title="Kinzler, K. W., Vogelstein, B. <strong>Gatekeepers and caretakers.</strong> Nature 386: 761-763, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126728</a>] [<a href="https://doi.org/10.1038/386761a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126728">Kinzler and Vogelstein (1997)</a> made a distinction between 'gatekeeper' genes and 'caretaker' genes in the determination of cancer. Gatekeepers are genes that directly regulate the growth of tumors by inhibiting growth or promoting death. Each cell type has only one, or a few, gatekeepers, and inactivation of the given gatekeeper leads to a very specific tissue distribution of cancer; for example, inherited mutations of the RB1 (<a href="/entry/614041">614041</a>), VHL (<a href="/entry/608537">608537</a>), NF1 (<a href="/entry/613113">613113</a>), and APC (<a href="/entry/611731">611731</a>) genes lead to tumors of the retina, kidney, Schwann cells, and colon, respectively. Both the maternal and the paternal copies of the gene must be altered for tumor development. It is in connection with these gatekeeper, or tumor suppressor, genes that the Knudson 2-hit hypothesis was advanced. In contrast, inactivation of a caretaker gene does not promote tumor initiation directly. Rather, neoplasia occurs indirectly; inactivation leads to genetic instability that results in increased mutation of all genes, including gatekeepers. Once a tumor is initiated by inactivation of a caretaker gene, it may progress rapidly due to an accelerated rate of mutation in other genes that directly control cell birth or death. Known caretaker genes include the nucleotide excision repair genes that are responsible for xeroderma pigmentosum, mismatch-repair genes that cause hereditary nonpolyposis colorectal cancer, and probably the ATM gene, which is responsible for ataxia-telangiectasia. <a href="#40" class="mim-tip-reference" title="Kinzler, K. W., Vogelstein, B. <strong>Gatekeepers and caretakers.</strong> Nature 386: 761-763, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126728</a>] [<a href="https://doi.org/10.1038/386761a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126728">Kinzler and Vogelstein (1997)</a> proposed that BRCA1 (<a href="/entry/113705">113705</a>) and BRCA2 should be added to the list of caretaker genes. Consistent with this hypothesis, mutations in BRCA1 and BRCA2 are rarely found in sporadic cancers, and the risk of cancer arising in people with BRCA mutations is relatively low. The distinction between gatekeepers and caretakers has important practical, as well as theoretical, ramifications. Tumors that have defective caretaker genes present an additional therapeutic target. Such tumors would be expected to respond favorably to therapeutic agents that induce the type of genomic damage that is normally detected or repaired by the particular caretaker gene involved. The discovery by <a href="#72" class="mim-tip-reference" title="Sharan, S. K., Morimatsu, M., Albrecht, U., Lim, D.-S., Regel, E., Dinh, C., Sands, A., Eichele, G., Hasty, P., Bradley, A. <strong>Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2.</strong> Nature 386: 804-810, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126738</a>] [<a href="https://doi.org/10.1038/386804a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126738">Sharan et al. (1997)</a> that most cells with defective Brca2 genes are sensitive to gamma-irradiation suggests that tumors from breast cancer patients with inherited BRCA mutations should be more sensitive to such radiation than other breast cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9126738+9126728" 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="#72" class="mim-tip-reference" title="Sharan, S. K., Morimatsu, M., Albrecht, U., Lim, D.-S., Regel, E., Dinh, C., Sands, A., Eichele, G., Hasty, P., Bradley, A. <strong>Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2.</strong> Nature 386: 804-810, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126738</a>] [<a href="https://doi.org/10.1038/386804a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126738">Sharan et al. (1997)</a> identified an interaction of the Brca2 protein with the DNA-repair protein Rad51 (<a href="/entry/179617">179617</a>). Developmental arrest in Brca2-deficient embryos, their radiation sensitivity, and the association of Brca2 with Rad51 indicated that Brca2 may be an essential cofactor in the Rad51-dependent DNA repair of double-strand breaks, thereby explaining the tumor-suppressor function of Brca2. <a href="#9" 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, 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. The authors suggested that 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/?term=9126738+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="#63" class="mim-tip-reference" title="Patel, K. J., Yu, V. P. C. C., Lee, H., Corcoran, A., Thistlethwaite, F. C., Evans, M. J., Colledge, W. H., Friedman, L. S., Ponder, B. A. J., Venkitaraman, A. R. <strong>Involvement of Brca2 in DNA repair.</strong> Molec. Cell 1: 347-357, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660919</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80035-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9660919">Patel et al. (1998)</a> showed that in culture, mouse cells harboring truncated Brca2 exhibited a proliferative impediment that worsened with successive passages. Arrest in the G1 and G2/M phases was accompanied by elevated p53 (<a href="/entry/191170">191170</a>) and p21 (<a href="/entry/116899">116899</a>) expression. Increased sensitivity to genotoxic agents, particularly ultraviolet light and methylmethanesulfonate, showed that Brca2 function was essential for the ability to survive DNA damage. Checkpoint activation and apoptotic mechanisms were largely unaffected, thereby implicating Brca2 in repair. This was substantiated by the spontaneous accumulation of chromosomal abnormalities, including breaks and aberrant chromatid exchanges. These findings defined a function of Brca2 in DNA repair, whose loss precipitates replicative failure, mutagen sensitivity, and genetic instability reminiscent of Bloom syndrome (<a href="/entry/210900">210900</a>) and Fanconi anemia (see <a href="/entry/227650">227650</a>) (<a href="#63" class="mim-tip-reference" title="Patel, K. J., Yu, V. P. C. C., Lee, H., Corcoran, A., Thistlethwaite, F. C., Evans, M. J., Colledge, W. H., Friedman, L. S., Ponder, B. A. J., Venkitaraman, A. R. <strong>Involvement of Brca2 in DNA repair.</strong> Molec. Cell 1: 347-357, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660919</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80035-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9660919">Patel et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9660919" 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="#99" class="mim-tip-reference" title="Xia, F., Taghian, D. G., DeFrank, J. S., Zeng, Z.-C., Willers, H., Iliakis, G., Powell, S. N. <strong>Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining.</strong> Proc. Nat. Acad. Sci. 98: 8644-8649, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11447276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11447276</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11447276[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.151253498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11447276">Xia et al. (2001)</a> provided direct functional evidence that the human BRCA2 gene promotes homologous recombination, which comprises 1 major pathway of DNA double-strand break repair. In contrast to BRCA1, which is involved in multiple DNA repair pathways, BRCA2 status has no impact on the other principal double-strand break repair pathway, namely, nonhomologous end joining. Thus, there exists a specific regulation of homologous recombination by BRCA2, which may function to maintain genomic integrity and suppress tumor development in proliferating cells. <a href="#53" class="mim-tip-reference" title="Moynahan, M. E., Pierce, A. J., Jasin, M. <strong>BRCA2 is required for homology-directed repair of chromosomal breaks.</strong> Molec. Cell 7: 263-272, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239455</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239455">Moynahan et al. (2001)</a> examined human and mouse cell lines containing different BRCA2 mutations for their ability to repair chromosomal breaks by homologous recombination. Using the I-SceI endonuclease to introduce a double-strand break at a specific chromosomal locus, they found that BRCA2 mutant cell lines were recombination deficient, such that homology-directed repair was reduced 6-fold to more than 100-fold depending on the cell line. Thus, BRCA2 is essential for efficient homology-directed repair, presumably in conjunction with the RAD51 recombinase. <a href="#53" class="mim-tip-reference" title="Moynahan, M. E., Pierce, A. J., Jasin, M. <strong>BRCA2 is required for homology-directed repair of chromosomal breaks.</strong> Molec. Cell 7: 263-272, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239455</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00174-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239455">Moynahan et al. (2001)</a> proposed that impaired homology-directed repair caused by BRCA2 deficiency leads to chromosomal instability and possibly tumorigenesis through lack of repair or misrepair of DNA damage. <a href="#13" class="mim-tip-reference" title="Davies, A. A., Masson, J.-Y., McIlwraith, M. J., Stasiak, A. Z., Stasiak, A., Venkitaraman, A. R., West, S. C. <strong>Role of BRCA2 in control of the RAD51 recombination and DNA repair protein.</strong> Molec. Cell 7: 273-282, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239456</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00175-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239456">Davies et al. (2001)</a> showed that BRCA2 plays a dual role in regulating the actions of RAD51, a protein essential for homologous recombination and DNA repair. First, interactions between RAD51 and the BRC3 or BRC4 regions of BRCA2 blocked nucleoprotein filament formation by RAD51. Alterations to the BRC3 region that mimicked cancer-associated BRCA2 mutations failed to exhibit this effect. Second, transport of RAD51 to the nucleus was defective in cells carrying a cancer-associated BRCA2 truncation. Thus, BRCA2 regulates both the intracellular localization and DNA-binding ability of RAD51. <a href="#13" class="mim-tip-reference" title="Davies, A. A., Masson, J.-Y., McIlwraith, M. J., Stasiak, A. Z., Stasiak, A., Venkitaraman, A. R., West, S. C. <strong>Role of BRCA2 in control of the RAD51 recombination and DNA repair protein.</strong> Molec. Cell 7: 273-282, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239456</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00175-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239456">Davies et al. (2001)</a> suggested that loss of these controls following BRCA2 inactivation may be a key event leading to genomic instability and tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11239455+11239456+11447276" 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 (FA) 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 (<a href="/entry/227646">227646</a>) by monoubiquitylation; this then forges an association with the BRCA1 protein at sites of DNA damage. <a href="#62" 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 (<a href="/entry/227645">227645</a>) 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="#32" class="mim-tip-reference" title="Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. <strong>Biallelic inactivation of BRCA2 in Fanconi anemia.</strong> Science 297: 606-609, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12065746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12065746</a>] [<a href="https://doi.org/10.1126/science.1073834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12065746">Howlett et al. (2002)</a> found that cell lines derived from FANCD1 (<a href="/entry/605724">605724</a>) patients had biallelic mutations in BRCA2 and expressed truncated BRCA2 proteins (see <a href="#0016">600185.0016</a>-<a href="#0023">600185.0023</a>). Functional complementation of FANCD1 fibroblasts with wildtype BRCA2 cDNA restored mitomycin C (MMC) resistance. <a href="#32" class="mim-tip-reference" title="Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. <strong>Biallelic inactivation of BRCA2 in Fanconi anemia.</strong> Science 297: 606-609, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12065746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12065746</a>] [<a href="https://doi.org/10.1126/science.1073834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12065746">Howlett et al. (2002)</a> concluded that the results link Fanconi anemia genes with BRCA1 and BRCA2 in a common pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12065746" 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 human genome is typically so stable that the many genetic alterations required for cancer to develop cannot accumulate unless the rate of mutation is increased, i.e., the genome becomes genetically unstable. Genetic instability is characteristic of BRCA2-deficient cells, which accumulate broken and deformed chromosomes as they divide. Similar abnormalities also occur in BRCA1-deficient cells. <a href="#86" class="mim-tip-reference" title="Venkitaraman, A. R. <strong>A growing network of cancer-susceptibility genes.</strong> New Eng. J. Med. 348: 1917-1919, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736286</a>] [<a href="https://doi.org/10.1056/NEJMcibr023150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736286">Venkitaraman (2003)</a> noted that the network of cancer susceptibility genes was growing and diagrammed the role of cancer susceptibility genes in DNA repair. The ATM (<a href="/entry/607585">607585</a>), CHEK2 (<a href="/entry/604373">604373</a>), BRCA1, and BRCA2 genes, which normally participate in the error-free repair of breaks in double-stranded DNA by homologous recombination, predispose people to breast and other cancers when inactivated. The process starts when ATM and CHEK2 protein kinases signal the presence of double-stranded breaks, caused by ionizing radiation, by phosphorylating proteins such as BRCA1, inducing their migration to sites where DNA is repaired. The DNA recombination enzyme RAD51 (<a href="/entry/179617">179617</a>) is carried to the same sites by BRCA2, and is guided there by the DNA-binding structures formed between its carboxy terminal and DSS1. The concerted activity of these proteins culminates in error-free DNA repair by recombination. <a href="#86" class="mim-tip-reference" title="Venkitaraman, A. R. <strong>A growing network of cancer-susceptibility genes.</strong> New Eng. J. Med. 348: 1917-1919, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736286</a>] [<a href="https://doi.org/10.1056/NEJMcibr023150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736286">Venkitaraman (2003)</a> stated that FA proteins are connected to this pathway, based on findings that a complex of FA proteins (termed A, C, D2, E, F, and G) triggers the ubiquitination of the Fanconi D2 protein alone and its colocalization with BRCA1 (<a href="#24" 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>) and that BRCA2 is mutated in a small group of patients with FA (<a href="#32" class="mim-tip-reference" title="Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. <strong>Biallelic inactivation of BRCA2 in Fanconi anemia.</strong> Science 297: 606-609, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12065746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12065746</a>] [<a href="https://doi.org/10.1126/science.1073834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12065746">Howlett et al., 2002</a>). The findings of <a href="#86" class="mim-tip-reference" title="Venkitaraman, A. R. <strong>A growing network of cancer-susceptibility genes.</strong> New Eng. J. Med. 348: 1917-1919, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736286</a>] [<a href="https://doi.org/10.1056/NEJMcibr023150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736286">Venkitaraman (2003)</a> emphasized the importance of the homologous recombination pathway in the pathogenesis of disorders involving chromosomal instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12065746+12736286+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>In a yeast 2-hybrid analysis, <a href="#33" class="mim-tip-reference" title="Hussain, S., Wilson, J. B., Medhurst, A. L., Hejna, J., Witt, E., Ananth, S., Davies, A., Masson, J. Y., Moses, R., West, S. C., de Winter, J. P., Ashworth, A., Jones, N. J., Mathew, C. G. <strong>Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways.</strong> Hum. Molec. Genet. 13: 1241-1248, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115758</a>] [<a href="https://doi.org/10.1093/hmg/ddh135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115758">Hussain et al. (2004)</a> observed that FANCD2 bound to a highly conserved C-terminal site in BRCA2 that also bound FANCG/XRCC9 (<a href="/entry/602956">602956</a>). FANCD2 and BRCA2 coimmunoprecipitated from cell extracts of both human and Chinese hamster wildtype cells, thus confirming that the interaction occurs in vivo. Formation of nuclear foci of FANCD2 was normal in the BRCA2 mutant CAPAN-1 cells, suggesting that recruitment of FANCD2 to sites of DNA repair is independent of wildtype BRCA2 function. FANCD2 colocalized with RAD51 in foci following treatment with mitomycin C or hydroxyurea, and colocalized very tightly with PCNA (<a href="/entry/176740">176740</a>) after treatment with hydroxyurea. <a href="#33" class="mim-tip-reference" title="Hussain, S., Wilson, J. B., Medhurst, A. L., Hejna, J., Witt, E., Ananth, S., Davies, A., Masson, J. Y., Moses, R., West, S. C., de Winter, J. P., Ashworth, A., Jones, N. J., Mathew, C. G. <strong>Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways.</strong> Hum. Molec. Genet. 13: 1241-1248, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115758</a>] [<a href="https://doi.org/10.1093/hmg/ddh135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115758">Hussain et al. (2004)</a> suggested that the observation that FANCD2 and FANCG bind to the same site in BRCA2 may indicate that these 3 proteins cooperate in the repair of replication-associated double-strand breaks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15115758" 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="Wilson, J. B., Yamamoto, K., Marriott, A. S., Hussain, S., Sung, P., Hoatlin, M. E., Mathew, C. G., Takata, M., Thompson, L. H., Kupfer, G. M., Jones, N. J. <strong>FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3.</strong> Oncogene 27: 3641-3652, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18212739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18212739</a>] [<a href="https://doi.org/10.1038/sj.onc.1211034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18212739">Wilson et al. (2008)</a> found that XRCC3 (<a href="/entry/600675">600675</a>), BRCA2, FANCD2, and FANCG (<a href="/entry/602956">602956</a>) formed a complex via multiple pairwise interactions following phosphorylation of FANCG. They proposed that a complex made up of at least these 4 proteins promotes homologous recombination repair of damaged DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18212739" 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="#47" class="mim-tip-reference" title="Lomonosov, M., Anand, S., Sangrithi, M., Davies, R., Venkitaraman, A. R. <strong>Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein.</strong> Genes Dev. 17: 3017-3022, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14681210[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.279003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14681210">Lomonosov et al. (2003)</a> presented evidence that BRCA2 has a role in the cellular response to blocked DNA replication. The Y-shaped DNA junctions normally found at stalled replication forks disappeared during replication arrest in Brca2-deficient murine embryonic fibroblasts, and this was accompanied by double-strand DNA breakage. Activation of the replication checkpoint kinase Chk2 was unaffected, suggesting that Brca2 stabilized the DNA structures at stalled forks. <a href="#47" class="mim-tip-reference" title="Lomonosov, M., Anand, S., Sangrithi, M., Davies, R., Venkitaraman, A. R. <strong>Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein.</strong> Genes Dev. 17: 3017-3022, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681210</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14681210[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.279003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14681210">Lomonosov et al. (2003)</a> hypothesized that the breakdown of replication forks in BRCA2 deficiency triggers spontaneous DNA breakage, leading to mutability and cancer predisposition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14681210" 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="#15" 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, 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="#15" 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="#101" class="mim-tip-reference" title="Yang, H., Li, Q., Fan, J., Holloman, W. K., Pavletich, N. P. <strong>The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction.</strong> Nature 433: 653-657, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703751</a>] [<a href="https://doi.org/10.1038/nature03234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703751">Yang et al. (2005)</a> showed that a full-length Brca2 homolog (Brh2, from the fungus Ustilago maydis) stimulates Rad51 (<a href="/entry/179617">179617</a>)-mediated recombination at substoichiometric concentrations relative to Rad51. Brh2 recruits Rad51 to DNA and facilitates the nucleation of the filament, which is then elongated by the pool of free Rad51. Brh2 acts preferentially at a junction between double-stranded DNA and single-stranded DNA, with strict specificity for the 3-prime overhang polarity of a resected double-stranded break. <a href="#101" class="mim-tip-reference" title="Yang, H., Li, Q., Fan, J., Holloman, W. K., Pavletich, N. P. <strong>The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction.</strong> Nature 433: 653-657, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703751</a>] [<a href="https://doi.org/10.1038/nature03234" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703751">Yang et al. (2005)</a> concluded that their results established a BRCA2 function in RAD51-mediated double-stranded break repair and explained the loss of this repair capacity in BRCA2-associated cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15703751" 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="#19" class="mim-tip-reference" title="Esashi, F., Christ, N., Gannon, J., Liu, Y., Hunt, T., Jasin, M., West, S. C. <strong>CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair.</strong> Nature 434: 598-604, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15800615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15800615</a>] [<a href="https://doi.org/10.1038/nature03404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15800615">Esashi et al. (2005)</a> demonstrated that the C-terminal region of BRCA2, which interacts directly with the essential recombination protein RAD51, contains a site (ser3291) that is phosphorylated by cyclin-dependent kinases. Phosphorylation of S3291 is low in S phase when recombination is active, but increases as cells progress toward mitosis. This modification blocks C-terminal interactions between BRCA2 and RAD51. However, DNA damage overcomes cell cycle regulation by decreasing S3291 phosphorylation and stimulating interactions with RAD51. <a href="#19" class="mim-tip-reference" title="Esashi, F., Christ, N., Gannon, J., Liu, Y., Hunt, T., Jasin, M., West, S. C. <strong>CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair.</strong> Nature 434: 598-604, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15800615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15800615</a>] [<a href="https://doi.org/10.1038/nature03404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15800615">Esashi et al. (2005)</a> concluded that S3291 phosphorylation might provide a molecular switch to regulate RAD51 recombination activity, providing insight into why BRCA2 C-terminal deletions lead to radiation sensitivity and cancer predisposition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15800615" 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="#7" class="mim-tip-reference" title="Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., Helleday, T. <strong>Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.</strong> Nature 434: 913-916, 2005. Note: Erratum: Nature 447: 346 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829966</a>] [<a href="https://doi.org/10.1038/nature03443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15829966">Bryant et al. (2005)</a> showed that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP (<a href="/entry/173870">173870</a>) inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. <a href="#7" class="mim-tip-reference" title="Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., Helleday, T. <strong>Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.</strong> Nature 434: 913-916, 2005. Note: Erratum: Nature 447: 346 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829966</a>] [<a href="https://doi.org/10.1038/nature03443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15829966">Bryant et al. (2005)</a> exploited this requirement in order to kill BRCA2-deficient tumors by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumor specific, because only the tumors (which are BRCA2-null) in BRCA2 heterozygous patients are defective in homologous recombination. <a href="#7" class="mim-tip-reference" title="Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., Helleday, T. <strong>Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.</strong> Nature 434: 913-916, 2005. Note: Erratum: Nature 447: 346 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829966</a>] [<a href="https://doi.org/10.1038/nature03443" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15829966">Bryant et al. (2005)</a> concluded that the use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumor, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15829966" 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="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 (<a href="/entry/113705">113705</a>) or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest, and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. <a href="#21" 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>By coimmunoprecipitation analysis, <a href="#98" class="mim-tip-reference" title="Xia, B., Sheng, Q., Nakanishi, K., Ohashi, A., Wu, J., Christ, N., Liu, X., Jasin, M., Couch, F. J., Livingston, D. M. <strong>Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2.</strong> Molec. Cell 22: 719-729, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16793542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16793542</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.05.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16793542">Xia et al. (2006)</a> found that PALB2 (<a href="/entry/610355">610355</a>) and BRCA2 coimmunoprecipitated from lysates of several human cell lines. Differential extraction showed that BRCA2 and PALB2 were associated with stable nuclear structures and were likely complexed in chromatin. Immunodepletion of BRCA2 codepleted much of PALB2, whereas immunodepletion of PALB2 codepleted nearly all BRCA2. BRCA1 abundance was not significantly affected. S-phase foci containing BRCA2 and PALB2 underwent dispersal and refocusing after ionizing radiation, suggesting that, like BRCA2, PALB2 participates in DNA damage response. Depletion of PALB2 by small interfering RNA largely abrogated BRCA2 focus formation. No BRCA2 foci were observed even after ionizing radiation in PALB2-depleted cells. PALB2 appeared to promote stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation. Multiple germline BRCA2 missense mutations identified in breast cancer patients appeared to disrupt PALB2 binding and disable the homologous recombination-based DNA double-strand break repair function of BRCA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16793542" 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="Shivji, M. K. K., Davies, O. R., Savill, J. M., Bates, D. L., Pellegrini, L., Venkitaraman, A. R. <strong>A region of human BRCA2 containing multiple BRC repeats promotes RAD51-mediated strand exchange.</strong> Nucleic Acids Res. 34: 4000-4011, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16914443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16914443</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16914443[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/nar/gkl505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16914443">Shivji et al. (2006)</a> noted that the individual BRC repeats of BRCA2 can either promote or inhibit the incorporation of RAD51 (<a href="/entry/179617">179617</a>) into active nucleoprotein filaments in vitro. Using coimmunoprecipitation analysis, they showed that a recombinant 1,127-amino acid BRCA2 fragment encompassing the entire BRC repeat domain (BRC1 to BRC8) of BRCA2 bound increasing amounts of RAD51, suggesting multiple RAD51-binding sites within each BRCA2(BRC1-8) molecule. Electrophoretic mobility shift assays revealed BRCA2(BRC1-8) enhanced the binding of RAD51 to dsDNA in a concentration-dependent manner. While isolated mammalian RAD51 shows relatively poor recombinase activity in vitro in the presence of ATP and physiologic ion concentrations, RAD51-dependent strand exchange was robustly stimulated by BRCA2(BRC1-8) and required Mg(2+) and ATP. <a href="#73" class="mim-tip-reference" title="Shivji, M. K. K., Davies, O. R., Savill, J. M., Bates, D. L., Pellegrini, L., Venkitaraman, A. R. <strong>A region of human BRCA2 containing multiple BRC repeats promotes RAD51-mediated strand exchange.</strong> Nucleic Acids Res. 34: 4000-4011, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16914443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16914443</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16914443[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/nar/gkl505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16914443">Shivji et al. (2006)</a> concluded that the complete BRC repeat domain of BRCA2 shows robust RAD51 binding and that BRCA2 is a critical cofactor for RAD51-mediated homologous recombination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16914443" 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="Jensen, R. B., Carreira, A., Kowalczykowski, S. C. <strong>Purified human BRCA2 stimulates RAD51-mediated recombination.</strong> Nature 467: 678-683, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20729832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20729832</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20729832[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/nature09399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20729832">Jensen et al. (2010)</a> reported the purification of BRCA2 and showed that it both binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto ssDNA. BRCA2 acts by targeting RAD51 to ssDNA over dsDNA, enabling RAD51 to displace replication protein-A (RPA; <a href="/entry/179835">179835</a>) from ssDNA and stabilizing RAD51 ssDNA filaments by blocking ATP hydrolysis. BRCA2 does not anneal ssDNA complexed with RPA, implying it does not directly function in repair processes that involve ssDNA annealing. The findings of <a href="#35" class="mim-tip-reference" title="Jensen, R. B., Carreira, A., Kowalczykowski, S. C. <strong>Purified human BRCA2 stimulates RAD51-mediated recombination.</strong> Nature 467: 678-683, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20729832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20729832</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20729832[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/nature09399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20729832">Jensen et al. (2010)</a> showed that BRCA2 is a key mediator of homologous recombination and provided a molecular basis for understanding how this DNA repair process is disrupted by BRCA2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20729832" 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="#36" class="mim-tip-reference" title="Jirawatnotai, S., Hu, Y., Michowski, W., Elias, J. E., Becks, L., Bienvenu, F., Zagozdzon, A., Goswami, T., Wang, Y. E., Clark, A. B., Kunkel, T. A., van Harn, T., Xia, B., Correll, M., Quackenbush, J., Livingston, D. M., Gygi, S. P., Sicinski, P. <strong>A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers.</strong> Nature 474: 230-234, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21654808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21654808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21654808[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/nature10155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21654808">Jirawatnotai et al. (2011)</a> performed a series of proteomic screens for cyclin D1 (<a href="/entry/168461">168461</a>) protein partners in several types of human tumors and found that cyclin D1 directly binds RAD51 and that cyclin D1-RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein (<a href="/entry/614041">614041</a>), which do not require D-cyclins for proliferation. <a href="#36" class="mim-tip-reference" title="Jirawatnotai, S., Hu, Y., Michowski, W., Elias, J. E., Becks, L., Bienvenu, F., Zagozdzon, A., Goswami, T., Wang, Y. E., Clark, A. B., Kunkel, T. A., van Harn, T., Xia, B., Correll, M., Quackenbush, J., Livingston, D. M., Gygi, S. P., Sicinski, P. <strong>A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers.</strong> Nature 474: 230-234, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21654808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21654808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21654808[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/nature10155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21654808">Jirawatnotai et al. (2011)</a> concluded that their findings revealed an unexpected function of a core cell-cycle protein in DNA repair and suggested that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers, which were thought to be unaffected by cyclin D1 inhibition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21654808" 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="#94" 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="#94" 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 (<a href="/entry/113705">113705</a>) 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 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="#94" 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>DNA repair by homologous recombination is highly suppressed in G1 cells to ensure that mitotic recombination occurs solely between sister chromatids. <a href="#60" 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="#60" 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="#60" 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><a href="#4" class="mim-tip-reference" title="Bhatia, V., Barroso, S. I., Garcia-Rubio, M. L., Tumini, E., Herrera-Moyano, E., Aguilera, A. <strong>BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2.</strong> Nature 511: 362-365, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24896180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24896180</a>] [<a href="https://doi.org/10.1038/nature13374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24896180">Bhatia et al. (2014)</a> demonstrated that the human TREX-2 complex, which is involved in mRNP biogenesis and export, prevents genome instability as determined by the accumulation of gamma-H2AX (ser139-phosphorylated histone H2AX, <a href="/entry/601772">601772</a>) and 53BP1 (<a href="/entry/605230">605230</a>) foci and single-cell electrophoresis in cells depleted of the TREX-2 subunits PCID2 (<a href="/entry/613713">613713</a>), GANP (<a href="/entry/603294">603294</a>), and DSS1 (<a href="/entry/601285">601285</a>). <a href="#4" class="mim-tip-reference" title="Bhatia, V., Barroso, S. I., Garcia-Rubio, M. L., Tumini, E., Herrera-Moyano, E., Aguilera, A. <strong>BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2.</strong> Nature 511: 362-365, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24896180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24896180</a>] [<a href="https://doi.org/10.1038/nature13374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24896180">Bhatia et al. (2014)</a> showed that the BRCA2 repair factor, which binds to DSS1, also associates with PCID2 in the cell. The use of an enhanced green fluorescent protein-tagged hybrid-binding domain of RNase H1 (<a href="/entry/604123">604123</a>) and the S9.6 antibody did not detect R-loops in TREX-2-depleted cells, but did detect the accumulation of R-loops in BRCA2-depleted cells. <a href="#4" class="mim-tip-reference" title="Bhatia, V., Barroso, S. I., Garcia-Rubio, M. L., Tumini, E., Herrera-Moyano, E., Aguilera, A. <strong>BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2.</strong> Nature 511: 362-365, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24896180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24896180</a>] [<a href="https://doi.org/10.1038/nature13374" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24896180">Bhatia et al. (2014)</a> concluded that the results indicated that R-loops are frequently formed in cells and that BRCA2 is required for their processing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24896180" 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 proximity ligation assays, <a href="#5" class="mim-tip-reference" title="Bolgi, O., Silva-Garcia, M., Ross, B., Pilla, E., Kari, V., Killisch, M., Spitzner, M., Stark, N., Lenz, C., Weiss, K., Donzelli, L., Gorrell, M. D., Grade, M., Riemer, J., Urlaub, H., Dobbelstein, M., Huber, R., Geiss-Friedlander, R. <strong>Dipeptidyl peptidase 9 triggers BRCA2 degradation and promotes DNA damage repair.</strong> EMBO Rep. 23: e54136, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35912982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35912982</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35912982[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/10.15252/embr.202154136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35912982">Bolgi et al. (2022)</a> showed that DPP9 (<a href="/entry/608258">608258</a>) and BRCA2 interacted in HeLa cells in response to DNA damage. DPP9 removed the dipeptide Met1Pro2 from the N terminus of BRCA2 by cleaving the peptide bond between Pro2 and Ile3. Similar to DPP9, DPP8 (<a href="/entry/606819">606819</a>) also hydrolyzed the N terminus of BRCA2. Pro2 played a stabilizing role for BRCA2, and its removal led to accelerated turnover of BRCA2 in response to DNA damage. In line with the results, DPP9-deficient HeLa cells showed defects in homologous recombination-mediated repair and hypersensitivity to genotoxic agents. Specifically, DPP9 activity promoted formation of RAD51 foci by processing the N terminus of BRCA2 in response to DNA damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35912982" 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 2</em></strong></p><p>
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In families with breast cancer linked to chromosome 13q12 (<a href="/entry/612555">612555</a>), <a href="#96" class="mim-tip-reference" title="Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., and 29 others. <strong>Identification of the breast cancer susceptibility gene BRCA2.</strong> Nature 378: 789-792, 1995. Note: Erratum: Nature 379: 749 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524414</a>] [<a href="https://doi.org/10.1038/378789a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8524414">Wooster et al. (1995)</a> identified 6 different germline mutations in the BRCA2 gene (see, e.g., <a href="#0001">600185.0001</a>), each causing serious disruption to the open reading frame of the transcriptional unit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8524414" 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 9 of 18 kindreds with familial breast cancer selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer, <a href="#78" class="mim-tip-reference" title="Tavtigian, S. V., Simard, J., Rommens, J., Couch, F., Shattuck-Eidens, D., Neuhausen, S., Merajver, S., Thorlacius, S., Offit, K., Stoppa-Lyonnet, D., Belanger, C., Bell, R., and 37 others. <strong>The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.</strong> Nature Genet. 12: 333-337, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589730</a>] [<a href="https://doi.org/10.1038/ng0396-333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589730">Tavtigian et al. (1996)</a> identified potentially deleterious sequence alterations in the BRCA2 gene (see, e.g., <a href="#0007">600185.0007</a>). All except 1, a deletion of 3 nucleotides, involved nucleotide deletions that altered the reading frame, leading to truncation of the BRCA2 protein. No missense or nonsense mutations were found. The authors noted that the mutational profile of BRCA2 differs from that of BRCA1: microinsertions and point mutations are about as common in BRCA1 as microdeletions, which predominate in BRCA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589730" 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="#91" class="mim-tip-reference" title="Weber, B. H. F., Brohm, M., Stec, I., Backe, J., Caffier, H. <strong>A somatic truncating mutation in BRCA2 in a sporadic breast tumor.</strong> Am. J. Hum. Genet. 59: 962-964, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8808615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8808615</a>]" pmid="8808615">Weber et al. (1996)</a> analyzed 3 large exons of BRCA2 (exons 10, 11, and 27) in 69 unselected samples of frozen breast tumor sections using the protein truncation test (PTT). They identified a truncating somatic mutation of BRCA2 in a primary ductal breast carcinoma: a 1-bp deletion of nucleotide 2882 in exon 11 that results in a frameshift, addition of 9 novel amino acids, and translation termination at codon 894. Loss of heterozygosity (LOH) was also demonstrated in 2 microsatellite markers, D13S260 and D13S171, which flank the BRCA2 locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8808615" 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="#51" class="mim-tip-reference" title="Miki, Y., Katagiri, T., Kasumi, F., Yoshimoto, T., Nakamura, Y. <strong>Mutation analysis in the BRCA2 gene in primary breast cancers.</strong> Nature Genet. 13: 245-247, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640237</a>] [<a href="https://doi.org/10.1038/ng0696-245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640237">Miki et al. (1996)</a> screened 100 primary breast cancers from Japanese patients for BRCA2 mutations using PCR-SSCP. They found 2 germline mutations and 1 somatic mutation. One of the germline mutations was an insertion of an Alu element into exon 22, which resulted in alternative splicing that skipped exon 22. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8640237" 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="#23" class="mim-tip-reference" title="Friedman, L. S., Gayther, S. A., Kurosaki, T., Gordon, D., Noble, B., Casey, G., Ponder, B. A. J., Anton-Culver, H. <strong>Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population.</strong> Am. J. Hum. Genet. 60: 313-319, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9012404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9012404</a>]" pmid="9012404">Friedman et al. (1997)</a> analyzed a population-based series of 54 male breast cancer cases from southern California for germline mutations in the BRCA1 and BRCA2 genes. A family history of breast and/or ovarian cancer in at least one first-degree relative was found in 9 patients (17%). A further 7 (13%) reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. The 54 patients showed no germline BRCA1 mutations. On the other hand, 2 of the male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only 1 of the 2 had a family history of cancer, with 1 case of ovarian cancer in a first-degree relative. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9012404" 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 define the role of BRCA2 in sporadic breast and ovarian cancer, <a href="#42" class="mim-tip-reference" title="Lancaster, J. M., Wooster, R., Mangion, J., Phelan, C. M., Cochran, C., Gumbs, C., Seal, S., Barfoot, R., Collins, N., Bignell, G., Patel, S., Hamoudi, R., Larsson, C., Wiseman, R. W., Berchuck, A., Iglehart, J. D., Marks, J. R., Ashworth, A., Stratton, M. R., Futreal, P. A. <strong>BRCA2 mutations in primary breast and ovarian cancers.</strong> Nature Genet. 13: 238-240, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640235</a>] [<a href="https://doi.org/10.1038/ng0696-238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640235">Lancaster et al. (1996)</a> screened the entire BRCA2 gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. They found alterations in 2 of 70 breast tumors and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-bp deletion (4710delAG) which was subsequently shown to be a germline mutation; the other was a somatic missense mutation (asp3095-to-glu) of unknown significance. The results suggested to <a href="#42" class="mim-tip-reference" title="Lancaster, J. M., Wooster, R., Mangion, J., Phelan, C. M., Cochran, C., Gumbs, C., Seal, S., Barfoot, R., Collins, N., Bignell, G., Patel, S., Hamoudi, R., Larsson, C., Wiseman, R. W., Berchuck, A., Iglehart, J. D., Marks, J. R., Ashworth, A., Stratton, M. R., Futreal, P. A. <strong>BRCA2 mutations in primary breast and ovarian cancers.</strong> Nature Genet. 13: 238-240, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640235</a>] [<a href="https://doi.org/10.1038/ng0696-238" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640235">Lancaster et al. (1996)</a> that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas. <a href="#80" class="mim-tip-reference" title="Teng, D. H.-F., Bogden, R., Mitchell, J., Baumgard, M., Bell, R., Berry, S., David, T., Ha, P. C., Kehrer, R., Jammulapati, S., Chen, Q., Offit, K., Skolnick, M. H., Tavtigian, S. V., Jhanwar, S., Swedlund, B., Wong, A. K. C., Kamb, A. <strong>Low incidence of BRCA2 mutations in breast carcinoma and other cancers.</strong> Nature Genet. 13: 241-244, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8640236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8640236</a>] [<a href="https://doi.org/10.1038/ng0696-241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8640236">Teng et al. (1996)</a> had similar results; mutations in BRCA2 appeared to be infrequent in all cancers including breast carcinoma. However, a probable germline mutation in a pancreatic tumor cell line suggested a role for BRCA2 in that neoplasm. <a href="#41" class="mim-tip-reference" title="Krainer, M., Silva-Arrieta, S., Fitzgerald, M. G., Shimada, A., Ishioka, C., Kanamaru, R., MacDonald, D. J., Unsal, H., Finkelstein, D. M., Bowcock, A., Isselbacher, K. J., Haber, D. A. <strong>Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer.</strong> New Eng. J. Med. 336: 1416-1421, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9145678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9145678</a>] [<a href="https://doi.org/10.1056/NEJM199705153362003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9145678">Krainer et al. (1997)</a> found definite BRCA2 mutations in 2 of 73 women with early onset (by age 32) breast cancer, suggesting that BRCA2 is associated with fewer cases than BRCA1 (p = 0.03). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9145678+8640235+8640236" 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>Most BRCA2 mutations are predicted to result in a truncated protein product. The smallest known cancer-associated deletion removes from the C terminus only 224 of the 3,418 residues constituting BRCA2, suggesting that these terminal amino acids are critical for BRCA2 function. By study of a series of green fluorescent protein (GFP)-tagged BRCA2 deletion mutants, <a href="#75" class="mim-tip-reference" title="Spain, B. H., Larson, C. J., Shihabuddin, L. S., Gage, F. H., Verma, I. M. <strong>Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.</strong> Proc. Nat. Acad. Sci. 96: 13920-13925, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10570174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10570174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10570174[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.96.24.13920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10570174">Spain et al. (1999)</a> found that nuclear localization depends on 2 nuclear localization signals that reside within the final 156 residues of BRCA2. Consistent with this observation, an endogenous truncated BRCA2 mutant, 6174delT, was found to be cytoplasmic. Together these studies provided a simple explanation for why the vast majority of BRCA2 mutants are nonfunctional: they are not translocated into the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10570174" 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="Welcsh, P. L., King, M.-C. <strong>BRCA1 and BRCA2 and the genetics of breast and ovarian cancer.</strong> Hum. Molec. Genet. 10: 705-713, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11257103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11257103</a>] [<a href="https://doi.org/10.1093/hmg/10.7.705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11257103">Welcsh and King (2001)</a> reviewed the mutagenicity of BRCA1 and BRCA2 and listed their interacting, modifying, and regulatory proteins, in order to explain why mutations in these 2 genes lead specifically to breast and ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11257103" 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="Fackenthal, J. D., Cartegni, L., Krainer, A. R., Olopade, O. I. <strong>BRCA2 T2722R is a deleterious allele that causes exon skipping.</strong> Am. J. Hum. Genet. 71: 625-631, 2002. Note: Erratum: Am. J. Hum. Genet. 73: 1477 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145750[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/10.1086/342192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145750">Fackenthal et al. (2002)</a> noted that a major limitation of genetic testing of the BRCA1 and BRCA2 genes in patients with a strong family history of breast cancer is the number of inconclusive results due to unclassified BRCA1 and BRCA2 sequence variants. Many known deleterious BRCA1 and BRCA2 mutations affect splicing, and these typically lie near intron/exon boundaries. However, there are also potential internal exonic mutations that disrupt functional exonic splicing enhancer (ESE) sequences, resulting in exon skipping. Using previously established sequence matrices for the scoring of putative ESE motifs, <a href="#20" class="mim-tip-reference" title="Fackenthal, J. D., Cartegni, L., Krainer, A. R., Olopade, O. I. <strong>BRCA2 T2722R is a deleterious allele that causes exon skipping.</strong> Am. J. Hum. Genet. 71: 625-631, 2002. Note: Erratum: Am. J. Hum. Genet. 73: 1477 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145750[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/10.1086/342192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145750">Fackenthal et al. (2002)</a> systematically examined several BRCA2 mutations for potential ESE disruption mutations and identified a thr2722-to-arg mutation (<a href="#0025">600185.0025</a>) that segregated with affected individuals in a family with breast cancer and disrupted 3 potential ESE sites. The mutation caused deleterious protein truncation and suggested a potentially useful method for determining the clinical significance of a subset of the many unclassified variants of BRCA1 and BRCA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12145750" 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="Lesnik Oberstein, S. A. J., Kriek, M., White, S. J., Kalf, M. E., Szuhai, K., den Dunnen, J. T., Breuning, M. H., Hennekam, R. C. M. <strong>Peters plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase.</strong> Am. J. Hum. Genet. 79: 562-566, 2006. Note: Erratum: Am. J. Hum. Genet. 79: 985 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16909395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16909395</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16909395[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/10.1086/507567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16909395">Lesnik Oberstein et al. (2006)</a> performed genomewide 1-Mb resolution array-based comparative genomic hybridization on genomic DNA of 2 brothers and 4 isolated patients who all carried the clinical diagnosis of Peters-plus syndrome, which is caused by mutations in the B3GALTL gene (<a href="/entry/610308">610308</a>) on chromosome 13q12. Both brothers were found to have an interstitial deletion of approximately 1.5 Mb on 13q12.3-q13.1, including the BRCA2 gene. The deletion was found in their mother and in 2 female relatives who had died of breast cancer. Thus the deletion constituted a large novel BRCA2 rearrangement associated with familial breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16909395" 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="#8" class="mim-tip-reference" title="Casilli, F., Tournier, I., Sinilnikova, O. M., Coulet, F., Soubrier, F., Houdayer, C., Hardouin, A., Berthet, P., Sobol, H., Bourdon, V., Muller, D., Fricker, J. P., and 23 others. <strong>The contribution of germline rearrangements to the spectrum of BRCA2 mutations.</strong> J. Med. Genet. 43: e49, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16950820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16950820</a>] [<a href="https://doi.org/10.1136/jmg.2005.040212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16950820">Casilli et al. (2006)</a> used quantitative multiplex PCR of short fluorescent fragments (QMPSF) to screen for BRCA2 germline rearrangements in 120 families with familial breast cancer who were negative for BRCA1 and BRCA2 mutations. Three novel and distinct BRCA2 deletions were identified in 3 families: deletion of exons 14 through 18, exons 15 and 16, and exons 12 and 13, respectively. Combined with data from the larger cohort of 194 families selected for the study in which 36 BRCA2 mutations were identified, <a href="#8" class="mim-tip-reference" title="Casilli, F., Tournier, I., Sinilnikova, O. M., Coulet, F., Soubrier, F., Houdayer, C., Hardouin, A., Berthet, P., Sobol, H., Bourdon, V., Muller, D., Fricker, J. P., and 23 others. <strong>The contribution of germline rearrangements to the spectrum of BRCA2 mutations.</strong> J. Med. Genet. 43: e49, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16950820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16950820</a>] [<a href="https://doi.org/10.1136/jmg.2005.040212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16950820">Casilli et al. (2006)</a> estimated that approximately 7.7% of germline BRCA2 mutations are rearrangements, which is similar to the contribution of rearrangements to the mutation spectrum of BRCA1 (approximately 15%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16950820" 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="#16" 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 (<a href="/entry/113705">113705</a>) and BRCA2 breast cancer predisposition genes. They identified 43 sequence variants with an 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>In a study of 9,442 BRCA1 and 5,665 BRCA2 mutation carriers from 33 study centers, <a href="#3" class="mim-tip-reference" title="Antoniou, A. C., Sinilnikova, O. M., McGuffog, L., Healey, S., Nevanlinna, H., Heikkinen, T., Simard, J., Spurdle, A. B., Beesley, J., Chen, X., Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Neuhausen, S. L., and 131 others. <strong>Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers.</strong> Hum. Molec. Genet. 18: 4442-4456, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19656774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19656774</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19656774[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/ddp372" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19656774">Antoniou et al. (2009)</a> found that the minor allele (C) of the SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3817198;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3817198</a> in LSP1 (<a href="/entry/153432">153432</a>) on chromosome 11p15.5 was associated with increased breast cancer risk only for BRCA2 mutation carriers (p trend = 2.8 x 10(-4)). <a href="#16" 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> had identified <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3817198;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3817198</a>. The SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3817198;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3817198</a> and another at 2q35, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs13387042;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs13387042</a>, appeared to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17924331+19656774" 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="#88" 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. In BRCA2 carriers, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9393597;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs9393597</a> in LOC134997 and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12652447;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12652447</a> in FBXL7 (<a href="/entry/605656">605656</a>) showed the strongest associations (p(trend) = 6 x 10(-5), 95% CI 1.25-1.92 and p(trend) = 1.7 x 10(-4), 95% CI 1.16-1.62, 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>Prostate Cancer</em></strong></p><p>
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<a href="#18" class="mim-tip-reference" title="Edwards, S. M., Kote-Jarai, Z., Meitz, J., Hamoudi, R., Hope, Q., Osin, P., Jackson, R., Southgate, C., Singh, R., Falconer, A., Dearnaley, D. P., Ardern-Jones, A., and 13 others. <strong>Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene.</strong> Am. J. Hum. Genet. 72: 1-12, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12474142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12474142</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12474142[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/10.1086/345310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12474142">Edwards et al. (2003)</a> screened the complete coding sequence of BRCA2 for germline mutations in 263 men with early-onset prostate cancer before age 55 (<a href="/entry/176807">176807</a>). Protein-truncating mutations (see, e.g., <a href="#0026">600185.0026</a>), all clustered outside the ovarian cancer cluster region, were found in 6 men (2.3%). The relative risk of developing prostate cancer by age 56 years from a deleterious germline BRCA2 mutation was 23-fold. Four of the patients with mutations had no family history of breast or ovarian cancer. These results confirmed that BRCA2 is a high-risk prostate cancer susceptibility gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12474142" 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="#27" 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="/entry/113705#0003">113705.0003</a>) and 5382insC (<a href="/entry/113705#0018">113705.0018</a>) in BRCA1 and 6174delT (<a href="#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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In a human pancreatic adenocarcinoma (<a href="/entry/260350">260350</a>), <a href="#71" class="mim-tip-reference" title="Schutte, M., da Costa, L. T., Hahn, S. A., Moskaluk, C., Hoque, A. T. M. S., Rozenblum, E., Weinstein, C. L., Bittner, M., Meltzer, P. S., Trent, J. M., Yeo, C. J., Hruban, R. H., Kern, S. E. <strong>Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies with the BRCA2 region.</strong> Proc. Nat. Acad. Sci. 92: 5950-5954, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7597059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7597059</a>] [<a href="https://doi.org/10.1073/pnas.92.13.5950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7597059">Schutte et al. (1995)</a> demonstrated a homozygous deletion in a 1-cM region of chromosome 13q12.3 within the 6-cM region identified as the BRCA2 locus. They suggested that the BRCA2 gene may be involved in multiple tumor types and that it may function as a tumor suppressor gene rather than a dominant oncogene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7597059" 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="Garcia-Marco, J. A., Caldas, C., Price, C. M., Wiedemann, L. M., Ashworth, A., Catovsky, D. <strong>Frequent somatic deletion of the 13q12.3 locus encompassing BRCA2 in chronic lymphocytic leukemia.</strong> Blood 88: 1568-1575, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8781411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8781411</a>]" pmid="8781411">Garcia-Marco et al. (1996)</a> used fluorescence in situ hybridization to analyze chromosome 13 deletions in chronic lymphocytic leukemia (CLL; see <a href="/entry/151400">151400</a>). They demonstrated deletion of the 1-Mb 13q12.3 locus, which encompasses the BRCA2 gene, in 80% of 35 cases with CLL. Homozygous deletion of BRCA2 was detected in 60% of cases. Deletion of DBM (<a href="/entry/109543">109543</a>), a previously described 13q14 locus detected with the probe D13S25, was seen in 63% of cases. <a href="#25" class="mim-tip-reference" title="Garcia-Marco, J. A., Caldas, C., Price, C. M., Wiedemann, L. M., Ashworth, A., Catovsky, D. <strong>Frequent somatic deletion of the 13q12.3 locus encompassing BRCA2 in chronic lymphocytic leukemia.</strong> Blood 88: 1568-1575, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8781411/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8781411</a>]" pmid="8781411">Garcia-Marco et al. (1996)</a> concluded that their data provided evidence for the existence of a new tumor suppressor locus in B-cell CLL located at 13q12.3. They postulated that BRCA2, which is located within the minimal deletion region, is a candidate for this new B-cell CLL tumor suppressor locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8781411" 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="#38" 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="#38" 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="#38" 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 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>Fanconi Anemia Type D1</em></strong></p><p>
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In 27 FANCD1 (<a href="/entry/605724">605724</a>) patients with biallelic mutations in BRCA2, 26 from the literature and 1 newly diagnosed, <a href="#1" class="mim-tip-reference" title="Alter, B. P., Rosenberg, P. S., Brody, L. C. <strong>Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.</strong> J. Med. Genet. 44: 1-9, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825431[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.2006.043257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16825431">Alter et al. (2007)</a> analyzed the severity of the mutations and classified them according to their association with breast cancer in heterozygotes and their predicted functional effect. Twenty mutations were frameshifts or truncations, 3 involved splice sites, 5 were missense variants of unknown severity, and 2 were benign polymorphisms. Five patients had features of the VATER association (<a href="/entry/192350">192350</a>), including 1 with VACTERL and hydrocephalus (VACTERL-H; <a href="/entry/276950">276950</a>). Leukemia was reported in 13 patients, and solid tumors in 15; 6 patients had 2 or more malignancies. The cumulative probability of any malignancy was 97% by age 5.2 years. IVS7+1G-A (<a href="#0033">600185.0033</a>) and IVS7+2T-G (<a href="#0034">600185.0034</a>) were associated with acute myelogenous leukemia, and 886delGT (<a href="#0027">600185.0027</a>) and 6174delT (<a href="#0009">600185.0009</a>) with brain tumors. However, patients with other alleles remained at very high risk for these events. Missense mutations formed a distinct cluster in a highly conserved region of the BRCA2 protein. A small group of patients with biallelic mutations in BRCA2 was distinctive in the severity of the phenotype, with early onset and high rates of leukemia and specific solid tumors, and may represent an extreme variant of Fanconi anemia. Several of the alleles were not associated with cancer in presumed carriers. Five of the 27 patients (from 21 families) with FANCD1 studied by <a href="#1" class="mim-tip-reference" title="Alter, B. P., Rosenberg, P. S., Brody, L. C. <strong>Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.</strong> J. Med. Genet. 44: 1-9, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825431[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.2006.043257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16825431">Alter et al. (2007)</a> had 3 or more of the VATER association anomalies. In these patients, both mutations in BRCA2 were considered to be deleterious or probably deleterious. Among the 5 patients with VATER association, 2 cousins had brain tumors; 1 had AML; another had Wilms tumor, neuroblastoma, and brain tumor; and another patient had medulloblastoma at the age of 3.1 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16825431" 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="Weinberg-Shukron, A., Rachmiel, M., Renbaum, P., Gulsuner, S., Walsh, T., Lobel, O., Dreifuss, A., Ben-Moshe, A., Zeligson, S., Segel, R., Shore, T., Kalifa, R., Goldberg, M., King, M.-C., Gerlitz, O., Levy-Lahad, E., Zangen, D. <strong>Essential role of BRCA2 in ovarian development and function.</strong> New Eng. J. Med. 379: 1042-1049, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30207912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30207912</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30207912[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/10.1056/NEJMoa1800024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30207912">Weinberg-Shukron et al. (2018)</a> reported 2 sisters with FANCD1 who presented with XX ovarian dysgenesis who were compound heterozygous for mutations in BRCA2. One was a nonsense mutation (V2527X) and the other was a 1-bp deletion (c.9693delA, Ser3231fsTer16) occurring at the end of the last exon. On closer examination, both girls had significant microcephaly and a few cafe-au-lait spots. One of the sisters had leukemia diagnosed at age 5 and had been in remission for 14 years. The other sister had no history of malignancy at time of evaluation. A brother had died of promyelocytic leukemia at 13 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30207912" 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="#26" class="mim-tip-reference" title="Gayther, S. A., Mangion, J., Russell, P., Seal, S., Barfoot, R., Ponder, B. A. J., Stratton, M. R., Easton, D. <strong>Variation in risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.</strong> Nature Genet. 15: 103-105, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988179</a>] [<a href="https://doi.org/10.1038/ng0197-103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988179">Gayther et al. (1997)</a> reported that families with a high proportion of ovarian cancers, relative to the frequency of breast cancer, tended to have mutations located within a 3.3-kb region in exon 11. They called this region of BRCA2, bounded by nucleotides 3035 and 6629, the 'ovarian cancer cluster region,' or OCCR. <a href="#57" class="mim-tip-reference" title="Neuhausen, S. L., Godwin, A. K., Gershoni-Baruch, R., Schubert, E., Garbert, J., Stoppa-Lyonnet, D., Olah, E., Csokay, B., Serova, O., Lalloo, F., Osorio, A., Stratton, M., and 18 others. <strong>Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: Results of an international study.</strong> Am. J. Hum. Genet. 62: 1381-1388, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585613</a>] [<a href="https://doi.org/10.1086/301885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585613">Neuhausen et al. (1998)</a> presented data consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in the OCCR, but the higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation, although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. Cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than were seen in those outside this region (48 vs 42 years; p = 0.0005). In an attempt to confirm and extend the observation of an OCCR, <a href="#82" class="mim-tip-reference" title="Thompson, D., Easton, D. <strong>Variation in cancer risks, by mutation position, in BRCA2 mutation carriers.</strong> Am. J. Hum. Genet. 68: 410-419, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11170890[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/10.1086/318181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170890">Thompson and Easton (2001)</a> analyzed a dataset of 164 BRCA2 families. They found that OCCR mutations were associated both with a significantly lower risk of breast cancer and with a significantly higher risk of ovarian cancer. There was some evidence for a lower risk of prostate cancer in carriers of an OCCR mutation, but there was no evidence of a difference in breast cancer risk in males. By age 80 years, the cumulative risk of breast cancer in male carriers of a BRCA2 mutation was estimated as 6.92%. Possible mechanisms for the variation in cancer risk were suggested by the coincidence of the OCCR with the RAD51-binding domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9585613+8988179+11170890" 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>Three Jewish founder mutations, 185delAG (<a href="/entry/113705#0003">113705.0003</a>) and 5382insC (<a href="/entry/113705#0018">113705.0018</a>) in BRCA1 and 6174delT (<a href="#0009">600185.0009</a>) in BRCA2, have been identified in breast cancer and ovarian cancer Ashkenazi patients. <a href="#22" class="mim-tip-reference" title="Friedman, E., Bar-Sade, R. B., Kruglikova, A., Risel, S., Levy-Lahad, E., Halle, D., Bar-On, E., Gershoni-Baruch, R., Dagan, E., Kepten, I., Peretz, T., Lerer, I., Wienberg, N., Shushan, A., Abeliovich, D. <strong>Double heterozygotes for the Ashkenazi founder mutations in BRCA1 and BRCA2 genes. (Letter)</strong> Am. J. Hum. Genet. 63: 1224-1227, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9758598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9758598</a>] [<a href="https://doi.org/10.1086/302040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9758598">Friedman et al. (1998)</a> pooled results from 4 cancer/genetic centers in Israel to analyze approximately 1,500 breast/ovarian cancer Ashkenazi patients for the presence of double heterozygosity as well as homozygosity for any of these mutations. Although the small number of cases precluded definite conclusions, the results suggested that the phenotypic effects of double heterozygosity for BRCA1 and BRCA2 germline mutations were not cumulative. This was in agreement with the observation that the phenotype of mice that are homozygous knockouts for the BRCA1 and BRCA2 genes is similar to that of mice that are BRCA1 knockouts. This suggests that the BRCA1 mutation is epistatic over the BRCA2 mutation. Two of the double heterozygotes described had had reproductive problems: one with primary sterility and irregular menses and another with premature menopause at the age of 37 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9758598" 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="Healey, C. S., Dunning, A. M., Teare, M. D., Chase, D., Parker, L., Burn, J., Chang-Claude, J., Mannermaa, A., Kataja, V., Huntsman, D. G., Pharoah, P. D. P., Luben, R. N., Easton, D. F., Ponder, B. A. J. <strong>A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability.</strong> Nature Genet. 26: 362-364, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062481</a>] [<a href="https://doi.org/10.1038/81691" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11062481">Healey et al. (2000)</a> pointed out that mutations in the BRCA2 gene account for fewer than 2% of all cases of breast cancer in East Anglia, U.K. They suggested that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; they viewed polymorphic variants in strongly predisposing genes, such as BRCA2, as candidates for this role. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11062481" 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 mathematical model to analyze the BRCA2 N372H polymorphism data reported by <a href="#30" class="mim-tip-reference" title="Healey, C. S., Dunning, A. M., Teare, M. D., Chase, D., Parker, L., Burn, J., Chang-Claude, J., Mannermaa, A., Kataja, V., Huntsman, D. G., Pharoah, P. D. P., Luben, R. N., Easton, D. F., Ponder, B. A. J. <strong>A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability.</strong> Nature Genet. 26: 362-364, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062481</a>] [<a href="https://doi.org/10.1038/81691" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11062481">Healey et al. (2000)</a> as well as data from 8 other populations, <a href="#79" class="mim-tip-reference" title="Teare, M. D., Cox, A., Shorto, J., Anderson, C., Bishop, D. T., Cannings, C. <strong>Heterozygote excess is repeatedly observed in females at the BRCA2 locus N372H. (Letter)</strong> J. Med. Genet. 41: 523-528, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235023</a>] [<a href="https://doi.org/10.1136/jmg.2003.017293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15235023">Teare et al. (2004)</a> found significant evidence consistent with a heterozygote advantage in females, but no evidence of genotype-specific selection in males. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11062481+15235023" 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="#68" class="mim-tip-reference" title="Risch, H. A., McLaughlin, J. R., Cole, D. E. C., Rosen, B., Bradley, L., Kwan, E., Jack, E., Vesprini, D. J., Kuperstein, G., Abrahamson, J. L. A., Fan, I., Wong, B., Narod, S. A. <strong>Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.</strong> Am. J. Hum. Genet. 68: 700-710, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179017</a>] [<a href="https://doi.org/10.1086/318787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179017">Risch et al. (2001)</a> found that ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer cluster region of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. The results suggested that BRCA2 mutations may prove to be a greater cause of cancer in male carriers than had previously been thought. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11179017" 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 study of Spanish families, <a href="#14" 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., Valasco, 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> could not confirm the conclusions of <a href="#26" class="mim-tip-reference" title="Gayther, S. A., Mangion, J., Russell, P., Seal, S., Barfoot, R., Ponder, B. A. J., Stratton, M. R., Easton, D. <strong>Variation in risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.</strong> Nature Genet. 15: 103-105, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8988179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8988179</a>] [<a href="https://doi.org/10.1038/ng0197-103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8988179">Gayther et al. (1997)</a> and <a href="#82" class="mim-tip-reference" title="Thompson, D., Easton, D. <strong>Variation in cancer risks, by mutation position, in BRCA2 mutation carriers.</strong> Am. J. Hum. Genet. 68: 410-419, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11170890[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/10.1086/318181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170890">Thompson and Easton (2001)</a> that the BRCA2 truncating mutations in families with a high proportion of ovarian cancer appear to be clustered in a 3.3-kb region in exon 11, between nucleotides 3035 and 6629. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12955716+8988179+11170890" 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="van Asperen, C. J., Brohet, R. M., Meijers-Heijboer, E. J., Hoogerbrugge, N., Verhoef, S., Vasen, H. F. A., Ausems, M. G. E. M., Menko, F. H., Gomez Garcia, E. B., Klijn, J. G. M., Hogervorst, F. B. L., van Houwelingen, J. C., van't Veer, L. J., Rookus, M. A., van Leeuwen, F. E. <strong>Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. (Letter)</strong> J. Med. Genet. 42: 711-719, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16141007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16141007</a>] [<a href="https://doi.org/10.1136/jmg.2004.028829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16141007">Van Asperen et al. (2005)</a> estimated the cancer risk for sites other than breast and ovary in 139 Dutch BRCA2 families with 66 different pathogenic mutations ascertained in a nationwide study. To avoid testing bias, they chose not to estimate risk in typed carriers but rather in 1,811 male and female family members with a 50% prior probability of being a carrier. The relative risk (RR) for each carrier site with the exception of breast and ovarian cancer was determined by comparing observed numbers with expected numbers based on Dutch cancer incidence rates. An excess risk for 4 cancer sites was observed: pancreas (RR 5.9), prostate (RR 2.5), bone (RR 14.4), and pharynx (RR 7.3). Nearly all increased risks reached statistical significance for men only. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16141007" 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="#43" class="mim-tip-reference" title="Lee, H., Trainer, A. H., Friedman, L. S., Thistlethwaite, F. C., Evans, M. J., Ponder, B. A. J., Venkitaraman, A. R. <strong>Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2.</strong> Molec. Cell 4: 1-10, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10445022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10445022</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80182-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10445022">Lee et al. (1999)</a> reported that tumors from Brca2-deficient mice exhibited dysfunction of the spindle assembly checkpoint, accompanied by mutations in the p53 (<a href="/entry/191170">191170</a>), Bub1 (<a href="/entry/602452">602452</a>), and Mad3L genes. The chromosomal aberrations precipitated by Brca2 truncation could be suppressed by mutant forms of Bub1 and p53. Thus, the authors concluded that inactivating mutations in mitotic checkpoint genes likely cooperate with BRCA2 deficiency in the pathogenesis of inherited breast cancer, with important implications for treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10445022" 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="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="#48" 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 the 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="#77" class="mim-tip-reference" title="Suzuki, A., de la Pompa, J. L., Hakem, R., Elia, A., Yoshida, R., Mo, R., Nishina, H., Chuang, T., Wakeham, A., Itie, A., Koo, W., Billia, P., Ho, A., Fukumoto, M., Hui, C. C., Mak, T. W. <strong>Brca2 is required for embryonic cellular proliferation in the mouse.</strong> Genes Dev. 11: 1242-1252, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171369</a>] [<a href="https://doi.org/10.1101/gad.11.10.1242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9171369">Suzuki et al. (1997)</a> generated mice deficient in Brca2 by targeted disruption of the Brca2 gene in which exons 10 and 11 were deleted. All homozygous mice died before embryonic day 9.5. Mutant phenotypes ranged from severely developmentally retarded embryos that did not gastrulate to embryos with reduced size that made mesoderm and survived until 8.5 days of development. Although apoptosis was normal, cellular proliferation was impaired in Brca2(10-11)-deletion mutants, both in vivo and in vitro. In addition, the expression of the cyclin-dependent kinase inhibitor p21 (<a href="/entry/116899">116899</a>) was increased. Thus, Brca2(10-11)-deletion mutant mice were similar in phenotype to Brca1(5-6)- deletion mutants but were less severely affected. Expression of either of these 2 genes was unaffected in mutant embryos of the other. <a href="#77" class="mim-tip-reference" title="Suzuki, A., de la Pompa, J. L., Hakem, R., Elia, A., Yoshida, R., Mo, R., Nishina, H., Chuang, T., Wakeham, A., Itie, A., Koo, W., Billia, P., Ho, A., Fukumoto, M., Hui, C. C., Mak, T. W. <strong>Brca2 is required for embryonic cellular proliferation in the mouse.</strong> Genes Dev. 11: 1242-1252, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9171369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9171369</a>] [<a href="https://doi.org/10.1101/gad.11.10.1242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9171369">Suzuki et al. (1997)</a> concluded that BRCA2, like BRCA1, is required for cellular proliferation during embryogenesis. The similarity in phenotype between Brca1 and Brca2 mutants suggested that these genes may have cooperative roles or convergent functions during embryogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9171369" 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="Jonkers, J., Meuwissen, R., van der Gulden, H., Peterse, H., van der Valk, M., Berns, A. <strong>Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer.</strong> Nature Genet. 29: 418-425, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11694875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11694875</a>] [<a href="https://doi.org/10.1038/ng747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11694875">Jonkers et al. (2001)</a> developed conditional mutants for Brca2 and/or p53 inactivated in various epithelial tissues, including mammary gland epithelium. Although no tumors arose in mice carrying conditional Brca2 alleles, mammary and skin tumors developed frequently in females carrying conditional Brca2 and Trp53 alleles. The presence of 1 wildtype Brca2 allele resulted in a markedly delayed tumor formation; loss of the wildtype Brca2 allele occurred in a subset of these tumors. <a href="#37" class="mim-tip-reference" title="Jonkers, J., Meuwissen, R., van der Gulden, H., Peterse, H., van der Valk, M., Berns, A. <strong>Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer.</strong> Nature Genet. 29: 418-425, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11694875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11694875</a>] [<a href="https://doi.org/10.1038/ng747" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11694875">Jonkers et al. (2001)</a> concluded that inactivation of BRCA2 and of p53 combine to mediate mammary tumorigenesis, and indicate that disruption of the p53 pathway is pivotal in BRCA2-associated breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11694875" 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="#89" class="mim-tip-reference" title="Warren, M., Lord, C. J., Masabanda, J., Griffin, D., Ashworth, A. <strong>Phenotypic effects of heterozygosity for a BRCA2 mutation.</strong> Hum. Molec. Genet. 12: 2645-2656, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12928478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12928478</a>] [<a href="https://doi.org/10.1093/hmg/ddg277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12928478">Warren et al. (2003)</a> demonstrated that in the chicken B cell line DT40, heterozygosity for a BRCA2 mutation resulted in a reduced growth rate, increased cell death, heightened sensitivity to specific DNA-damaging agents, and reduced RAD51 (<a href="/entry/179617">179617</a>) focus formation after irradiation. The authors hypothesized that in certain cell types, genome instability may be driven directly by heterozygosity for BRCA2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12928478" 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="Weinberg-Shukron, A., Rachmiel, M., Renbaum, P., Gulsuner, S., Walsh, T., Lobel, O., Dreifuss, A., Ben-Moshe, A., Zeligson, S., Segel, R., Shore, T., Kalifa, R., Goldberg, M., King, M.-C., Gerlitz, O., Levy-Lahad, E., Zangen, D. <strong>Essential role of BRCA2 in ovarian development and function.</strong> New Eng. J. Med. 379: 1042-1049, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30207912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30207912</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30207912[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/10.1056/NEJMoa1800024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30207912">Weinberg-Shukron et al. (2018)</a> crossed female and male Dmbrca2-null flies with wildtype controls. Egg production by the Dmbrca2-null female flies that were crossed with wildtype control male flies was less than 5 percent of that of wildtype fly controls, and the few eggs laid by these mutant female flies had abnormal morphologic features including eggshell transparency, round and flattened shape, and fused or no dorsal appendages. In crosses of Dmbrca2-null male flies with wildtype control female flies, egg production was not significantly altered, and the morphologic features of the eggs were normal. However, virtually no progeny survived from either cross. Heterozygous Dmbrca2 matings had no effect on the numbers of eggs or progeny. The morphologic findings of ovaries from Dmbrca2-null female flies ranged from complete ovarian dysgenesis (69% of ovaries) to underdeveloped ovaries that had fewer ovarioles, with small, disordered, and misshapen egg chambers, and few mature eggs (4% of ovaries). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30207912" 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=600185[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397507890 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397507890;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=rs397507890" 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=rs397507890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family in which breast-ovarian cancer (BROVCA2; <a href="/entry/612555">612555</a>) was clearly linked to chromosome 13q, <a href="#96" class="mim-tip-reference" title="Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., and 29 others. <strong>Identification of the breast cancer susceptibility gene BRCA2.</strong> Nature 378: 789-792, 1995. Note: Erratum: Nature 379: 749 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524414</a>] [<a href="https://doi.org/10.1038/378789a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8524414">Wooster et al. (1995)</a> identified a heterozygous 6-bp deletion in the BRCA2 gene, resulting in the removal of the last 5 bases of 1 exon, deletion of the conserved G of the 5-prime splice site of the intron, and direct conversion of the codon TTT for phenylalanine to the termination codon TAA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8524414" 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> rs11571658 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11571658;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/rs11571658?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=rs11571658" 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=rs11571658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>By sequencing the putative BRCA2 gene in individuals with early-onset breast cancer who shared only the haplotype of 13q microsatellite markers that segregated with the disease (BROVCA2; <a href="/entry/612555">612555</a>), <a href="#96" class="mim-tip-reference" title="Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., and 29 others. <strong>Identification of the breast cancer susceptibility gene BRCA2.</strong> Nature 378: 789-792, 1995. Note: Erratum: Nature 379: 749 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524414</a>] [<a href="https://doi.org/10.1038/378789a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8524414">Wooster et al. (1995)</a> found a TG deletion (<a href="#0003">600185.0003</a>) and a TT deletion in families CRC B196 and CRC B211, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8524414" 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 2 sisters of a family of Indian origin living in Mauritius for at least 5 generations, <a href="#39" class="mim-tip-reference" title="Khittoo, G., Manning, A., Mustun, H., Appadoo, J., Venkatasamy, S., Fagoonee, I., Ghadirian, P., Tonin, P. N. <strong>Mutation analysis of a Mauritian hereditary breast cancer family reveals the BRCA2 6503delTT mutation previously found to recur in different ethnic populations.</strong> Hum. Hered. 52: 55-58, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11359068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11359068</a>] [<a href="https://doi.org/10.1159/000053354" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11359068">Khittoo et al. (2001)</a> found that the 6503delTT mutation was associated with breast cancer. This mutation had been found in geographically diverse populations, and in some cases families that harbor this mutation had been shown to share intragenic polymorphisms (<a href="#57" class="mim-tip-reference" title="Neuhausen, S. L., Godwin, A. K., Gershoni-Baruch, R., Schubert, E., Garbert, J., Stoppa-Lyonnet, D., Olah, E., Csokay, B., Serova, O., Lalloo, F., Osorio, A., Stratton, M., and 18 others. <strong>Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: Results of an international study.</strong> Am. J. Hum. Genet. 62: 1381-1388, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585613</a>] [<a href="https://doi.org/10.1086/301885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585613">Neuhausen et al., 1998</a>). The haplotype of the mutation found in the Mauritian family differed from that found in other populations harboring the same mutation, suggesting that it had arisen independently in that population. Mauritius, a small island situated in the Indian Ocean off the southeast coast of Africa, was colonized by the French in 1715 and was a British possession from 1810 to 1968, when it became independent. The present-day Mauritian population is composed of at least 4 major ethnic groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11359068+9585613" 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> rs80359605 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359605;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/rs80359605?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=rs80359605" 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=rs80359605" 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 2-bp deletion in the BRCA2 gene (6503delTT) that was found in compound heterozygous state in patients with early-onset breast cancer (BROVCA2; <a href="/entry/612555">612555</a>) by <a href="#96" class="mim-tip-reference" title="Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., and 29 others. <strong>Identification of the breast cancer susceptibility gene BRCA2.</strong> Nature 378: 789-792, 1995. Note: Erratum: Nature 379: 749 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524414</a>] [<a href="https://doi.org/10.1038/378789a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8524414">Wooster et al. (1995)</a>, see <a href="#0002">600185.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8524414" 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> rs80359530 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359530;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/rs80359530?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=rs80359530" 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=rs80359530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family with breast-ovarian cancer (BROVCA2; <a href="/entry/612555">612555</a>), <a href="#96" class="mim-tip-reference" title="Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., and 29 others. <strong>Identification of the breast cancer susceptibility gene BRCA2.</strong> Nature 378: 789-792, 1995. Note: Erratum: Nature 379: 749 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524414</a>] [<a href="https://doi.org/10.1038/378789a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8524414">Wooster et al. (1995)</a> found a CT deletion which had arisen within a short repetitive sequence: CTCTCT. This feature is characteristic of deletion/insertion mutations in many genes and is presumed to be due to slippage during DNA synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8524414" 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> rs80359550 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359550;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/rs80359550?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=rs80359550" 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=rs80359550" 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=RCV000009910 OR RCV000009911 OR RCV000009912 OR RCV000034451 OR RCV000044800 OR RCV000129627 OR RCV000212245 OR RCV000367838 OR RCV000414179 OR RCV000768632 OR RCV000785226 OR RCV001535431 OR RCV003128125 OR RCV004566711 OR RCV005007837" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009910, RCV000009911, RCV000009912, RCV000034451, RCV000044800, RCV000129627, RCV000212245, RCV000367838, RCV000414179, RCV000768632, RCV000785226, RCV001535431, RCV003128125, RCV004566711, RCV005007837" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009910...</a>
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<p>In 2 families from Montreal with breast-ovarian cancer (BROVCA2; <a href="/entry/612555">612555</a>), <a href="#96" class="mim-tip-reference" title="Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., and 29 others. <strong>Identification of the breast cancer susceptibility gene BRCA2.</strong> Nature 378: 789-792, 1995. Note: Erratum: Nature 379: 749 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524414</a>] [<a href="https://doi.org/10.1038/378789a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8524414">Wooster et al. (1995)</a> found a T deletion and an AAAC deletion (<a href="#0006">600185.0006</a>), respectively, in the BRCA2 gene. Both of these families included a male breast cancer case; previous analyses had indicated that the large majority of such families have BRCA2 mutations (<a href="#76" 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.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8075631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8075631</a>] [<a href="https://doi.org/10.1038/ng0594-103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8075631">Stratton et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8075631+8524414" 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> rs80359351 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359351;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/rs80359351?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=rs80359351" 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=rs80359351" 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=RCV000009907 OR RCV000044064 OR RCV000131102 OR RCV000160273 OR RCV000210161 OR RCV000240755 OR RCV000458791 OR RCV000735443 OR RCV001354011 OR RCV001849261 OR RCV003128124 OR RCV003162225 OR RCV003483429 OR RCV004795387 OR RCV004802927" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009907, RCV000044064, RCV000131102, RCV000160273, RCV000210161, RCV000240755, RCV000458791, RCV000735443, RCV001354011, RCV001849261, RCV003128124, RCV003162225, RCV003483429, RCV004795387, RCV004802927" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009907...</a>
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<p>For discussion of the 4-bp AAAC deletion in the BRCA2 gene that was found in compound heterozygous state in patients with breast-ovarian cancer (BROVCA2; <a href="/entry/612555">612555</a>) by <a href="#96" class="mim-tip-reference" title="Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., and 29 others. <strong>Identification of the breast cancer susceptibility gene BRCA2.</strong> Nature 378: 789-792, 1995. Note: Erratum: Nature 379: 749 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524414</a>] [<a href="https://doi.org/10.1038/378789a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8524414">Wooster et al. (1995)</a>, see <a href="#0005">600185.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8524414" 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">rs80359705 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359705;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=rs80359705" 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=rs80359705" 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=RCV000031732 OR RCV000034463 OR RCV000045466 OR RCV000163359 OR RCV000210122 OR RCV002477039 OR RCV003473217 OR RCV004532459" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000031732, RCV000034463, RCV000045466, RCV000163359, RCV000210122, RCV002477039, RCV003473217, RCV004532459" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000031732...</a>
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<p>In 10 of 18 breast cancer families (BROVCA2; <a href="/entry/612555">612555</a>) selected on the basis of linkage analysis and/or the presence of 1 or more cases of male breast cancer, <a href="#78" class="mim-tip-reference" title="Tavtigian, S. V., Simard, J., Rommens, J., Couch, F., Shattuck-Eidens, D., Neuhausen, S., Merajver, S., Thorlacius, S., Offit, K., Stoppa-Lyonnet, D., Belanger, C., Bell, R., and 37 others. <strong>The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.</strong> Nature Genet. 12: 333-337, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589730</a>] [<a href="https://doi.org/10.1038/ng0396-333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589730">Tavtigian et al. (1996)</a> identified microdeletions in the BRCA2 gene. One of the microdeletions involved nucleotide C8525 in codon 2766. This deletion caused a frameshift, generating a termination signal at codon 2776. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589730" 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">rs80359414 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359414;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=rs80359414" 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=rs80359414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>One of the 10 breast cancer families (BROVCA2; <a href="/entry/612555">612555</a>) with microdeletions studied by <a href="#78" class="mim-tip-reference" title="Tavtigian, S. V., Simard, J., Rommens, J., Couch, F., Shattuck-Eidens, D., Neuhausen, S., Merajver, S., Thorlacius, S., Offit, K., Stoppa-Lyonnet, D., Belanger, C., Bell, R., and 37 others. <strong>The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.</strong> Nature Genet. 12: 333-337, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589730</a>] [<a href="https://doi.org/10.1038/ng0396-333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589730">Tavtigian et al. (1996)</a> had deletion of 3 nucleotides constituting codon 1302 for threonine. Except for a deletion of exon 2 in the mRNA in 1 family, all of the microdeletion families had frameshift mutations leading to premature termination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589730" 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=RCV000009910 OR RCV000009911 OR RCV000009912 OR RCV000034451 OR RCV000044800 OR RCV000129627 OR RCV000212245 OR RCV000367838 OR RCV000414179 OR RCV000768632 OR RCV000785226 OR RCV001535431 OR RCV003128125 OR RCV004566711 OR RCV005007837" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009910, RCV000009911, RCV000009912, RCV000034451, RCV000044800, RCV000129627, RCV000212245, RCV000367838, RCV000414179, RCV000768632, RCV000785226, RCV001535431, RCV003128125, RCV004566711, RCV005007837" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009910...</a>
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<p><strong><em>Breast Cancer</em></strong></p><p>
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<a href="#56" class="mim-tip-reference" title="Neuhausen, S., Gilewski, T., Norton, L., Tran, T., McGuire, P., Swensen, J., Hampel, H., Borgen, P., Brown, K., Skolnick, M., Shattuck-Eidens, D., Jhanwar, S., Goldgar, D., Offit, K. <strong>Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer.</strong> Nature Genet. 13: 126-128, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673092</a>] [<a href="https://doi.org/10.1038/ng0596-126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673092">Neuhausen et al. (1996)</a> investigated the frequency of a 6174delT frameshift mutation in 200 women with early-onset breast cancer (BROVCA2; <a href="/entry/612555">612555</a>). Six of 80 Ashkenazi Jewish women diagnosed with breast cancer before the age of 42 years were found to be heterozygous for the mutation, whereas the mutation was not detected in 93 non-Jewish women diagnosed with breast cancer at the same age. The mutation was detected in 2 of 27 additional Jewish families in which breast cancer occurred at age 42 to 50 years in the proband. The frequency of the 6174delT mutation in Ashkenazim was estimated to be 3 per 1000. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8673092" 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 population-based study of approximately 3,000 Ashkenazi Jewish samples, <a href="#69" 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> determined that the BRCA1 185delAG mutation (<a href="/entry/113705#0003">113705.0003</a>) and the BRCA2 6174delT mutation constitute the 2 most frequent mutant alleles predisposing to hereditary breast cancer among the Ashkenazim. The 6174delT mutation in BRCA2 appeared to have a relatively lower penetrance because it had a carrier frequency of 1.52% whereas the 185delAG mutation, which is a more frequent cause of breast cancer, had a frequency of 1.09%. <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="#58" class="mim-tip-reference" title="Oddoux, C., Struewing, J. P., Clayton, C. M., Neuhausen, S., Brody, L. C., Kaback, M., Haas, B., Norton, L., Borgen, P., Jhanwar, S., Goldgar, D., Ostrer, H., Offit, K. <strong>The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%.</strong> Nature Genet. 14: 188-190, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8841192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8841192</a>] [<a href="https://doi.org/10.1038/ng1096-188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8841192">Oddoux et al. (1996)</a> found a prevalence of approximately 1% for the del6174T mutation (confidence interval 0.6-1.5). Relative risk of developing breast cancer by age 42 is estimated to be 9.2 for the del6174T mutation, compared to 31 for the 185delAG mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8841192" 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>As indicated elsewhere, in Ashkenazi Jewish individuals, the BRCA1 185delAG and the BRCA2 6174delT mutations are estimated to be present in 1.05% and 1.36% of the population, respectively. Approximately 20% of Jewish breast cancer cases under age 42, and about 32% of Jewish breast cancer families, can be attributed to the BRCA1 185delAG mutation. In comparison, only about 8% of breast cancer cases less than age 42, and about 4% of breast cancer families can be attributed to the BRCA2 6174delT mutation. Cancers of male breast and several other sites are overrepresented in BRCA2 families (summary by <a href="#61" class="mim-tip-reference" title="Ozcelik, H., Schmocker, B., Di Nicola, N., Shi, X.-H., Langer, B., Moore, M., Taylor, B. R., Narod, S. A., Darlington, G., Andrulis, I. L., Gallinger, S., Redston, M. <strong>Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. (Letter)</strong> Nature Genet. 16: 17-18, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9140390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9140390</a>] [<a href="https://doi.org/10.1038/ng0597-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9140390">Ozcelik et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9140390" 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 patient who developed high-grade breast cancer with axillary nodal metastases before the age of 40 years, <a href="#81" 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 de novo mutation of BRCA1 (3888delGA; <a href="/entry/113705#0028">113705.0028</a>) and this mutation, 6174delT, of the BRCA2 gene. Although the 6174delT mutation of BRCA2 is frequent in individuals of Jewish descent (<a href="#56" class="mim-tip-reference" title="Neuhausen, S., Gilewski, T., Norton, L., Tran, T., McGuire, P., Swensen, J., Hampel, H., Borgen, P., Brown, K., Skolnick, M., Shattuck-Eidens, D., Jhanwar, S., Goldgar, D., Offit, K. <strong>Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer.</strong> Nature Genet. 13: 126-128, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673092</a>] [<a href="https://doi.org/10.1038/ng0596-126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673092">Neuhausen et al., 1996</a>), there was no known Jewish ancestry in the family studied. The 3888delGA mutation of BRCA1 originated in the father's germline; the 6174delT mutation of BRCA2 was inherited from the father, who developed prostate carcinoma during his early fifties. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10417300+8673092" 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</em></strong></p><p>
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<a href="#61" class="mim-tip-reference" title="Ozcelik, H., Schmocker, B., Di Nicola, N., Shi, X.-H., Langer, B., Moore, M., Taylor, B. R., Narod, S. A., Darlington, G., Andrulis, I. L., Gallinger, S., Redston, M. <strong>Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. (Letter)</strong> Nature Genet. 16: 17-18, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9140390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9140390</a>] [<a href="https://doi.org/10.1038/ng0597-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9140390">Ozcelik et al. (1997)</a> investigated the contribution of germline BRCA2 mutations to the development of pancreatic cancer (PNCA2; <a href="/entry/613347">613347</a>) in 41 patients seen over a 4-month period, and selected without regard for family history. Mutations were identified in 2 patients (4.9%); one had a previously undescribed 6076delGTTA mutation, and the other had a 6174delT mutation. The latter patient was 1 of 13 Jewish individuals in the cohort. In a subsequent study of 26 pancreatic cancers in Jewish individuals seen over a 15-year period, they found the 6174delT mutation in 3; no 6174delT mutations were identified in 55 non-Jewish pancreatic controls. The investigators suggested that the ability to identify a population at high risk for the development of pancreatic cancer might provide an opportunity to develop and evaluate prevention and early detection protocols aimed at reducing mortality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9140390" 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="Murphy, K. M., Brune, K. A., Griffin, C., Sollenberger, J. E., Petersen, G. M., Bansal, R., Hruban, R. H., Kern, S. E. <strong>Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%.</strong> Cancer Res. 62: 3789-3793, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12097290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12097290</a>]" pmid="12097290">Murphy et al. (2002)</a> sequenced the BRCA2 gene in 29 kindreds with pancreatic cancer and found that 5 patients (17.2%) had mutations that had previously been reported to be deleterious. Three patients harbored the common 6174delT frameshift mutation, and 2 had splice site mutations. A family history of breast cancer was reported in 2 of the 5 BRCA2 mutation carriers; none reported a family history of ovarian cancer. These findings confirmed an increased risk of pancreatic cancer in individuals with BRCA2 mutations and identified germline BRCA2 mutations as the most common inherited genetic alteration in familial pancreatic cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12097290" 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</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Alter, B. P., Rosenberg, P. S., Brody, L. C. <strong>Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.</strong> J. Med. Genet. 44: 1-9, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825431[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.2006.043257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16825431">Alter et al. (2007)</a> described a female infant with Fanconi anemia of complementation group D1 (FANCD1; <a href="/entry/605724">605724</a>) who carried the 6174delT mutation in compound heterozygosity with Q3066X (<a href="#0032">600185.0032</a>). Hydrocephalus, fused kidneys, and growth retardation had been identified in utero. At birth, she had intrauterine growth retardation, corneal opacities (diagnosed as Peter anomaly; see <a href="/entry/604229">604229</a>), an anteriorly placed anus, small kidneys, and long thumbs with increased laxity; this constellation led to a later diagnosis of VACTERL-H (<a href="/entry/276950">276950</a>). At age 3.1 years, she was diagnosed with medulloblastoma. <a href="#1" class="mim-tip-reference" title="Alter, B. P., Rosenberg, P. S., Brody, L. C. <strong>Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.</strong> J. Med. Genet. 44: 1-9, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825431[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.2006.043257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16825431">Alter et al. (2007)</a> described a strong family history of breast cancer and breast cancer-associated cancers. <a href="#1" class="mim-tip-reference" title="Alter, B. P., Rosenberg, P. S., Brody, L. C. <strong>Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.</strong> J. Med. Genet. 44: 1-9, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825431[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.2006.043257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16825431">Alter et al. (2007)</a> noted that 2 other FANCD1 patients with features of the VATER association (<a href="/entry/192350">192350</a>) carrying this mutation had been reported (<a href="#2" class="mim-tip-reference" title="Alter, B. P., Tenner, M. S. <strong>Brain tumors in patients with Fanconi's anemia.</strong> Arch. Pediat. Adolesc. Med. 148: 661-663, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8193701/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8193701</a>] [<a href="https://doi.org/10.1001/archpedi.1994.02170060115027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8193701">Alter and Tenner, 1994</a>; <a href="#59" class="mim-tip-reference" title="Offit, K., Levran, O., Mullaney, B., Mah, K., Nafa, K., Batish, S. D., Diotti, R., Schneider, H., Deffenbaugh, A., Scholl, T., Proud, V. K., Robson, M., Norton, L., Ellis, N., Hanenberg, H., Auerbach, A. D. <strong>Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.</strong> J. Nat. Cancer Inst. 95: 1548-1551, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14559878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14559878</a>] [<a href="https://doi.org/10.1093/jnci/djg072" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14559878">Offit et al., 2003</a>). These patients, who were sibs, also had brain tumors. A third FANCD1 patient carrying this mutation and 886delGT (<a href="#0027">600185.0027</a>) had medulloblastoma (<a href="#59" class="mim-tip-reference" title="Offit, K., Levran, O., Mullaney, B., Mah, K., Nafa, K., Batish, S. D., Diotti, R., Schneider, H., Deffenbaugh, A., Scholl, T., Proud, V. K., Robson, M., Norton, L., Ellis, N., Hanenberg, H., Auerbach, A. D. <strong>Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.</strong> J. Nat. Cancer Inst. 95: 1548-1551, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14559878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14559878</a>] [<a href="https://doi.org/10.1093/jnci/djg072" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14559878">Offit et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14559878+8193701+16825431" 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="#17" class="mim-tip-reference" title="Edwards, S. L., Brough, R., Lord, C. J., Natrajan, R., Vatcheva, R., Levine, D. A., Boyd, J., Reis-Filho, J. S., Ashworth, A. <strong>Resistance to therapy caused by intragenic deletion in BRCA2.</strong> Nature 451: 1111-1115, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18264088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18264088</a>] [<a href="https://doi.org/10.1038/nature06548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18264088">Edwards et al. (2008)</a> found that resistance to poly(ADP-ribose) polymerase (PARP; <a href="/entry/173870">173870</a>) inhibition can be acquired by deletion of a mutation in BRCA2. <a href="#17" class="mim-tip-reference" title="Edwards, S. L., Brough, R., Lord, C. J., Natrajan, R., Vatcheva, R., Levine, D. A., Boyd, J., Reis-Filho, J. S., Ashworth, A. <strong>Resistance to therapy caused by intragenic deletion in BRCA2.</strong> Nature 451: 1111-1115, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18264088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18264088</a>] [<a href="https://doi.org/10.1038/nature06548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18264088">Edwards et al. (2008)</a> derived PARP inhibitor-resistant clones from the human CAPAN1 pancreatic cancer cell line, which carries the 6174delT mutation in BRCA2. PARP inhibitor-resistant clones could form DNA damage-induced RAD51 (<a href="/entry/179617">179617</a>) nuclear foci and were able to limit genotoxin-induced genomic instability, both hallmarks of a competent homologous recombination pathway. New BRCA2 isoforms were expressed in the resistant lines as a result of intragenic deletion of the 6174delT mutation and restoration of the open reading frame (ORF). Reconstitution of BRCA2-deficient cells with these revertant BRCA2 alleles rescued PARP inhibitor sensitivity and homologous recombination deficiency. Most of the deletions in BRCA2 were associated with small tracts of homology, and possibly arose from error-prone repair caused by BRCA2 deficiency. Similar ORF-restoring mutations were present in carboplatin-resistant ovarian tumors from 6174delT mutation carriers. <a href="#17" class="mim-tip-reference" title="Edwards, S. L., Brough, R., Lord, C. J., Natrajan, R., Vatcheva, R., Levine, D. A., Boyd, J., Reis-Filho, J. S., Ashworth, A. <strong>Resistance to therapy caused by intragenic deletion in BRCA2.</strong> Nature 451: 1111-1115, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18264088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18264088</a>] [<a href="https://doi.org/10.1038/nature06548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18264088">Edwards et al. (2008)</a> concluded that their observations have implications for understanding drug resistance in BRCA mutation carriers as well as in defining functionally important domains within BRCA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18264088" 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 connection with the germline mutations of BRCA1 and BRCA2 that are frequent causes of hereditary breast cancer in Ashkenazi Jewish women, <a href="#55" 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> studied the frequency of these mutations in Ashkenazi Jewish men with prostate cancer. They found no increased incidence and concluded that it is unlikely that either of these 2 mutations predispose men to prostate cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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>
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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> rs80359671 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359671;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/rs80359671?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=rs80359671" 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=rs80359671" 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=RCV000009913 OR RCV000056288 OR RCV000131848 OR RCV000195405 OR RCV000212208 OR RCV001310167 OR RCV001554244 OR RCV004732541 OR RCV004802928" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009913, RCV000056288, RCV000131848, RCV000195405, RCV000212208, RCV001310167, RCV001554244, RCV004732541, RCV004802928" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009913...</a>
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<p><a href="#83" class="mim-tip-reference" title="Thorlacius, S., Sigurdsson, S., Bjarnadottir, H., Olafsdottir, G., Jonasson, J. G., Tryggvadottir, L., Tulinius, H., Eyfjord, J. E. <strong>Study of a single BRCA2 mutation with high carrier frequency in a small population.</strong> Am. J. Hum. Genet. 60: 1079-1084, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150155</a>]" pmid="9150155">Thorlacius et al. (1997)</a> found a 5-bp deletion in exon 9 starting at nucleotide 999 (999del5) and leading to early protein termination, in 16 of 21 Icelandic breast cancer families (BROVCA2; <a href="/entry/612555">612555</a>), indicating a founder effect. They detected a 999del5 germline mutation in 0.6% of the Icelandic population, in 7.7% of female breast cancer patients, and in 40% of males with breast cancer. The mutation was strongly associated with onset of female breast cancer at age less than 50 years. A number of cancers other than breast cancer were found to be increased in relatives of mutation carriers, including those with prostate and pancreatic cancer. Comparison of the age at onset for mother/daughter pairs with the 999del5 mutation in breast cancer indicated that age at onset was decreasing in the younger generation. Increasing breast cancer incidence and lower age at onset suggested a possible contributing environmental factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150155" 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 Icelandic patients, <a href="#74" class="mim-tip-reference" title="Sigbjornsdottir, B. I., Ragnarsson, G., Agnarsson, B. A., Huiping, C., Barkardottir, R. B., Egilsson, V., Ingvarsson, S. <strong>Chromosome 8p alterations in sporadic and BRCA2 999del5 linked breast cancer.</strong> J. Med. Genet. 37: 342-347, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10807692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10807692</a>] [<a href="https://doi.org/10.1136/jmg.37.5.342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10807692">Sigbjornsdottir et al. (2000)</a> found loss of heterozygosity (LOH) at chromosome 8p in 50% of sporadic breast tumors and 78% of BRCA2-linked tumors carrying the 999del5 mutation. The pattern of LOH was different in the 2 groups with a high proportion of BRCA2 tumors having LOH in a large region of chromosome 8p. Patients with LOH at 8p have a worse prognosis than patients without this defect. Multivariate analysis suggested that LOH at 8p is an independent prognostic factor. <a href="#74" class="mim-tip-reference" title="Sigbjornsdottir, B. I., Ragnarsson, G., Agnarsson, B. A., Huiping, C., Barkardottir, R. B., Egilsson, V., Ingvarsson, S. <strong>Chromosome 8p alterations in sporadic and BRCA2 999del5 linked breast cancer.</strong> J. Med. Genet. 37: 342-347, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10807692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10807692</a>] [<a href="https://doi.org/10.1136/jmg.37.5.342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10807692">Sigbjornsdottir et al. (2000)</a> concluded that chromosome 8p carries a tumor suppressor gene(s), the loss of which results in growth advantage of breast tumor cells, especially in carriers of the BRCA2 999del5 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10807692" 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=RCV000113129 OR RCV000496220" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000113129, RCV000496220" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000113129...</a>
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<p>In a breast cancer patient (BROVCA2; <a href="/entry/612555">612555</a>) of Scottish descent, <a href="#46" 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 breast cancer mutations: 2508G-T in BRCA1 (<a href="/entry/113705#0023">113705.0023</a>) and 3295insA, resulting in an in-frame stop codon 1025, in BRCA2. <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"><span class="text-primary">●</span> rs80359714 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359714;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/rs80359714?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=rs80359714" 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=rs80359714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#65" class="mim-tip-reference" title="Phelan, C. M., Lancaster, J. M., Tonin, P., Gumbs, C., Cochran, C., Carter, R., Ghadirian, P., Perret, C., Moslehi, R., Dion, F., Faucher, M. C., Dole, K., Karimi, S., Foulkes, W., Lounis, H., Warner, E., Goss, P., Anderson, D., Larsson, C., Narod, S. A., Futreal, P. A. <strong>Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families.</strong> Nature Genet. 13: 120-122, 1996. Note: Erratum: Nature Genet. 13: 374 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673090</a>] [<a href="https://doi.org/10.1038/ng0596-120" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673090">Phelan et al. (1996)</a> identified an 8765delAG mutation in the BRCA2 gene in 2 French Canadian patients whose families included 22 females with breast cancer (BROVCA2; <a href="/entry/612555">612555</a>) only, with mean age of diagnosis of 49.2 years. <a href="#44" class="mim-tip-reference" title="Lerer, I., Wang, T., Peretz, T., Sagi, M., Kaduri, L., Orr-Urtreger, A., Stadler, J., Gutman, H., Abeliovich, D. <strong>The 8765delAG mutation in BRCA2 is common among Jews of Yemenite extraction. (Letter)</strong> Am. J. Hum. Genet. 63: 272-274, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634522</a>] [<a href="https://doi.org/10.1086/301924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634522">Lerer et al. (1998)</a> found the same mutation in 3 Yemenite Jewish families with breast cancer; haplotype analysis indicated that the mutation was derived from a common ancestor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9634522+8673090" 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> rs144848 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144848;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/rs144848?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=rs144848" 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=rs144848" 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=RCV000009916 OR RCV000034427 OR RCV000120303 OR RCV000130720 OR RCV000207052 OR RCV000260146 OR RCV000320173 OR RCV000468776 OR RCV000768560 OR RCV002476952 OR RCV004802930" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009916, RCV000034427, RCV000120303, RCV000130720, RCV000207052, RCV000260146, RCV000320173, RCV000468776, RCV000768560, RCV002476952, RCV004802930" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009916...</a>
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<p>This variant, formerly titled BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2, has been reclassified based on the findings of <a href="#29" class="mim-tip-reference" title="Guidugli, L., Carreira, A., Caputo, S. M., Ehlen, A., Galli, A., Monteiro, A. N. A., Neuhausen, S. L., Hansen, T. V. O., Couch, F. J., Vreeswijk, M. P. G. <strong>Functional assays for analysis of variants of uncertain significance in BRCA2.</strong> Hum. Mutat. 35: 151-164, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24323938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24323938</a>] [<a href="https://doi.org/10.1002/humu.22478" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24323938">Guidugli et al. (2014)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24323938" 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="Healey, C. S., Dunning, A. M., Teare, M. D., Chase, D., Parker, L., Burn, J., Chang-Claude, J., Mannermaa, A., Kataja, V., Huntsman, D. G., Pharoah, P. D. P., Luben, R. N., Easton, D. F., Ponder, B. A. J. <strong>A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability.</strong> Nature Genet. 26: 362-364, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062481</a>] [<a href="https://doi.org/10.1038/81691" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11062481">Healey et al. (2000)</a> described a polymorphism of the BRCA2 gene, asn372 to his (N372H), located in exon 10 and associated not only with an increased risk of breast cancer (BROVCA2; <a href="/entry/612555">612555</a>) but also with an effect on prenatal viability with increased fitness of males and decreased fitness of females. The rarer allele (372H) had a frequency of 0.221 in Finnish, 0.285 in German, and a frequency intermediate between these 2 in British populations. HH homozygotes were found to have a 1.31-fold (95% confidence interval, 1.07-1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there was a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there was an excess of homozygotes: the HH group had an estimated fitness of 0.82 in females and 1.38 in males. The authors suggested that the differences in genotype may be due to selection, and concluded that this variant of BRCA2 may also affect fetal survival in a sex-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11062481" 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 mathematical model to analyze the BRCA2 N372H polymorphism data reported by <a href="#30" class="mim-tip-reference" title="Healey, C. S., Dunning, A. M., Teare, M. D., Chase, D., Parker, L., Burn, J., Chang-Claude, J., Mannermaa, A., Kataja, V., Huntsman, D. G., Pharoah, P. D. P., Luben, R. N., Easton, D. F., Ponder, B. A. J. <strong>A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability.</strong> Nature Genet. 26: 362-364, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11062481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11062481</a>] [<a href="https://doi.org/10.1038/81691" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11062481">Healey et al. (2000)</a> as well as data from 8 other populations, <a href="#79" class="mim-tip-reference" title="Teare, M. D., Cox, A., Shorto, J., Anderson, C., Bishop, D. T., Cannings, C. <strong>Heterozygote excess is repeatedly observed in females at the BRCA2 locus N372H. (Letter)</strong> J. Med. Genet. 41: 523-528, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15235023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15235023</a>] [<a href="https://doi.org/10.1136/jmg.2003.017293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15235023">Teare et al. (2004)</a> found significant evidence consistent with a heterozygote advantage in females, but no evidence of genotype-specific selection in males. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11062481+15235023" 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 N372H variant indicated that N372H 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="#29" class="mim-tip-reference" title="Guidugli, L., Carreira, A., Caputo, S. M., Ehlen, A., Galli, A., Monteiro, A. N. A., Neuhausen, S. L., Hansen, T. V. O., Couch, F. J., Vreeswijk, M. P. G. <strong>Functional assays for analysis of variants of uncertain significance in BRCA2.</strong> Hum. Mutat. 35: 151-164, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24323938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24323938</a>] [<a href="https://doi.org/10.1002/humu.22478" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24323938">Guidugli et al., 2014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24323938" 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> rs81002862 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs81002862;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/rs81002862?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=rs81002862" 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=rs81002862" 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=RCV000077460 OR RCV000212285 OR RCV000496786 OR RCV000771399" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000077460, RCV000212285, RCV000496786, RCV000771399" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000077460...</a>
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<p><a href="#70" 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> studied a recurrent BRCA2 mutation in Finnish breast cancer families (BROVCA2; <a href="/entry/612555">612555</a>), an A-to-G transition at position -2 in the splice donor site of intron 23. In 9 Finnish families carrying this mutation, <a href="#70" 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> found by haplotype analysis that the spread of the mutation was estimated to have started 7 to 11 generations (150-200 years) ago. This was also supported by the distribution of the origins of the families in the northern and eastern parts of the country that were settled after the 15th century, followed by regional population expansions in the 17th century. <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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<strong>.0015 PROSTATE CANCER</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">rs80359540 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359540;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=rs80359540" 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=rs80359540" 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=RCV000009918 OR RCV000113489 OR RCV000217033 OR RCV001269662 OR RCV001852945" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009918, RCV000113489, RCV000217033, RCV001269662, RCV001852945" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009918...</a>
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<p><a href="#28" class="mim-tip-reference" title="Gronberg, H., Ahman, A.-K., Emanuelsson, M., Bergh, A., Damber, J.-E., Borg, A. <strong>BRCA2 mutation in a family with hereditary prostate cancer.</strong> Genes Chromosomes Cancer 30: 299-301, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170288</a>]" pmid="11170288">Gronberg et al. (2001)</a> described a family in which the father and 4 of his sons had prostate cancer (<a href="/entry/176807">176807</a>) at an early age: 51, 52, 56, 58, and 63 years, respectively. In addition, 3 daughters had breast cancer between the ages of 47 and 61. In this family, a truncating mutation, 6051delA, was identified in exon 11 of the BRCA2 gene, leading to an early termination of the protein at codon 1962. In addition, loss of heterozygosity indicating a change in the other allele supported the role of the BRCA2 gene in this family as a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170288" 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, 2</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009907 OR RCV000044064 OR RCV000131102 OR RCV000160273 OR RCV000210161 OR RCV000240755 OR RCV000458791 OR RCV000735443 OR RCV001354011 OR RCV001849261 OR RCV003128124 OR RCV003162225 OR RCV003483429 OR RCV004795387 OR RCV004802927" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009907, RCV000044064, RCV000131102, RCV000160273, RCV000210161, RCV000240755, RCV000458791, RCV000735443, RCV001354011, RCV001849261, RCV003128124, RCV003162225, RCV003483429, RCV004795387, RCV004802927" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009907...</a>
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<p>In a patient with early-onset breast cancer (BROVCA2; <a href="/entry/612555">612555</a>) and no strong family history of the disease, <a href="#85" class="mim-tip-reference" title="van der Luijt, R. B., van Zon, P. H. A., Jansen, R. P. M., van der Sijs-Bos, C. J. M., Warlam-Rodenhuis, C. C., Ausems, M. G. E. M. <strong>De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer.</strong> J. Med. Genet. 38: 102-105, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11158174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11158174</a>] [<a href="https://doi.org/10.1136/jmg.38.2.102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11158174">van der Luijt et al. (2001)</a> found a 4-bp deletion in exon 11 of the BRCA2 gene (3034del4) as a de novo mutation in genomic DNA from peripheral lymphocytes. Paternity was established using highly polymorphic markers. <a href="#85" class="mim-tip-reference" title="van der Luijt, R. B., van Zon, P. H. A., Jansen, R. P. M., van der Sijs-Bos, C. J. M., Warlam-Rodenhuis, C. C., Ausems, M. G. E. M. <strong>De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer.</strong> J. Med. Genet. 38: 102-105, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11158174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11158174</a>] [<a href="https://doi.org/10.1136/jmg.38.2.102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11158174">Van der Luijt et al. (2001)</a> believed this to be the first report of a de novo germline mutation in the BRCA2 gene. In an international study of recurrent BRCA2 mutations, <a href="#57" class="mim-tip-reference" title="Neuhausen, S. L., Godwin, A. K., Gershoni-Baruch, R., Schubert, E., Garbert, J., Stoppa-Lyonnet, D., Olah, E., Csokay, B., Serova, O., Lalloo, F., Osorio, A., Stratton, M., and 18 others. <strong>Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: Results of an international study.</strong> Am. J. Hum. Genet. 62: 1381-1388, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585613</a>] [<a href="https://doi.org/10.1086/301885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585613">Neuhausen et al. (1998)</a> had investigated 11 families from 7 different western European and North American countries carrying this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9585613+11158174" 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 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</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">rs397507404 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397507404;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=rs397507404" 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=rs397507404" 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=RCV000009920 OR RCV000031747 OR RCV000160152 OR RCV000213906 OR RCV000231355 OR RCV000763329 OR RCV002221480 OR RCV003162283 OR RCV003473221 OR RCV004803081" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009920, RCV000031747, RCV000160152, RCV000213906, RCV000231355, RCV000763329, RCV002221480, RCV003162283, RCV003473221, RCV004803081" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009920...</a>
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<p>In the Fanconi anemia complementation group D1 (FANCD1; <a href="/entry/605724">605724</a>) reference cell line HSC62, <a href="#32" class="mim-tip-reference" title="Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. <strong>Biallelic inactivation of BRCA2 in Fanconi anemia.</strong> Science 297: 606-609, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12065746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12065746</a>] [<a href="https://doi.org/10.1126/science.1073834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12065746">Howlett et al. (2002)</a> identified homozygosity for an intron 19 mutation, IVS19-1G-A, in the BRCA2 gene. This mutation results in deletion of 12 nucleotides or 4 amino acids in exon 20. <a href="#32" class="mim-tip-reference" title="Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. <strong>Biallelic inactivation of BRCA2 in Fanconi anemia.</strong> Science 297: 606-609, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12065746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12065746</a>] [<a href="https://doi.org/10.1126/science.1073834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12065746">Howlett et al. (2002)</a> suggested that the mutant protein may have partial activity since the HSC62 patient has a relatively mild clinical Fanconi anemia phenotype and HSC62 cells have only modest mitomycin C sensitivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12065746" 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">rs886038169 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886038169;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=rs886038169" 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=rs886038169" 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=RCV000009921 OR RCV000241322" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009921, RCV000241322" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009921...</a>
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<p>In the Fanconi anemia complementation group D1 (FANCD1; <a href="/entry/605724">605724</a>) cell line EUFA423, <a href="#32" class="mim-tip-reference" title="Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. <strong>Biallelic inactivation of BRCA2 in Fanconi anemia.</strong> Science 297: 606-609, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12065746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12065746</a>] [<a href="https://doi.org/10.1126/science.1073834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12065746">Howlett et al. (2002)</a> identified 2 BRCA2 mutations. One was an insertion of AT at nucleotide 7691 in exon 15, and the other was an insertion of A at nucleotide 9900 in exon 27 (<a href="#0019">600185.0019</a>). Both mutations created frameshifts that were predicted to encode carboxy-terminal truncated BRCA2 proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12065746" 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">rs80359773 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359773;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=rs80359773" 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=rs80359773" 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=RCV000009922 OR RCV000114151 OR RCV000130631 OR RCV000197712 OR RCV000372727 OR RCV001353641 OR RCV003460795 OR RCV004529911 OR RCV004804111" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009922, RCV000114151, RCV000130631, RCV000197712, RCV000372727, RCV001353641, RCV003460795, RCV004529911, RCV004804111" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009922...</a>
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<p>In the Fanconi anemia complementation group D1 (FANCD1; <a href="/entry/605724">605724</a>) reference cell line EUFA423, <a href="#32" class="mim-tip-reference" title="Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. <strong>Biallelic inactivation of BRCA2 in Fanconi anemia.</strong> Science 297: 606-609, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12065746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12065746</a>] [<a href="https://doi.org/10.1126/science.1073834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12065746">Howlett et al. (2002)</a> found a 9900insA mutation in the BRCA2 gene in compound heterozygosity with 7691insAT (<a href="#0018">600185.0018</a>). The 9900insA mutant allele was previously identified in a breast cancer kindred (<a href="#6" class="mim-tip-reference" title="Breast Cancer Linkage Consortium. <strong>Cancer risks in BRCA2 mutation carriers.</strong> J. Nat. Cancer Inst. 91: 1310-1316, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10433620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10433620</a>] [<a href="https://doi.org/10.1093/jnci/91.15.1310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10433620">Breast Cancer Linkage Consortium, 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12065746+10433620" 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> rs28897743 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28897743;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/rs28897743?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=rs28897743" 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=rs28897743" 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=RCV000009923 OR RCV000031659 OR RCV000045112 OR RCV000131031 OR RCV000174440 OR RCV000475925 OR RCV000735595 OR RCV002496486 OR RCV004732575" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009923, RCV000031659, RCV000045112, RCV000131031, RCV000174440, RCV000475925, RCV000735595, RCV002496486, RCV004732575" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009923...</a>
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<p>In the Fanconi anemia (FANCD1; <a href="/entry/605724">605724</a>) cell line EUFA579, <a href="#32" class="mim-tip-reference" title="Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. <strong>Biallelic inactivation of BRCA2 in Fanconi anemia.</strong> Science 297: 606-609, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12065746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12065746</a>] [<a href="https://doi.org/10.1126/science.1073834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12065746">Howlett et al. (2002)</a> identified a G-to-A transition at nucleotide 7235 in exon 13 on 1 allele of the BRCA2 gene, and a 5837TC to AG mutation on the other allele (<a href="#0021">600185.0021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12065746" 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">rs276174859 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs276174859;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=rs276174859" 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=rs276174859" 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=RCV000009924 OR RCV000044694 OR RCV000113449 OR RCV000129595 OR RCV000214770 OR RCV000255347 OR RCV001310124 OR RCV003473362" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009924, RCV000044694, RCV000113449, RCV000129595, RCV000214770, RCV000255347, RCV001310124, RCV003473362" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009924...</a>
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<p>In the EUFA579 cell line from a patient with Fanconi anemia (FANCD1; <a href="/entry/605724">605724</a>), <a href="#32" class="mim-tip-reference" title="Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. <strong>Biallelic inactivation of BRCA2 in Fanconi anemia.</strong> Science 297: 606-609, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12065746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12065746</a>] [<a href="https://doi.org/10.1126/science.1073834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12065746">Howlett et al. (2002)</a> identified compound heterozygosity for 2 BRCA2 mutations: 7235G-A in exon 13 (<a href="#0020">600185.0020</a>) and 5837TC to AG in exon 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12065746" 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> rs80359065 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359065;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/rs80359065?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=rs80359065" 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=rs80359065" 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=RCV000009925 OR RCV000045445 OR RCV000113885 OR RCV000120363 OR RCV000129090 OR RCV000735610 OR RCV001353739 OR RCV002250493 OR RCV003476912" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009925, RCV000045445, RCV000113885, RCV000120363, RCV000129090, RCV000735610, RCV001353739, RCV002250493, RCV003476912" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009925...</a>
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<p>In the Fanconi anemia (FANCD1; <a href="/entry/605724">605724</a>) cell line AP37P, <a href="#32" class="mim-tip-reference" title="Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. <strong>Biallelic inactivation of BRCA2 in Fanconi anemia.</strong> Science 297: 606-609, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12065746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12065746</a>] [<a href="https://doi.org/10.1126/science.1073834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12065746">Howlett et al. (2002)</a> identified a G-to-T transversion at nucleotide 8415 in exon 18 of the BRCA2 gene. This mutation was in compound heterozygosity with a C-to-A transversion at nucleotide 8732 in exon 20 (<a href="#0023">600185.0023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12065746" 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> rs80359130 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359130;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/rs80359130?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=rs80359130" 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=rs80359130" 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=RCV000009926 OR RCV003114180" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009926, RCV003114180" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009926...</a>
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<p>For discussion of the C-to-A transversion at nucleotide 8732 in exon 20 in the BRCA2 gene that was found in compound heterozygous state in the Fanconi anemia (FANCD1; <a href="/entry/605724">605724</a>) cell line AP37P by <a href="#32" class="mim-tip-reference" title="Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., de Die-Smulders, C., Persky, N., Grompe, M., Joenje, H., Pals, G., Ikeda, H., Fox, E. A., D'Andrea, A. D. <strong>Biallelic inactivation of BRCA2 in Fanconi anemia.</strong> Science 297: 606-609, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12065746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12065746</a>] [<a href="https://doi.org/10.1126/science.1073834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12065746">Howlett et al. (2002)</a>, see <a href="#0022">600185.0022</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12065746" 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=RCV000031723 OR RCV000163026 OR RCV000405476 OR RCV000414368 OR RCV001193120 OR RCV003460448" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000031723, RCV000163026, RCV000405476, RCV000414368, RCV001193120, RCV003460448" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000031723...</a>
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<p>This variant, formerly titled BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2, has been reclassified based on findings discussed in an erratum pertaining to <a href="#20" class="mim-tip-reference" title="Fackenthal, J. D., Cartegni, L., Krainer, A. R., Olopade, O. I. <strong>BRCA2 T2722R is a deleterious allele that causes exon skipping.</strong> Am. J. Hum. Genet. 71: 625-631, 2002. Note: Erratum: Am. J. Hum. Genet. 73: 1477 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145750[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/10.1086/342192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145750">Fackenthal et al. (2002)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12145750" 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 several BRCA2 mutations for potential exon splicing enhancer (ESE) disruption mutations, <a href="#20" class="mim-tip-reference" title="Fackenthal, J. D., Cartegni, L., Krainer, A. R., Olopade, O. I. <strong>BRCA2 T2722R is a deleterious allele that causes exon skipping.</strong> Am. J. Hum. Genet. 71: 625-631, 2002. Note: Erratum: Am. J. Hum. Genet. 73: 1477 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145750[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/10.1086/342192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145750">Fackenthal et al. (2002)</a> found a C-to-G transition at nucleotide 8393 at exon 18 of the BRCA2 gene. The transition caused a thr2722-to-arg (T2722R) mutation which segregated with affected individuals in a family with breast cancer (<a href="/entry/612555">612555</a>) and disrupted 3 potential ESE sites. RT-PCR analysis confirmed that this mutation caused exon skipping, leading to an out-of-frame fusion of BRCA2 exons 17 and 19. The mutation caused deleterious protein truncation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12145750" 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 erratum, the authors of <a href="#20" class="mim-tip-reference" title="Fackenthal, J. D., Cartegni, L., Krainer, A. R., Olopade, O. I. <strong>BRCA2 T2722R is a deleterious allele that causes exon skipping.</strong> Am. J. Hum. Genet. 71: 625-631, 2002. Note: Erratum: Am. J. Hum. Genet. 73: 1477 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145750/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145750</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12145750[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/10.1086/342192" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145750">Fackenthal et al. (2002)</a> stated that they and others had sequenced the full-length T2722R RT-PCR product and found on several occasions that both mutant and wildtype alleles were detectable. Thus, the putative T2722R-specific exon skipping event is not complete. As this evidence suggested that exon skipping may not be fully penetrant in blood cells, the authors recommended that the BRCA2 T2722R allele be regarded as an unclassified variant until further analysis can provide definitive evidence of clinically deleterious behavior in breast epithelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12145750" 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">rs80359328 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359328;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=rs80359328" 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=rs80359328" 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=RCV000009928 OR RCV000077683 OR RCV000160270 OR RCV000163933 OR RCV000206474 OR RCV000735532 OR RCV001353737 OR RCV002272056 OR RCV004804074" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009928, RCV000077683, RCV000160270, RCV000163933, RCV000206474, RCV000735532, RCV001353737, RCV002272056, RCV004804074" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009928...</a>
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<p>One of 6 truncating mutations of the BRCA2 gene identified by <a href="#18" class="mim-tip-reference" title="Edwards, S. M., Kote-Jarai, Z., Meitz, J., Hamoudi, R., Hope, Q., Osin, P., Jackson, R., Southgate, C., Singh, R., Falconer, A., Dearnaley, D. P., Ardern-Jones, A., and 13 others. <strong>Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene.</strong> Am. J. Hum. Genet. 72: 1-12, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12474142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12474142</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12474142[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/10.1086/345310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12474142">Edwards et al. (2003)</a> in 6 men with prostate cancer (<a href="/entry/176807">176807</a>) was a 1-bp insertion of an adenine after nucleotide 2558. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12474142" 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">rs80359604 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359604;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=rs80359604" 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=rs80359604" 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=RCV000009929 OR RCV000009930 OR RCV000009931 OR RCV000009932 OR RCV000031637 OR RCV000044988 OR RCV000074548 OR RCV000131858 OR RCV000210073 OR RCV000466729 OR RCV000735587 OR RCV001356991 OR RCV001843452 OR RCV002496316 OR RCV003128126 OR RCV003162226 OR RCV003335024 OR RCV004802931" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009929, RCV000009930, RCV000009931, RCV000009932, RCV000031637, RCV000044988, RCV000074548, RCV000131858, RCV000210073, RCV000466729, RCV000735587, RCV001356991, RCV001843452, RCV002496316, RCV003128126, RCV003162226, RCV003335024, RCV004802931" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009929...</a>
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<p><strong><em>Fanconi Anemia</em></strong></p><p>
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In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; <a href="/entry/605724">605724</a>), <a href="#31" class="mim-tip-reference" title="Hirsch, B., Shimamura, A., Moreau, L., Baldinger, S., Hag-alshiekh, M., Bostrom, B., Sencer, S., D'Andrea, A. D. <strong>Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.</strong> Blood 103: 2554-2559, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14670928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14670928</a>] [<a href="https://doi.org/10.1182/blood-2003-06-1970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14670928">Hirsch et al. (2004)</a> identified compound heterozygosity for mutations in the BRCA2 gene: a 2-bp deletion in exon 8 (886delGT), inherited from the father, and an 8447T-A transversion in exon 18, resulting in a leu2740-to-ter substitution (L2740X; <a href="#0028">600185.0028</a>), inherited from the mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14670928" 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>Wilms Tumor/Medulloblastoma/Glioblastoma</em></strong></p><p>
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In 2 brothers who developed Wilms tumor (WT1; <a href="/entry/194070">194070</a>) and brain tumors, <a href="#67" class="mim-tip-reference" title="Reid, S., Renwick, A., Seal, S., Baskcomb, L., Barfoot, R., Jayatilake, H., The Breast Cancer Susceptibility Collaboration (UK), Pritchard-Jones, K., Stratton, M. R., Ridolfi-Luthy, A., Rahman, N. <strong>Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. (Letter)</strong> J. Med. Genet. 42: 147-151, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689453</a>] [<a href="https://doi.org/10.1136/jmg.2004.022673" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689453">Reid et al. (2005)</a> identified 2 truncating BRCA2 mutations: a paternally inherited 886delGT, predicted to truncate the protein at codon 223 before the 8 BRC repeats, and a maternally inherited 5873C-A transversion in exon 11, resulting in a ser1882-to-ter substitution (S1882X; <a href="#0031">600185.0031</a>) predicted to truncate the protein such that BRC7 and BRC8 would be missing. One boy developed a glioblastoma (GLM3; <a href="/entry/613029">613029</a>); the other had recurrent medulloblastoma (MDB; <a href="/entry/155255">155255</a>) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689453" 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="Alter, B. P., Rosenberg, P. S., Brody, L. C. <strong>Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.</strong> J. Med. Genet. 44: 1-9, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825431[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.2006.043257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16825431">Alter et al. (2007)</a> included this mutation in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. They noted that the 886delGT mutation is associated with brain tumors. They also concluded that small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, with early onset and high rates of leukaemia and specific solid tumours. These features may comprise an extreme variant of Fanconi anemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16825431" 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>.0028 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</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">rs80359070 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359070;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=rs80359070" 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=rs80359070" 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=RCV000009934 OR RCV000113889 OR RCV000236578 OR RCV001380789" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009934, RCV000113889, RCV000236578, RCV001380789" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009934...</a>
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<p>For discussion of the leu274-to-ter (L274X) mutation in the BRCA2 gene that was found in compound heterozygous state in patients with Fanconi anemia complementation group D1 (FANCD1; <a href="/entry/605724">605724</a>) by <a href="#31" class="mim-tip-reference" title="Hirsch, B., Shimamura, A., Moreau, L., Baldinger, S., Hag-alshiekh, M., Bostrom, B., Sencer, S., D'Andrea, A. D. <strong>Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.</strong> Blood 103: 2554-2559, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14670928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14670928</a>] [<a href="https://doi.org/10.1182/blood-2003-06-1970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14670928">Hirsch et al. (2004)</a>, see <a href="#0027">600185.0027</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14670928" 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>.0029 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
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BRCA2, GLU1550TER
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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> rs80358695 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80358695;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/rs80358695?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=rs80358695" 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=rs80358695" 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=RCV000009935 OR RCV000044460 OR RCV000113326 OR RCV000571951 OR RCV001530923 OR RCV003473074" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009935, RCV000044460, RCV000113326, RCV000571951, RCV001530923, RCV003473074" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009935...</a>
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<p>In 2 sibs with Fanconi anemia complementation group D1 (FANCD1; <a href="/entry/605724">605724</a>), <a href="#31" class="mim-tip-reference" title="Hirsch, B., Shimamura, A., Moreau, L., Baldinger, S., Hag-alshiekh, M., Bostrom, B., Sencer, S., D'Andrea, A. D. <strong>Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.</strong> Blood 103: 2554-2559, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14670928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14670928</a>] [<a href="https://doi.org/10.1182/blood-2003-06-1970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14670928">Hirsch et al. (2004)</a> identified compound heterozygosity for mutations in the BRCA2 gene: a 4876G-T transversion, resulting in a glu1550-to-ter (E1550X) substitution, and a 7757T-C transition, resulting in a leu2510-to-pro substitution (L2510P; <a href="#0030">600185.0030</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14670928" 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 id="0030" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0030 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
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</h4>
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BRCA2, LEU2510PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80358979 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80358979;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=rs80358979" 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=rs80358979" 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=RCV000009936 OR RCV000113772 OR RCV000478444 OR RCV000509658 OR RCV001290186" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009936, RCV000113772, RCV000478444, RCV000509658, RCV001290186" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009936...</a>
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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 leu2510-to-pro (L2510P) mutation in the BRCA2 gene that was found in compound heterozygous state in patients with Fanconi anemia complementation group D1 (FANCD1; <a href="/entry/605724">605724</a>) by <a href="#31" class="mim-tip-reference" title="Hirsch, B., Shimamura, A., Moreau, L., Baldinger, S., Hag-alshiekh, M., Bostrom, B., Sencer, S., D'Andrea, A. D. <strong>Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood.</strong> Blood 103: 2554-2559, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14670928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14670928</a>] [<a href="https://doi.org/10.1182/blood-2003-06-1970" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14670928">Hirsch et al. (2004)</a>, see <a href="#0029">600185.0029</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14670928" 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>
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<div>
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<a id="0031" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0031 WILMS TUMOR</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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GLIOMA SUSCEPTIBILITY 3, INCLUDED<br />
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MEDULLOBLASTOMA, INCLUDED
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<span class="mim-text-font">
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<div style="float: left;">
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BRCA2, SER1882TER
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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> rs80358785 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80358785;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/rs80358785?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=rs80358785" 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=rs80358785" 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=RCV000009937 OR RCV000009938 OR RCV000009939 OR RCV000113452 OR RCV000496664 OR RCV000568762 OR RCV001284577" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009937, RCV000009938, RCV000009939, RCV000113452, RCV000496664, RCV000568762, RCV001284577" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009937...</a>
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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 ser1882-to-ter (S1882X) mutation in the BRCA2 gene that was found in compound heterozygous state in patients with Wilms tumor (WT1; <a href="/entry/194070">194070</a>) and brain tumors by <a href="#67" class="mim-tip-reference" title="Reid, S., Renwick, A., Seal, S., Baskcomb, L., Barfoot, R., Jayatilake, H., The Breast Cancer Susceptibility Collaboration (UK), Pritchard-Jones, K., Stratton, M. R., Ridolfi-Luthy, A., Rahman, N. <strong>Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. (Letter)</strong> J. Med. Genet. 42: 147-151, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15689453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15689453</a>] [<a href="https://doi.org/10.1136/jmg.2004.022673" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15689453">Reid et al. (2005)</a>, see <a href="#0027">600185.0027</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15689453" 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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</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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<a id="0032" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0032 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</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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<div style="float: left;">
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BRCA2, GLN3066TER
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80359180 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80359180;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=rs80359180" 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=rs80359180" 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=RCV000009941 OR RCV000077463 OR RCV000131052 OR RCV000210196 OR RCV000235644 OR RCV000257912 OR RCV001357808 OR RCV003460449 OR RCV004802932" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009941, RCV000077463, RCV000131052, RCV000210196, RCV000235644, RCV000257912, RCV001357808, RCV003460449, RCV004802932" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009941...</a>
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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 gln3066-to-ter (Q3066X) mutation in the BRCA2 gene that was found in compound heterozygous state in a patient with Fanconi anemia of complementation group D1 (FANCD1; <a href="/entry/605724">605724</a>) by <a href="#1" class="mim-tip-reference" title="Alter, B. P., Rosenberg, P. S., Brody, L. C. <strong>Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.</strong> J. Med. Genet. 44: 1-9, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825431[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.2006.043257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16825431">Alter et al. (2007)</a>, see <a href="#0009">600185.0009</a>. This mutation arises from a 9424C-T transition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16825431" 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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<br />
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<div>
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<div>
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<a id="0033" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0033 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</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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BRCA2, IVS7DS, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs81002897 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs81002897;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=rs81002897" 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=rs81002897" 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=RCV000009942 OR RCV000044895 OR RCV000113913 OR RCV000131851 OR RCV000985563 OR RCV001310166" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009942, RCV000044895, RCV000113913, RCV000131851, RCV000985563, RCV001310166" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009942...</a>
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</span>
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<span class="mim-text-font">
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<p>In 2 sisters with Fanconi anemia complementation group D1 (FANCD1; <a href="/entry/605724">605724</a>), <a href="#87" class="mim-tip-reference" title="Wagner, J. E., Tolar, J., Levran, O., Scholl, T., Deffenbaugh, A., Satagopan, J., Ben-Porat, L., Mah, K., Batish, S. D., Kutler, D. I., MacMillan, M. L., Hanenberg, H., Auerbach, A. D. <strong>Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia.</strong> Blood 103: 3226-3229, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15070707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15070707</a>] [<a href="https://doi.org/10.1182/blood-2003-09-3138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15070707">Wagner et al. (2004)</a> found a splice site mutation in intron 7 of the BRCA2 gene, IVS7+1G-A, in compound heterozygosity with a premature termination mutation. Both sisters developed acute myeloblastic leukemia, at 3 and 1.8 years of age, respectively. <a href="#1" class="mim-tip-reference" title="Alter, B. P., Rosenberg, P. S., Brody, L. C. <strong>Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.</strong> J. Med. Genet. 44: 1-9, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825431[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.2006.043257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16825431">Alter et al. (2007)</a> included these patients in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15070707+16825431" 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>.0034 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</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">rs81002899 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs81002899;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=rs81002899" 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=rs81002899" 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=RCV000009943 OR RCV000031615 OR RCV000044897 OR RCV000129071 OR RCV000195357 OR RCV000769680 OR RCV000826135 OR RCV001353557 OR RCV003147279 OR RCV004802933" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009943, RCV000031615, RCV000044897, RCV000129071, RCV000195357, RCV000769680, RCV000826135, RCV001353557, RCV003147279, RCV004802933" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009943...</a>
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<p>In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; <a href="/entry/605724">605724</a>), <a href="#87" class="mim-tip-reference" title="Wagner, J. E., Tolar, J., Levran, O., Scholl, T., Deffenbaugh, A., Satagopan, J., Ben-Porat, L., Mah, K., Batish, S. D., Kutler, D. I., MacMillan, M. L., Hanenberg, H., Auerbach, A. D. <strong>Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia.</strong> Blood 103: 3226-3229, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15070707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15070707</a>] [<a href="https://doi.org/10.1182/blood-2003-09-3138" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15070707">Wagner et al. (2004)</a> found a splice site mutation in intron 7 of the BRCA2 gene, IVS7+2T-G, in compound heterozygosity with a 4-bp deletion. One of the brothers developed acute myeloblastic leukemia and the other Wilms tumor, both before 1 year of age. An unrelated patient identified by <a href="#50" class="mim-tip-reference" title="Meyer, S., Fergusson, W. D., Oostra, A. B., Medhurst, A. L., Waisfisz, Q., de Winter, J. P., Chen, F., Carr, T. F., Clayton-Smith, J., Clancy, T., Green, M., Barber, L., Eden, O. B., Will, A. M., Joenje, H., Taylor, G. M. <strong>A cross-linker-sensitive myeloid leukemia cell line from a 2-year-old boy with severe Fanconi anemia and biallelic FANCD1/BRCA2 mutations.</strong> Genes Chromosomes Cancer 42: 404-415, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15645491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15645491</a>] [<a href="https://doi.org/10.1002/gcc.20153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15645491">Meyer et al. (2005)</a> also carried this mutation; he developed acute myeloblastic leukemia as well. <a href="#1" class="mim-tip-reference" title="Alter, B. P., Rosenberg, P. S., Brody, L. C. <strong>Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.</strong> J. Med. Genet. 44: 1-9, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825431[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.2006.043257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16825431">Alter et al. (2007)</a> included these patients in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15070707+15645491+16825431" 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>See Also:</strong>
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<a href="#Mazoyer1996" class="mim-tip-reference" title="Mazoyer, S., Dunning, A. M., Serova, O., Dearden, J., Puget, N., Healey, C. S., Gayther, S. A., Mangion, J., Stratton, M. R., Lynch, H. T., Goldgar, D. E., Ponder, B. A., Lenoir, G. M. <strong>A polymorphic stop codon in BRCA2. (Letter)</strong> Nature Genet. 14: 253-254, 1996.">Mazoyer et al. (1996)</a>
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<strong>REFERENCES</strong>
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<a id="Alter2007" class="mim-anchor"></a>
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Alter, B. P., Rosenberg, P. S., Brody, L. C.
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<strong>Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.</strong>
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J. Med. Genet. 44: 1-9, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16825431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16825431</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16825431[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=16825431" 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/10.1136/jmg.2006.043257" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archpedi.1994.02170060115027" target="_blank">Full Text</a>]
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<a id="Antoniou2009" class="mim-anchor"></a>
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Antoniou, A. C., Sinilnikova, O. M., McGuffog, L., Healey, S., Nevanlinna, H., Heikkinen, T., Simard, J., Spurdle, A. B., Beesley, J., Chen, X., Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Neuhausen, S. L., and 131 others.
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<strong>Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19656774/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19656774</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19656774[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=19656774" 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/ddp372" target="_blank">Full Text</a>]
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Bhatia, V., Barroso, S. I., Garcia-Rubio, M. L., Tumini, E., Herrera-Moyano, E., Aguilera, A.
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<strong>BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2.</strong>
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Nature 511: 362-365, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24896180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24896180</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24896180" 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/nature13374" target="_blank">Full Text</a>]
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<a id="Bolgi2022" class="mim-anchor"></a>
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Bolgi, O., Silva-Garcia, M., Ross, B., Pilla, E., Kari, V., Killisch, M., Spitzner, M., Stark, N., Lenz, C., Weiss, K., Donzelli, L., Gorrell, M. D., Grade, M., Riemer, J., Urlaub, H., Dobbelstein, M., Huber, R., Geiss-Friedlander, R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35912982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35912982</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35912982[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=35912982" 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/10.15252/embr.202154136" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/jnci/91.15.1310" target="_blank">Full Text</a>]
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<a id="Bryant2005" class="mim-anchor"></a>
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Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., Helleday, T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15829966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15829966</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15829966" 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/nature03443" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2005.040212" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(00)80276-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/6.2.291" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1996.0428" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1102574" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(01)00175-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.10260" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(03)00424-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/521032" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature06548" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/345310" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature03404" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1097-2765(00)80182-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/507567" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.7.841" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1800024" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11257103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11257103</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11257103" 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/10.7.705" target="_blank">Full Text</a>]
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<a id="Willis2014" class="mim-anchor"></a>
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<strong>BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks.</strong>
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature13295" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18212739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18212739</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18212739" 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/sj.onc.1211034" target="_blank">Full Text</a>]
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Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., and 29 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524414</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8524414" 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/10.1038/378789a0" target="_blank">Full Text</a>]
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Wooster, R., Neuhausen, S. L., Mangion, J., Quirk, Y., Ford, D., Collins, N., Nguyen, K., Seal, S., Tran, T., Averill, D., Fields, P., Marshall, G., and 19 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8091231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8091231</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8091231" 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/10.1126/science.8091231" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16793542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16793542</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16793542" 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/j.molcel.2006.05.022" target="_blank">Full Text</a>]
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Xia, F., Taghian, D. G., DeFrank, J. S., Zeng, Z.-C., Willers, H., Iliakis, G., Powell, S. N.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11447276/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11447276</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11447276[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=11447276" 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/10.1073/pnas.151253498" target="_blank">Full Text</a>]
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Yang, H., Jeffrey, P. D., Miller, J., Kinnucan, E., Sun, Y., Thoma, N. H., Zheng, N., Chen, P.-L., Lee, W.-H., Pavletich, N. P.
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<strong>BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.</strong>
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Science 297: 1837-1848, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12228710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12228710</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12228710" 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/10.1126/science.297.5588.1837" target="_blank">Full Text</a>]
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<a id="Yang2005" class="mim-anchor"></a>
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Yang, H., Li, Q., Fan, J., Holloman, W. K., Pavletich, N. P.
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<strong>The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction.</strong>
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Nature 433: 653-657, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703751</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15703751" 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/nature03234" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Bao Lige - updated : 05/10/2023
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Ada Hamosh - updated : 03/27/2020<br>Ada Hamosh - updated : 07/31/2019<br>Ada Hamosh - updated : 11/28/2017<br>Ada Hamosh - updated : 02/04/2016<br>Carol A. Bocchini - updated : 11/10/2015<br>Ada Hamosh - updated : 7/17/2014<br>George E. Tiller - updated : 9/5/2013<br>Ada Hamosh - updated : 7/26/2011<br>Ada Hamosh - updated : 10/27/2010<br>George E. Tiller - updated : 10/4/2010<br>Patricia A. Hartz - updated : 8/12/2010<br>Patricia A. Hartz - updated : 7/14/2009<br>Cassandra L. Kniffin - updated : 4/28/2008<br>Ada Hamosh - updated : 3/18/2008<br>Cassandra L. Kniffin - updated : 1/8/2008<br>Ada Hamosh - updated : 11/28/2007<br>Cassandra L. Kniffin - updated : 8/27/2007<br>Ada Hamosh - updated : 5/30/2007<br>Victor A. McKusick - updated : 2/21/2007<br>Cassandra L. Kniffin - updated : 2/15/2007<br>Patricia A. Hartz - updated : 12/5/2006<br>George E. Tiller - updated : 9/7/2006<br>Victor A. McKusick - updated : 8/23/2006<br>Victor A. McKusick - updated : 12/20/2005<br>George E. Tiller - updated : 9/12/2005<br>Ada Hamosh - updated : 5/25/2005<br>Ada Hamosh - updated : 4/15/2005<br>Marla J. F. O'Neill - updated : 3/1/2005<br>Ada Hamosh - updated : 1/14/2005<br>Ada Hamosh - updated : 11/11/2004<br>Tyler D. Kritzer - updated : 9/3/2004<br>Victor A. McKusick - updated : 9/3/2004<br>Marla J. F. O'Neill - updated : 8/27/2004<br>Patricia A. Hartz - updated : 3/10/2004<br>Victor A. McKusick - updated : 1/13/2004<br>Cassandra L. Kniffin - updated : 11/11/2003<br>Victor A. McKusick - updated : 10/23/2003<br>Cassandra L. Kniffin - reorganized : 9/12/2003<br>Victor A. McKusick - updated : 6/3/2003<br>Victor A. McKusick - updated : 1/22/2003<br>Ada Hamosh - updated : 11/12/2002<br>George E. Tiller - updated : 10/29/2002<br>Victor A. McKusick - updated : 10/9/2002<br>Victor A. McKusick - updated : 10/1/2002<br>Ada Hamosh - updated : 9/30/2002<br>Victor A. McKusick - updated : 9/19/2002<br>Victor A. McKusick - updated : 9/17/2002<br>Anne M. Stumpf - updated : 8/7/2002<br>Ada Hamosh - updated : 8/6/2002<br>Victor A. McKusick - updated : 6/12/2002<br>Michael B. Petersen - updated : 3/4/2002<br>Michael B. Petersen - updated : 11/19/2001<br>Ada Hamosh - updated : 11/13/2001<br>Victor A. McKusick - updated : 9/26/2001<br>Victor A. McKusick - updated : 9/13/2001<br>Michael J. Wright - updated : 7/20/2001<br>George E. Tiller - updated : 6/18/2001<br>Michael J. Wright - updated : 6/6/2001<br>Victor A. McKusick - updated : 4/10/2001<br>Victor A. McKusick - updated : 3/16/2001<br>Victor A. McKusick - updated : 3/15/2001<br>Stylianos E. Antonarakis - updated : 3/12/2001<br>Victor A. McKusick - updated : 3/8/2001<br>Victor A. McKusick - updated : 10/26/2000<br>Ada Hamosh - updated : 8/18/2000<br>Ada Hamosh - updated : 7/20/2000<br>Victor A. McKusick - updated : 1/11/2000<br>Victor A. McKusick - updated : 12/8/1999<br>Victor A. McKusick - updated : 11/1/1999<br>Stylianos E. Antonarakis - updated : 8/3/1999<br>Ada Hamosh - updated : 3/25/1999<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>Stylianos E. Antonarakis - updated : 10/8/1998<br>Victor A. McKusick - updated : 7/20/1998<br>Victor A. McKusick - updated : 6/23/1998<br>Victor A. McKusick - updated : 2/11/1998<br>Victor A. McKusick - updated : 1/10/1998<br>Victor A. McKusick - updated : 8/20/1997<br>Victor A. McKusick - updated : 6/16/1997<br>Victor A. McKusick - updated : 5/2/1997<br>Victor A. McKusick - updated : 4/23/1997<br>Victor A. McKusick - updated : 4/8/1997<br>Victor A. McKusick - updated : 2/26/1997<br>Moyra Smith - updated : 11/9/1996<br>Moyra Smith - updated : 4/29/1996
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Victor A. McKusick : 11/9/1994
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carol : 10/06/2021<br>carol : 10/06/2021<br>alopez : 03/27/2020<br>alopez : 03/27/2020<br>carol : 01/14/2020<br>alopez : 07/31/2019<br>alopez : 11/28/2017<br>carol : 01/27/2017<br>carol : 09/12/2016<br>carol : 09/12/2016<br>carol : 09/09/2016<br>alopez : 02/04/2016<br>carol : 11/11/2015<br>carol : 11/11/2015<br>carol : 11/10/2015<br>mcolton : 6/3/2015<br>alopez : 4/23/2015<br>mcolton : 4/14/2015<br>alopez : 7/17/2014<br>alopez : 4/8/2014<br>carol : 2/25/2014<br>alopez : 9/5/2013<br>terry : 11/9/2012<br>terry : 10/3/2012<br>terry : 9/4/2012<br>alopez : 8/7/2012<br>carol : 5/10/2012<br>alopez : 3/8/2012<br>alopez : 8/8/2011<br>alopez : 8/8/2011<br>terry : 7/26/2011<br>carol : 6/17/2011<br>terry : 11/30/2010<br>alopez : 11/10/2010<br>alopez : 10/27/2010<br>alopez : 10/26/2010<br>terry : 10/4/2010<br>wwang : 9/21/2010<br>terry : 8/12/2010<br>alopez : 5/12/2010<br>alopez : 4/8/2010<br>carol : 11/23/2009<br>ckniffin : 10/2/2009<br>alopez : 9/25/2009<br>mgross : 7/15/2009<br>terry : 7/14/2009<br>ckniffin : 2/11/2009<br>carol : 2/9/2009<br>carol : 2/6/2009<br>ckniffin : 1/30/2009<br>wwang : 5/1/2008<br>ckniffin : 4/28/2008<br>alopez : 3/26/2008<br>terry : 3/18/2008<br>ckniffin : 2/5/2008<br>wwang : 1/28/2008<br>ckniffin : 1/8/2008<br>carol : 12/26/2007<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>terry : 5/30/2007<br>alopez : 2/23/2007<br>terry : 2/21/2007<br>wwang : 2/19/2007<br>ckniffin : 2/15/2007<br>mgross : 12/5/2006<br>terry : 11/16/2006<br>wwang : 10/16/2006<br>alopez : 9/7/2006<br>alopez : 8/28/2006<br>terry : 8/23/2006<br>wwang : 1/3/2006<br>wwang : 12/28/2005<br>terry : 12/20/2005<br>alopez : 10/11/2005<br>alopez : 10/11/2005<br>alopez : 10/3/2005<br>terry : 9/12/2005<br>wwang : 5/27/2005<br>wwang : 5/25/2005<br>terry : 5/25/2005<br>alopez : 4/22/2005<br>alopez : 4/22/2005<br>terry : 4/15/2005<br>carol : 3/17/2005<br>wwang : 3/17/2005<br>terry : 3/1/2005<br>alopez : 1/18/2005<br>terry : 1/14/2005<br>alopez : 11/29/2004<br>tkritzer : 11/11/2004<br>carol : 9/3/2004<br>tkritzer : 9/3/2004<br>carol : 9/2/2004<br>carol : 8/27/2004<br>terry : 8/27/2004<br>ckniffin : 3/23/2004<br>alopez : 3/17/2004<br>mgross : 3/10/2004<br>tkritzer : 2/6/2004<br>terry : 1/13/2004<br>alopez : 11/21/2003<br>tkritzer : 11/17/2003<br>ckniffin : 11/11/2003<br>cwells : 10/24/2003<br>terry : 10/23/2003<br>carol : 9/12/2003<br>ckniffin : 9/9/2003<br>tkritzer : 6/3/2003<br>terry : 6/3/2003<br>tkritzer : 1/31/2003<br>tkritzer : 1/22/2003<br>terry : 1/22/2003<br>alopez : 12/3/2002<br>tkritzer : 11/19/2002<br>alopez : 11/13/2002<br>terry : 11/12/2002<br>terry : 11/12/2002<br>cwells : 10/29/2002<br>carol : 10/11/2002<br>tkritzer : 10/10/2002<br>terry : 10/9/2002<br>alopez : 10/1/2002<br>alopez : 9/30/2002<br>tkritzer : 9/30/2002<br>tkritzer : 9/30/2002<br>tkritzer : 9/25/2002<br>tkritzer : 9/20/2002<br>carol : 9/19/2002<br>mgross : 9/17/2002<br>alopez : 8/7/2002<br>alopez : 8/7/2002<br>terry : 8/6/2002<br>cwells : 6/24/2002<br>terry : 6/12/2002<br>mgross : 3/4/2002<br>mgross : 3/4/2002<br>alopez : 12/5/2001<br>cwells : 11/29/2001<br>cwells : 11/19/2001<br>alopez : 11/13/2001<br>terry : 11/13/2001<br>carol : 10/9/2001<br>mcapotos : 9/26/2001<br>mcapotos : 9/18/2001<br>mcapotos : 9/13/2001<br>alopez : 7/26/2001<br>terry : 7/20/2001<br>cwells : 6/20/2001<br>cwells : 6/18/2001<br>alopez : 6/6/2001<br>mcapotos : 4/11/2001<br>mcapotos : 4/10/2001<br>terry : 4/10/2001<br>mcapotos : 3/27/2001<br>terry : 3/26/2001<br>mcapotos : 3/23/2001<br>terry : 3/16/2001<br>terry : 3/15/2001<br>mgross : 3/12/2001<br>mgross : 3/12/2001<br>terry : 3/8/2001<br>alopez : 10/31/2000<br>terry : 10/26/2000<br>alopez : 8/18/2000<br>mcapotos : 8/1/2000<br>mcapotos : 7/28/2000<br>terry : 7/20/2000<br>mgross : 2/15/2000<br>mcapotos : 2/7/2000<br>terry : 1/11/2000<br>carol : 12/10/1999<br>mcapotos : 12/10/1999<br>mcapotos : 12/10/1999<br>terry : 12/8/1999<br>carol : 11/9/1999<br>carol : 11/8/1999<br>terry : 11/1/1999<br>mgross : 8/3/1999<br>mgross : 3/29/1999<br>mgross : 3/25/1999<br>alopez : 2/17/1999<br>carol : 12/14/1998<br>dkim : 12/14/1998<br>terry : 12/7/1998<br>carol : 11/10/1998<br>terry : 10/29/1998<br>carol : 10/27/1998<br>terry : 10/27/1998<br>terry : 10/23/1998<br>carol : 10/8/1998<br>terry : 8/20/1998<br>carol : 7/22/1998<br>terry : 7/20/1998<br>terry : 7/20/1998<br>carol : 7/1/1998<br>terry : 6/23/1998<br>terry : 6/23/1998<br>mark : 2/11/1998<br>mark : 1/10/1998<br>jenny : 8/22/1997<br>terry : 8/20/1997<br>alopez : 7/10/1997<br>mark : 6/18/1997<br>terry : 6/16/1997<br>terry : 6/5/1997<br>mark : 5/2/1997<br>terry : 4/29/1997<br>alopez : 4/23/1997<br>terry : 4/23/1997<br>jenny : 4/8/1997<br>terry : 4/4/1997<br>mark : 2/26/1997<br>terry : 2/24/1997<br>terry : 1/2/1997<br>jamie : 12/18/1996<br>terry : 12/5/1996<br>mark : 11/9/1996<br>mark : 11/9/1996<br>mark : 10/5/1996<br>terry : 10/1/1996<br>terry : 9/12/1996<br>terry : 9/12/1996<br>terry : 9/5/1996<br>mark : 5/30/1996<br>carol : 5/30/1996<br>terry : 5/29/1996<br>carol : 5/22/1996<br>mark : 5/21/1996<br>carol : 4/29/1996<br>mark : 4/26/1996<br>terry : 4/19/1996<br>mark : 2/29/1996<br>terry : 2/27/1996<br>terry : 2/7/1996<br>mark : 1/5/1996<br>terry : 1/3/1996<br>mark : 11/2/1995<br>mimadm : 9/23/1995<br>carol : 12/6/1994<br>terry : 11/9/1994
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600185
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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BRCA2 DNA REPAIR-ASSOCIATED PROTEIN; BRCA2
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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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<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">
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BRCA2 GENE<br />
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FANCD1 GENE; FANCD1
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: BRCA2</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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1156923005, 25081006, 302849000, 399068003, 443333004;
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<strong>ICD10CM:</strong> C61;
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<strong>ICD9CM:</strong> 185;
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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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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 13q13.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 13:32,315,077-32,400,268 </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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</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>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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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>
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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>
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<tr>
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<td rowspan="8">
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<span class="mim-font">
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13q13.1
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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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{Breast cancer, male, susceptibility to}
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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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114480
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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 dominant; Somatic mutation
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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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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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{Breast-ovarian cancer, familial, 2}
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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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612555
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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 dominant
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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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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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{Glioblastoma 3}
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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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613029
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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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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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{Medulloblastoma}
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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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155255
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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 dominant; Autosomal recessive; Somatic mutation
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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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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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{Pancreatic cancer 2}
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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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613347
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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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</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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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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{Prostate cancer}
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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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176807
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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 dominant; Somatic mutation
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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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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Fanconi anemia, complementation group D1
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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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605724
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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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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Wilms tumor
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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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194070
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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 dominant; Somatic mutation
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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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</span>
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</td>
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</tr>
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</tbody>
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</table>
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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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<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>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>Wooster et al. (1995) identified the BRCA2 gene by positional cloning of a region on chromosome 13q12-q13 implicated in Icelandic families with breast cancer (612555). The candidate disease gene was likely to be located in a 600-kb interval centered around D13S171. Using yeast artificial chromosome and P1 artificial chromosome contigs to identify trapped exons within that region, Wooster et al. (1995) screened human fetal brain, placental, monocyte, and breast cancer cDNA libraries. They identified a cDNA encoding a 2,329-amino acid protein, but suggested that it may not represent the entire gene. Northern blot analysis demonstrated expression in normal breast epithelial cells, placenta, and a breast cancer cell line (MCF7). </p><p>Tavtigian et al. (1996) determined the complete coding sequence and exonic structure of BRCA2 and examined its pattern of expression. The composite BRCA2 cDNA sequence assembled consisted of 11,385 bp, but did not include the polyadenylation signal or poly(A) tail. Conceptual translation of the cDNA revealed an ORF beginning at nucleotide 229 and encoding a protein of 3,418 amino acids. There was no signal sequence at the end of terminus, and there were no obvious membrane-spanning regions. The highest levels of expression were observed in breast and thymus, with slightly lower levels in lung, ovary, and spleen. Tavtigian et al. (1996) noted that the BRCA2 protein, like the BRCA1 protein (113705), is highly charged; roughly one-quarter of the residues are acidic or basic. </p><p>Connor et al. (1997) described the mouse Brca2 gene. They sequenced cDNA for the entire 3,329-amino acid Brca2 protein and found that, like Brca1, Brca2 is relatively poorly conserved between humans and mice (approximately 60%). Brca2 was transcribed in a diverse range of mouse tissues, especially the testis, ovary, and midgestation embryo. Brca2 was also expressed in the mammary gland and was apparently induced upon pregnancy. The pattern of expression was strikingly similar to that of Brca1. </p><p>Warren et al. (2002) cloned and characterized the chicken Brca2 gene. The gene is organized similarly to the human BRCA2 gene, but is more compact. The chicken gene encodes a protein of 3,399 amino acids, which is poorly conserved with mammalian BRCA2 proteins, having only 37% overall amino acid sequence identity with human BRCA2. However, certain domains are much more highly conserved, indicating functional significance. The authors speculated that knowledge of the evolutionarily divergent chicken Brca2 sequence may be useful in distinguishing sequence variants from mutations in the human BRCA2 gene. </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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<strong>Gene Structure</strong>
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<p>Tavtigian et al. (1996) determined that the human BRCA2 gene contains 27 exons. They noted that both the BRCA1 and BRCA2 genes have a large exon 11, translational start sites in exon 2, and coding sequences that are AT-rich; both span approximately 70 kb of genomic DNA and are expressed at high levels in testis. </p>
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<strong>Mapping</strong>
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<p>Wooster et al. (1994) mapped the BRCA2 gene to chromosome 13q12-q13. </p><p>Couch et al. (1996) generated a detailed transcription map of the 1.0-Mb region on 13q12-q13 containing the BRCA2 gene. Evidence for 7 genes, 2 putative pseudogenes, and 9 additional putative transcription units was obtained. </p><p>Connor et al. (1997) found that the mouse Brca2 gene maps to mouse chromosome 5. </p>
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<strong>Biochemical Features</strong>
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Yang et al. (2002) determined the 3.1-angstrom crystal structure of an approximately 90-kD BRCA2 domain bound to DSS1 (601285), which revealed 3 oligonucleotide-binding folds and a helix-turn-helix motif. Yang et al. (2002) also demonstrated that this BRCA2 domain binds single-stranded DNA, presented its 3.5-angstrom structure bound to oligo(dT)9, provided data that implicate the helix-turn-helix motif in double-stranded DNA binding, and showed that BRCA2 stimulates RAD51 (179617)-mediated recombination in vitro. Yang et al. (2002) concluded that BRCA2 functions directly in homologous recombination and provided a structural and biochemical basis for understanding the loss of recombination-mediated double-strand break repair in BRCA2-associated cancers. </p><p>Pellegrini et al. (2002) reported the structure of a complex between an evolutionarily conserved sequence in BRCA2 (the BRC repeat) and the RecA-homology domain of RAD51. The BRC repeat mimics a motif in RAD51 that serves as an interface for oligomerization between individual RAD51 monomers, thus enabling BRCA2 to control the assembly of the RAD51 nucleoprotein filament, which is essential for strand-pairing reactions during DNA recombination. The RAD51 oligomerization motif is highly conserved among RecA-like recombinases, highlighting a common evolutionary origin for the mechanism of nucleoprotein filament formation, mirrored in the BRC repeat. Pellegrini et al. (2002) showed that cancer-associated mutations that affect the BRC repeat disrupt its predicted interaction with RAD51, yielding structural insight into mechanisms for cancer susceptibility. </p>
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<strong>Gene Function</strong>
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<p>Jensen et al. (1996) noted that BRCA2 includes a motif similar to the granin consensus at the C terminus of the protein. BRCA1 also has sequence homology and biochemical analogy to the granin protein family. </p><p>Studying the expression of Brca2 in murine mammary epithelial cells as a function of proliferation and differentiation, Rajan et al. (1996) demonstrated that Brca2 mRNA expression is tightly regulated during mammary epithelial proliferation and differentiation, and appears to be coordinately regulated with Brca1 expression. Both genes showed mRNA expression that was upregulated in rapidly proliferating cells; was downregulated in response to serum deprivation; was expressed in a cell cycle-dependent manner, peaking at the G1/S boundary; and was upregulated in the differentiating mammary epithelial cells in response to glucocorticoids. The results suggested that these genes are induced by, and may function in, overlapping regulatory pathways involved in the control of cell proliferation and differentiation. </p><p>Milner et al. (1997) showed that the portion of human BRCA2 encoded by its third exon shares homology with a known transcription factor and is capable of activating transcription, thus indicating a potential function of BRCA2. The exon 3 sequence at the N terminus of BRCA2 (within a region highly conserved between human and mouse) showed sequence similarity to the activation domain of JUN (165160). They found that the activation potential within exon 3 is under negative control of inhibitory regions (IR1 and IR2) present immediately on either side of exon 3. The finding that BRCA2, like BRCA1, has transcriptional activation potential provides functional evidence of a relationship between the 2 proteins. Indeed, the fact that mutations found naturally in breast cancers disrupt the activation potential of both BRCA1 and BRCA2, indicates that compromising this activity may be an important step in the generation of a subset of familial breast cancers. Mutations found outside these activation domains may affect other functions. </p><p>Daniels et al. (2004) showed that BRCA2 deficiency impairs the completion of cell division by cytokinesis. Brca2 inactivation in mouse embryo fibroblasts (MEFs) and HeLa cells by targeted gene disruption or RNA interference delayed and prevented cell cleavage. Impeded cell separation was accompanied by abnormalities in myosin II organization during the late stages in cytokinesis. Daniels et al. (2004) suggested that BRCA2 may have a role in regulating these events, as it localizes to the cytokinetic midbody. The authors concluded that their findings linked cytokinetic abnormalities to a hereditary cancer syndrome characterized by chromosomal instability and may help to explain why BRCA2-deficient tumors are frequently aneuploid. </p><p><strong><em>Role in DNA Repair</em></strong></p><p>
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Kinzler and Vogelstein (1997) made a distinction between 'gatekeeper' genes and 'caretaker' genes in the determination of cancer. Gatekeepers are genes that directly regulate the growth of tumors by inhibiting growth or promoting death. Each cell type has only one, or a few, gatekeepers, and inactivation of the given gatekeeper leads to a very specific tissue distribution of cancer; for example, inherited mutations of the RB1 (614041), VHL (608537), NF1 (613113), and APC (611731) genes lead to tumors of the retina, kidney, Schwann cells, and colon, respectively. Both the maternal and the paternal copies of the gene must be altered for tumor development. It is in connection with these gatekeeper, or tumor suppressor, genes that the Knudson 2-hit hypothesis was advanced. In contrast, inactivation of a caretaker gene does not promote tumor initiation directly. Rather, neoplasia occurs indirectly; inactivation leads to genetic instability that results in increased mutation of all genes, including gatekeepers. Once a tumor is initiated by inactivation of a caretaker gene, it may progress rapidly due to an accelerated rate of mutation in other genes that directly control cell birth or death. Known caretaker genes include the nucleotide excision repair genes that are responsible for xeroderma pigmentosum, mismatch-repair genes that cause hereditary nonpolyposis colorectal cancer, and probably the ATM gene, which is responsible for ataxia-telangiectasia. Kinzler and Vogelstein (1997) proposed that BRCA1 (113705) and BRCA2 should be added to the list of caretaker genes. Consistent with this hypothesis, mutations in BRCA1 and BRCA2 are rarely found in sporadic cancers, and the risk of cancer arising in people with BRCA mutations is relatively low. The distinction between gatekeepers and caretakers has important practical, as well as theoretical, ramifications. Tumors that have defective caretaker genes present an additional therapeutic target. Such tumors would be expected to respond favorably to therapeutic agents that induce the type of genomic damage that is normally detected or repaired by the particular caretaker gene involved. The discovery by Sharan et al. (1997) that most cells with defective Brca2 genes are sensitive to gamma-irradiation suggests that tumors from breast cancer patients with inherited BRCA mutations should be more sensitive to such radiation than other breast cancers. </p><p>Sharan et al. (1997) identified an interaction of the Brca2 protein with the DNA-repair protein Rad51 (179617). Developmental arrest in Brca2-deficient embryos, their radiation sensitivity, and the association of Brca2 with Rad51 indicated that Brca2 may be an essential cofactor in the Rad51-dependent DNA repair of double-strand breaks, thereby explaining the tumor-suppressor function of Brca2. 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, 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. The authors suggested that dysfunction of this pathway may be a general phenomenon in the majority of cases of hereditary breast and/or ovarian cancer. </p><p>Patel et al. (1998) showed that in culture, mouse cells harboring truncated Brca2 exhibited a proliferative impediment that worsened with successive passages. Arrest in the G1 and G2/M phases was accompanied by elevated p53 (191170) and p21 (116899) expression. Increased sensitivity to genotoxic agents, particularly ultraviolet light and methylmethanesulfonate, showed that Brca2 function was essential for the ability to survive DNA damage. Checkpoint activation and apoptotic mechanisms were largely unaffected, thereby implicating Brca2 in repair. This was substantiated by the spontaneous accumulation of chromosomal abnormalities, including breaks and aberrant chromatid exchanges. These findings defined a function of Brca2 in DNA repair, whose loss precipitates replicative failure, mutagen sensitivity, and genetic instability reminiscent of Bloom syndrome (210900) and Fanconi anemia (see 227650) (Patel et al., 1998). </p><p>Xia et al. (2001) provided direct functional evidence that the human BRCA2 gene promotes homologous recombination, which comprises 1 major pathway of DNA double-strand break repair. In contrast to BRCA1, which is involved in multiple DNA repair pathways, BRCA2 status has no impact on the other principal double-strand break repair pathway, namely, nonhomologous end joining. Thus, there exists a specific regulation of homologous recombination by BRCA2, which may function to maintain genomic integrity and suppress tumor development in proliferating cells. Moynahan et al. (2001) examined human and mouse cell lines containing different BRCA2 mutations for their ability to repair chromosomal breaks by homologous recombination. Using the I-SceI endonuclease to introduce a double-strand break at a specific chromosomal locus, they found that BRCA2 mutant cell lines were recombination deficient, such that homology-directed repair was reduced 6-fold to more than 100-fold depending on the cell line. Thus, BRCA2 is essential for efficient homology-directed repair, presumably in conjunction with the RAD51 recombinase. Moynahan et al. (2001) proposed that impaired homology-directed repair caused by BRCA2 deficiency leads to chromosomal instability and possibly tumorigenesis through lack of repair or misrepair of DNA damage. Davies et al. (2001) showed that BRCA2 plays a dual role in regulating the actions of RAD51, a protein essential for homologous recombination and DNA repair. First, interactions between RAD51 and the BRC3 or BRC4 regions of BRCA2 blocked nucleoprotein filament formation by RAD51. Alterations to the BRC3 region that mimicked cancer-associated BRCA2 mutations failed to exhibit this effect. Second, transport of RAD51 to the nucleus was defective in cells carrying a cancer-associated BRCA2 truncation. Thus, BRCA2 regulates both the intracellular localization and DNA-binding ability of RAD51. Davies et al. (2001) suggested that loss of these controls following BRCA2 inactivation may be a key event leading to genomic instability and tumorigenesis. </p><p>The Fanconi anemia (FA) 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 (227646) 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 (227645) 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>Howlett et al. (2002) found that cell lines derived from FANCD1 (605724) patients had biallelic mutations in BRCA2 and expressed truncated BRCA2 proteins (see 600185.0016-600185.0023). Functional complementation of FANCD1 fibroblasts with wildtype BRCA2 cDNA restored mitomycin C (MMC) resistance. Howlett et al. (2002) concluded that the results link Fanconi anemia genes with BRCA1 and BRCA2 in a common pathway. </p><p>The human genome is typically so stable that the many genetic alterations required for cancer to develop cannot accumulate unless the rate of mutation is increased, i.e., the genome becomes genetically unstable. Genetic instability is characteristic of BRCA2-deficient cells, which accumulate broken and deformed chromosomes as they divide. Similar abnormalities also occur in BRCA1-deficient cells. Venkitaraman (2003) noted that the network of cancer susceptibility genes was growing and diagrammed the role of cancer susceptibility genes in DNA repair. The ATM (607585), CHEK2 (604373), BRCA1, and BRCA2 genes, which normally participate in the error-free repair of breaks in double-stranded DNA by homologous recombination, predispose people to breast and other cancers when inactivated. The process starts when ATM and CHEK2 protein kinases signal the presence of double-stranded breaks, caused by ionizing radiation, by phosphorylating proteins such as BRCA1, inducing their migration to sites where DNA is repaired. The DNA recombination enzyme RAD51 (179617) is carried to the same sites by BRCA2, and is guided there by the DNA-binding structures formed between its carboxy terminal and DSS1. The concerted activity of these proteins culminates in error-free DNA repair by recombination. Venkitaraman (2003) stated that FA proteins are connected to this pathway, based on findings that a complex of FA proteins (termed A, C, D2, E, F, and G) triggers the ubiquitination of the Fanconi D2 protein alone and its colocalization with BRCA1 (Garcia-Higuera et al., 2001) and that BRCA2 is mutated in a small group of patients with FA (Howlett et al., 2002). The findings of Venkitaraman (2003) emphasized the importance of the homologous recombination pathway in the pathogenesis of disorders involving chromosomal instability. </p><p>In a yeast 2-hybrid analysis, Hussain et al. (2004) observed that FANCD2 bound to a highly conserved C-terminal site in BRCA2 that also bound FANCG/XRCC9 (602956). FANCD2 and BRCA2 coimmunoprecipitated from cell extracts of both human and Chinese hamster wildtype cells, thus confirming that the interaction occurs in vivo. Formation of nuclear foci of FANCD2 was normal in the BRCA2 mutant CAPAN-1 cells, suggesting that recruitment of FANCD2 to sites of DNA repair is independent of wildtype BRCA2 function. FANCD2 colocalized with RAD51 in foci following treatment with mitomycin C or hydroxyurea, and colocalized very tightly with PCNA (176740) after treatment with hydroxyurea. Hussain et al. (2004) suggested that the observation that FANCD2 and FANCG bind to the same site in BRCA2 may indicate that these 3 proteins cooperate in the repair of replication-associated double-strand breaks. </p><p>Wilson et al. (2008) found that XRCC3 (600675), BRCA2, FANCD2, and FANCG (602956) formed a complex via multiple pairwise interactions following phosphorylation of FANCG. They proposed that a complex made up of at least these 4 proteins promotes homologous recombination repair of damaged DNA. </p><p>Lomonosov et al. (2003) presented evidence that BRCA2 has a role in the cellular response to blocked DNA replication. The Y-shaped DNA junctions normally found at stalled replication forks disappeared during replication arrest in Brca2-deficient murine embryonic fibroblasts, and this was accompanied by double-strand DNA breakage. Activation of the replication checkpoint kinase Chk2 was unaffected, suggesting that Brca2 stabilized the DNA structures at stalled forks. Lomonosov et al. (2003) hypothesized that the breakdown of replication forks in BRCA2 deficiency triggers spontaneous DNA breakage, leading to mutability and cancer predisposition. </p><p>Dong et al. (2003) isolated a holoenzyme complex containing BRCA1, BRCA2, BARD1 (601593), and RAD51, 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>Yang et al. (2005) showed that a full-length Brca2 homolog (Brh2, from the fungus Ustilago maydis) stimulates Rad51 (179617)-mediated recombination at substoichiometric concentrations relative to Rad51. Brh2 recruits Rad51 to DNA and facilitates the nucleation of the filament, which is then elongated by the pool of free Rad51. Brh2 acts preferentially at a junction between double-stranded DNA and single-stranded DNA, with strict specificity for the 3-prime overhang polarity of a resected double-stranded break. Yang et al. (2005) concluded that their results established a BRCA2 function in RAD51-mediated double-stranded break repair and explained the loss of this repair capacity in BRCA2-associated cancers. </p><p>Esashi et al. (2005) demonstrated that the C-terminal region of BRCA2, which interacts directly with the essential recombination protein RAD51, contains a site (ser3291) that is phosphorylated by cyclin-dependent kinases. Phosphorylation of S3291 is low in S phase when recombination is active, but increases as cells progress toward mitosis. This modification blocks C-terminal interactions between BRCA2 and RAD51. However, DNA damage overcomes cell cycle regulation by decreasing S3291 phosphorylation and stimulating interactions with RAD51. Esashi et al. (2005) concluded that S3291 phosphorylation might provide a molecular switch to regulate RAD51 recombination activity, providing insight into why BRCA2 C-terminal deletions lead to radiation sensitivity and cancer predisposition. </p><p>Bryant et al. (2005) showed that BRCA2-deficient cells, as a result of their deficiency in homologous recombination, are acutely sensitive to PARP (173870) inhibitors, presumably because resultant collapsed replication forks are no longer repaired. Thus, PARP1 activity is essential in homologous recombination-deficient BRCA2 mutant cells. Bryant et al. (2005) exploited this requirement in order to kill BRCA2-deficient tumors by PARP inhibition alone. Treatment with PARP inhibitors is likely to be highly tumor specific, because only the tumors (which are BRCA2-null) in BRCA2 heterozygous patients are defective in homologous recombination. Bryant et al. (2005) concluded that the use of an inhibitor of a DNA repair enzyme alone to selectively kill a tumor, in the absence of an exogenous DNA-damaging agent, represents a new concept in cancer treatment. </p><p>Farmer et al. (2005) showed that BRCA1 (113705) or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest, and subsequent apoptosis. 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>By coimmunoprecipitation analysis, Xia et al. (2006) found that PALB2 (610355) and BRCA2 coimmunoprecipitated from lysates of several human cell lines. Differential extraction showed that BRCA2 and PALB2 were associated with stable nuclear structures and were likely complexed in chromatin. Immunodepletion of BRCA2 codepleted much of PALB2, whereas immunodepletion of PALB2 codepleted nearly all BRCA2. BRCA1 abundance was not significantly affected. S-phase foci containing BRCA2 and PALB2 underwent dispersal and refocusing after ionizing radiation, suggesting that, like BRCA2, PALB2 participates in DNA damage response. Depletion of PALB2 by small interfering RNA largely abrogated BRCA2 focus formation. No BRCA2 foci were observed even after ionizing radiation in PALB2-depleted cells. PALB2 appeared to promote stable association of BRCA2 with nuclear structures, allowing BRCA2 to escape the effects of proteasome-mediated degradation. Multiple germline BRCA2 missense mutations identified in breast cancer patients appeared to disrupt PALB2 binding and disable the homologous recombination-based DNA double-strand break repair function of BRCA2. </p><p>Shivji et al. (2006) noted that the individual BRC repeats of BRCA2 can either promote or inhibit the incorporation of RAD51 (179617) into active nucleoprotein filaments in vitro. Using coimmunoprecipitation analysis, they showed that a recombinant 1,127-amino acid BRCA2 fragment encompassing the entire BRC repeat domain (BRC1 to BRC8) of BRCA2 bound increasing amounts of RAD51, suggesting multiple RAD51-binding sites within each BRCA2(BRC1-8) molecule. Electrophoretic mobility shift assays revealed BRCA2(BRC1-8) enhanced the binding of RAD51 to dsDNA in a concentration-dependent manner. While isolated mammalian RAD51 shows relatively poor recombinase activity in vitro in the presence of ATP and physiologic ion concentrations, RAD51-dependent strand exchange was robustly stimulated by BRCA2(BRC1-8) and required Mg(2+) and ATP. Shivji et al. (2006) concluded that the complete BRC repeat domain of BRCA2 shows robust RAD51 binding and that BRCA2 is a critical cofactor for RAD51-mediated homologous recombination. </p><p>Jensen et al. (2010) reported the purification of BRCA2 and showed that it both binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto ssDNA. BRCA2 acts by targeting RAD51 to ssDNA over dsDNA, enabling RAD51 to displace replication protein-A (RPA; 179835) from ssDNA and stabilizing RAD51 ssDNA filaments by blocking ATP hydrolysis. BRCA2 does not anneal ssDNA complexed with RPA, implying it does not directly function in repair processes that involve ssDNA annealing. The findings of Jensen et al. (2010) showed that BRCA2 is a key mediator of homologous recombination and provided a molecular basis for understanding how this DNA repair process is disrupted by BRCA2 mutations. </p><p>Jirawatnotai et al. (2011) performed a series of proteomic screens for cyclin D1 (168461) protein partners in several types of human tumors and found that cyclin D1 directly binds RAD51 and that cyclin D1-RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2-dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination-mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein (614041), which do not require D-cyclins for proliferation. Jirawatnotai et al. (2011) concluded that their findings revealed an unexpected function of a core cell-cycle protein in DNA repair and suggested that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers, which were thought to be unaffected by cyclin D1 inhibition. </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 (113705) 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 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>DNA repair by homologous recombination is highly suppressed in G1 cells to ensure that mitotic recombination occurs solely between sister chromatids. 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>Bhatia et al. (2014) demonstrated that the human TREX-2 complex, which is involved in mRNP biogenesis and export, prevents genome instability as determined by the accumulation of gamma-H2AX (ser139-phosphorylated histone H2AX, 601772) and 53BP1 (605230) foci and single-cell electrophoresis in cells depleted of the TREX-2 subunits PCID2 (613713), GANP (603294), and DSS1 (601285). Bhatia et al. (2014) showed that the BRCA2 repair factor, which binds to DSS1, also associates with PCID2 in the cell. The use of an enhanced green fluorescent protein-tagged hybrid-binding domain of RNase H1 (604123) and the S9.6 antibody did not detect R-loops in TREX-2-depleted cells, but did detect the accumulation of R-loops in BRCA2-depleted cells. Bhatia et al. (2014) concluded that the results indicated that R-loops are frequently formed in cells and that BRCA2 is required for their processing. </p><p>Using proximity ligation assays, Bolgi et al. (2022) showed that DPP9 (608258) and BRCA2 interacted in HeLa cells in response to DNA damage. DPP9 removed the dipeptide Met1Pro2 from the N terminus of BRCA2 by cleaving the peptide bond between Pro2 and Ile3. Similar to DPP9, DPP8 (606819) also hydrolyzed the N terminus of BRCA2. Pro2 played a stabilizing role for BRCA2, and its removal led to accelerated turnover of BRCA2 in response to DNA damage. In line with the results, DPP9-deficient HeLa cells showed defects in homologous recombination-mediated repair and hypersensitivity to genotoxic agents. Specifically, DPP9 activity promoted formation of RAD51 foci by processing the N terminus of BRCA2 in response to DNA damage. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Familial Breast-Ovarian Cancer Susceptibility 2</em></strong></p><p>
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In families with breast cancer linked to chromosome 13q12 (612555), Wooster et al. (1995) identified 6 different germline mutations in the BRCA2 gene (see, e.g., 600185.0001), each causing serious disruption to the open reading frame of the transcriptional unit. </p><p>In 9 of 18 kindreds with familial breast cancer selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer, Tavtigian et al. (1996) identified potentially deleterious sequence alterations in the BRCA2 gene (see, e.g., 600185.0007). All except 1, a deletion of 3 nucleotides, involved nucleotide deletions that altered the reading frame, leading to truncation of the BRCA2 protein. No missense or nonsense mutations were found. The authors noted that the mutational profile of BRCA2 differs from that of BRCA1: microinsertions and point mutations are about as common in BRCA1 as microdeletions, which predominate in BRCA2. </p><p>Weber et al. (1996) analyzed 3 large exons of BRCA2 (exons 10, 11, and 27) in 69 unselected samples of frozen breast tumor sections using the protein truncation test (PTT). They identified a truncating somatic mutation of BRCA2 in a primary ductal breast carcinoma: a 1-bp deletion of nucleotide 2882 in exon 11 that results in a frameshift, addition of 9 novel amino acids, and translation termination at codon 894. Loss of heterozygosity (LOH) was also demonstrated in 2 microsatellite markers, D13S260 and D13S171, which flank the BRCA2 locus. </p><p>Miki et al. (1996) screened 100 primary breast cancers from Japanese patients for BRCA2 mutations using PCR-SSCP. They found 2 germline mutations and 1 somatic mutation. One of the germline mutations was an insertion of an Alu element into exon 22, which resulted in alternative splicing that skipped exon 22. </p><p>Friedman et al. (1997) analyzed a population-based series of 54 male breast cancer cases from southern California for germline mutations in the BRCA1 and BRCA2 genes. A family history of breast and/or ovarian cancer in at least one first-degree relative was found in 9 patients (17%). A further 7 (13%) reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. The 54 patients showed no germline BRCA1 mutations. On the other hand, 2 of the male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only 1 of the 2 had a family history of cancer, with 1 case of ovarian cancer in a first-degree relative. </p><p>To define the role of BRCA2 in sporadic breast and ovarian cancer, Lancaster et al. (1996) screened the entire BRCA2 gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. They found alterations in 2 of 70 breast tumors and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-bp deletion (4710delAG) which was subsequently shown to be a germline mutation; the other was a somatic missense mutation (asp3095-to-glu) of unknown significance. The results suggested to Lancaster et al. (1996) that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas. Teng et al. (1996) had similar results; mutations in BRCA2 appeared to be infrequent in all cancers including breast carcinoma. However, a probable germline mutation in a pancreatic tumor cell line suggested a role for BRCA2 in that neoplasm. Krainer et al. (1997) found definite BRCA2 mutations in 2 of 73 women with early onset (by age 32) breast cancer, suggesting that BRCA2 is associated with fewer cases than BRCA1 (p = 0.03). </p><p>Most BRCA2 mutations are predicted to result in a truncated protein product. The smallest known cancer-associated deletion removes from the C terminus only 224 of the 3,418 residues constituting BRCA2, suggesting that these terminal amino acids are critical for BRCA2 function. By study of a series of green fluorescent protein (GFP)-tagged BRCA2 deletion mutants, Spain et al. (1999) found that nuclear localization depends on 2 nuclear localization signals that reside within the final 156 residues of BRCA2. Consistent with this observation, an endogenous truncated BRCA2 mutant, 6174delT, was found to be cytoplasmic. Together these studies provided a simple explanation for why the vast majority of BRCA2 mutants are nonfunctional: they are not translocated into the nucleus. </p><p>Welcsh and King (2001) reviewed the mutagenicity of BRCA1 and BRCA2 and listed their interacting, modifying, and regulatory proteins, in order to explain why mutations in these 2 genes lead specifically to breast and ovarian cancer. </p><p>Fackenthal et al. (2002) noted that a major limitation of genetic testing of the BRCA1 and BRCA2 genes in patients with a strong family history of breast cancer is the number of inconclusive results due to unclassified BRCA1 and BRCA2 sequence variants. Many known deleterious BRCA1 and BRCA2 mutations affect splicing, and these typically lie near intron/exon boundaries. However, there are also potential internal exonic mutations that disrupt functional exonic splicing enhancer (ESE) sequences, resulting in exon skipping. Using previously established sequence matrices for the scoring of putative ESE motifs, Fackenthal et al. (2002) systematically examined several BRCA2 mutations for potential ESE disruption mutations and identified a thr2722-to-arg mutation (600185.0025) that segregated with affected individuals in a family with breast cancer and disrupted 3 potential ESE sites. The mutation caused deleterious protein truncation and suggested a potentially useful method for determining the clinical significance of a subset of the many unclassified variants of BRCA1 and BRCA2. </p><p>Lesnik Oberstein et al. (2006) performed genomewide 1-Mb resolution array-based comparative genomic hybridization on genomic DNA of 2 brothers and 4 isolated patients who all carried the clinical diagnosis of Peters-plus syndrome, which is caused by mutations in the B3GALTL gene (610308) on chromosome 13q12. Both brothers were found to have an interstitial deletion of approximately 1.5 Mb on 13q12.3-q13.1, including the BRCA2 gene. The deletion was found in their mother and in 2 female relatives who had died of breast cancer. Thus the deletion constituted a large novel BRCA2 rearrangement associated with familial breast cancer. </p><p>Casilli et al. (2006) used quantitative multiplex PCR of short fluorescent fragments (QMPSF) to screen for BRCA2 germline rearrangements in 120 families with familial breast cancer who were negative for BRCA1 and BRCA2 mutations. Three novel and distinct BRCA2 deletions were identified in 3 families: deletion of exons 14 through 18, exons 15 and 16, and exons 12 and 13, respectively. Combined with data from the larger cohort of 194 families selected for the study in which 36 BRCA2 mutations were identified, Casilli et al. (2006) estimated that approximately 7.7% of germline BRCA2 mutations are rearrangements, which is similar to the contribution of rearrangements to the mutation spectrum of BRCA1 (approximately 15%). </p><p>Easton et al. (2007) undertook a systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 (113705) and BRCA2 breast cancer predisposition genes. They identified 43 sequence variants with an 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>In a study of 9,442 BRCA1 and 5,665 BRCA2 mutation carriers from 33 study centers, Antoniou et al. (2009) found that the minor allele (C) of the SNP rs3817198 in LSP1 (153432) on chromosome 11p15.5 was associated with increased breast cancer risk only for BRCA2 mutation carriers (p trend = 2.8 x 10(-4)). Easton et al. (2007) had identified rs3817198. The SNP rs3817198 and another at 2q35, rs13387042, appeared to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. </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. In BRCA2 carriers, rs9393597 in LOC134997 and rs12652447 in FBXL7 (605656) showed the strongest associations (p(trend) = 6 x 10(-5), 95% CI 1.25-1.92 and p(trend) = 1.7 x 10(-4), 95% CI 1.16-1.62, 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>Prostate Cancer</em></strong></p><p>
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Edwards et al. (2003) screened the complete coding sequence of BRCA2 for germline mutations in 263 men with early-onset prostate cancer before age 55 (176807). Protein-truncating mutations (see, e.g., 600185.0026), all clustered outside the ovarian cancer cluster region, were found in 6 men (2.3%). The relative risk of developing prostate cancer by age 56 years from a deleterious germline BRCA2 mutation was 23-fold. Four of the patients with mutations had no family history of breast or ovarian cancer. These results confirmed that BRCA2 is a high-risk prostate cancer susceptibility gene. </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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In a human pancreatic adenocarcinoma (260350), Schutte et al. (1995) demonstrated a homozygous deletion in a 1-cM region of chromosome 13q12.3 within the 6-cM region identified as the BRCA2 locus. They suggested that the BRCA2 gene may be involved in multiple tumor types and that it may function as a tumor suppressor gene rather than a dominant oncogene. </p><p>Garcia-Marco et al. (1996) used fluorescence in situ hybridization to analyze chromosome 13 deletions in chronic lymphocytic leukemia (CLL; see 151400). They demonstrated deletion of the 1-Mb 13q12.3 locus, which encompasses the BRCA2 gene, in 80% of 35 cases with CLL. Homozygous deletion of BRCA2 was detected in 60% of cases. Deletion of DBM (109543), a previously described 13q14 locus detected with the probe D13S25, was seen in 63% of cases. Garcia-Marco et al. (1996) concluded that their data provided evidence for the existence of a new tumor suppressor locus in B-cell CLL located at 13q12.3. They postulated that BRCA2, which is located within the minimal deletion region, is a candidate for this new B-cell CLL tumor suppressor locus. </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 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>Fanconi Anemia Type D1</em></strong></p><p>
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In 27 FANCD1 (605724) patients with biallelic mutations in BRCA2, 26 from the literature and 1 newly diagnosed, Alter et al. (2007) analyzed the severity of the mutations and classified them according to their association with breast cancer in heterozygotes and their predicted functional effect. Twenty mutations were frameshifts or truncations, 3 involved splice sites, 5 were missense variants of unknown severity, and 2 were benign polymorphisms. Five patients had features of the VATER association (192350), including 1 with VACTERL and hydrocephalus (VACTERL-H; 276950). Leukemia was reported in 13 patients, and solid tumors in 15; 6 patients had 2 or more malignancies. The cumulative probability of any malignancy was 97% by age 5.2 years. IVS7+1G-A (600185.0033) and IVS7+2T-G (600185.0034) were associated with acute myelogenous leukemia, and 886delGT (600185.0027) and 6174delT (600185.0009) with brain tumors. However, patients with other alleles remained at very high risk for these events. Missense mutations formed a distinct cluster in a highly conserved region of the BRCA2 protein. A small group of patients with biallelic mutations in BRCA2 was distinctive in the severity of the phenotype, with early onset and high rates of leukemia and specific solid tumors, and may represent an extreme variant of Fanconi anemia. Several of the alleles were not associated with cancer in presumed carriers. Five of the 27 patients (from 21 families) with FANCD1 studied by Alter et al. (2007) had 3 or more of the VATER association anomalies. In these patients, both mutations in BRCA2 were considered to be deleterious or probably deleterious. Among the 5 patients with VATER association, 2 cousins had brain tumors; 1 had AML; another had Wilms tumor, neuroblastoma, and brain tumor; and another patient had medulloblastoma at the age of 3.1 years. </p><p>Weinberg-Shukron et al. (2018) reported 2 sisters with FANCD1 who presented with XX ovarian dysgenesis who were compound heterozygous for mutations in BRCA2. One was a nonsense mutation (V2527X) and the other was a 1-bp deletion (c.9693delA, Ser3231fsTer16) occurring at the end of the last exon. On closer examination, both girls had significant microcephaly and a few cafe-au-lait spots. One of the sisters had leukemia diagnosed at age 5 and had been in remission for 14 years. The other sister had no history of malignancy at time of evaluation. A brother had died of promyelocytic leukemia at 13 years of age. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Gayther et al. (1997) reported that families with a high proportion of ovarian cancers, relative to the frequency of breast cancer, tended to have mutations located within a 3.3-kb region in exon 11. They called this region of BRCA2, bounded by nucleotides 3035 and 6629, the 'ovarian cancer cluster region,' or OCCR. Neuhausen et al. (1998) presented data consistent with the previous report of a higher incidence of ovarian cancer in families with mutations in the OCCR, but the higher incidence was not statistically significant. There was significant evidence that age at diagnosis of breast cancer varied by mutation, although only 8% of the variance in age at diagnosis could be explained by the specific mutation, and there was no evidence of family-specific effects. Cases associated with mutations in the OCCR had a significantly older mean age at diagnosis than were seen in those outside this region (48 vs 42 years; p = 0.0005). In an attempt to confirm and extend the observation of an OCCR, Thompson and Easton (2001) analyzed a dataset of 164 BRCA2 families. They found that OCCR mutations were associated both with a significantly lower risk of breast cancer and with a significantly higher risk of ovarian cancer. There was some evidence for a lower risk of prostate cancer in carriers of an OCCR mutation, but there was no evidence of a difference in breast cancer risk in males. By age 80 years, the cumulative risk of breast cancer in male carriers of a BRCA2 mutation was estimated as 6.92%. Possible mechanisms for the variation in cancer risk were suggested by the coincidence of the OCCR with the RAD51-binding domain. </p><p>Three Jewish founder mutations, 185delAG (113705.0003) and 5382insC (113705.0018) in BRCA1 and 6174delT (600185.0009) in BRCA2, have been identified in breast cancer and ovarian cancer Ashkenazi patients. Friedman et al. (1998) pooled results from 4 cancer/genetic centers in Israel to analyze approximately 1,500 breast/ovarian cancer Ashkenazi patients for the presence of double heterozygosity as well as homozygosity for any of these mutations. Although the small number of cases precluded definite conclusions, the results suggested that the phenotypic effects of double heterozygosity for BRCA1 and BRCA2 germline mutations were not cumulative. This was in agreement with the observation that the phenotype of mice that are homozygous knockouts for the BRCA1 and BRCA2 genes is similar to that of mice that are BRCA1 knockouts. This suggests that the BRCA1 mutation is epistatic over the BRCA2 mutation. Two of the double heterozygotes described had had reproductive problems: one with primary sterility and irregular menses and another with premature menopause at the age of 37 years. </p><p>Healey et al. (2000) pointed out that mutations in the BRCA2 gene account for fewer than 2% of all cases of breast cancer in East Anglia, U.K. They suggested that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; they viewed polymorphic variants in strongly predisposing genes, such as BRCA2, as candidates for this role. </p><p>Using a mathematical model to analyze the BRCA2 N372H polymorphism data reported by Healey et al. (2000) as well as data from 8 other populations, Teare et al. (2004) found significant evidence consistent with a heterozygote advantage in females, but no evidence of genotype-specific selection in males. </p><p>Risch et al. (2001) found that ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer cluster region of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. The results suggested that BRCA2 mutations may prove to be a greater cause of cancer in male carriers than had previously been thought. </p><p>In a study of Spanish families, Diez et al. (2003) could not confirm the conclusions of Gayther et al. (1997) and Thompson and Easton (2001) that the BRCA2 truncating mutations in families with a high proportion of ovarian cancer appear to be clustered in a 3.3-kb region in exon 11, between nucleotides 3035 and 6629. </p><p>Van Asperen et al. (2005) estimated the cancer risk for sites other than breast and ovary in 139 Dutch BRCA2 families with 66 different pathogenic mutations ascertained in a nationwide study. To avoid testing bias, they chose not to estimate risk in typed carriers but rather in 1,811 male and female family members with a 50% prior probability of being a carrier. The relative risk (RR) for each carrier site with the exception of breast and ovarian cancer was determined by comparing observed numbers with expected numbers based on Dutch cancer incidence rates. An excess risk for 4 cancer sites was observed: pancreas (RR 5.9), prostate (RR 2.5), bone (RR 14.4), and pharynx (RR 7.3). Nearly all increased risks reached statistical significance for men only. </p>
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<strong>Animal Model</strong>
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</h4>
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<span class="mim-text-font">
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<p>Lee et al. (1999) reported that tumors from Brca2-deficient mice exhibited dysfunction of the spindle assembly checkpoint, accompanied by mutations in the p53 (191170), Bub1 (602452), and Mad3L genes. The chromosomal aberrations precipitated by Brca2 truncation could be suppressed by mutant forms of Bub1 and p53. Thus, the authors concluded that inactivating mutations in mitotic checkpoint genes likely cooperate with BRCA2 deficiency in the pathogenesis of inherited breast cancer, with important implications for treatment. </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 the Brca1- or Brca2-null mutation was less severe in a p53-null background. </p><p>Suzuki et al. (1997) generated mice deficient in Brca2 by targeted disruption of the Brca2 gene in which exons 10 and 11 were deleted. All homozygous mice died before embryonic day 9.5. Mutant phenotypes ranged from severely developmentally retarded embryos that did not gastrulate to embryos with reduced size that made mesoderm and survived until 8.5 days of development. Although apoptosis was normal, cellular proliferation was impaired in Brca2(10-11)-deletion mutants, both in vivo and in vitro. In addition, the expression of the cyclin-dependent kinase inhibitor p21 (116899) was increased. Thus, Brca2(10-11)-deletion mutant mice were similar in phenotype to Brca1(5-6)- deletion mutants but were less severely affected. Expression of either of these 2 genes was unaffected in mutant embryos of the other. Suzuki et al. (1997) concluded that BRCA2, like BRCA1, is required for cellular proliferation during embryogenesis. The similarity in phenotype between Brca1 and Brca2 mutants suggested that these genes may have cooperative roles or convergent functions during embryogenesis. </p><p>Jonkers et al. (2001) developed conditional mutants for Brca2 and/or p53 inactivated in various epithelial tissues, including mammary gland epithelium. Although no tumors arose in mice carrying conditional Brca2 alleles, mammary and skin tumors developed frequently in females carrying conditional Brca2 and Trp53 alleles. The presence of 1 wildtype Brca2 allele resulted in a markedly delayed tumor formation; loss of the wildtype Brca2 allele occurred in a subset of these tumors. Jonkers et al. (2001) concluded that inactivation of BRCA2 and of p53 combine to mediate mammary tumorigenesis, and indicate that disruption of the p53 pathway is pivotal in BRCA2-associated breast cancer. </p><p>Warren et al. (2003) demonstrated that in the chicken B cell line DT40, heterozygosity for a BRCA2 mutation resulted in a reduced growth rate, increased cell death, heightened sensitivity to specific DNA-damaging agents, and reduced RAD51 (179617) focus formation after irradiation. The authors hypothesized that in certain cell types, genome instability may be driven directly by heterozygosity for BRCA2 mutations. </p><p>Weinberg-Shukron et al. (2018) crossed female and male Dmbrca2-null flies with wildtype controls. Egg production by the Dmbrca2-null female flies that were crossed with wildtype control male flies was less than 5 percent of that of wildtype fly controls, and the few eggs laid by these mutant female flies had abnormal morphologic features including eggshell transparency, round and flattened shape, and fused or no dorsal appendages. In crosses of Dmbrca2-null male flies with wildtype control female flies, egg production was not significantly altered, and the morphologic features of the eggs were normal. However, virtually no progeny survived from either cross. Heterozygous Dmbrca2 matings had no effect on the numbers of eggs or progeny. The morphologic findings of ovaries from Dmbrca2-null female flies ranged from complete ovarian dysgenesis (69% of ovaries) to underdeveloped ovaries that had fewer ovarioles, with small, disordered, and misshapen egg chambers, and few mature eggs (4% of ovaries). </p>
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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>34 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2</strong>
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BRCA2, 6-BP DEL, PHE-TER
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SNP: rs397507890,
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ClinVar: RCV000009902, RCV000637710, RCV002371768
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<p>In a family in which breast-ovarian cancer (BROVCA2; 612555) was clearly linked to chromosome 13q, Wooster et al. (1995) identified a heterozygous 6-bp deletion in the BRCA2 gene, resulting in the removal of the last 5 bases of 1 exon, deletion of the conserved G of the 5-prime splice site of the intron, and direct conversion of the codon TTT for phenylalanine to the termination codon TAA. </p>
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<span class="mim-font">
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<strong>.0002 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2</strong>
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BRCA2, 2-BP DEL, 6503TT
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SNP: rs11571658,
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gnomAD: rs11571658,
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ClinVar: RCV000009903, RCV000044884, RCV000131029, RCV000160300, RCV000735583, RCV003128122, RCV003473073, RCV004732540, RCV004802925, RCV005007836
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<p>By sequencing the putative BRCA2 gene in individuals with early-onset breast cancer who shared only the haplotype of 13q microsatellite markers that segregated with the disease (BROVCA2; 612555), Wooster et al. (1995) found a TG deletion (600185.0003) and a TT deletion in families CRC B196 and CRC B211, respectively. </p><p>In 2 sisters of a family of Indian origin living in Mauritius for at least 5 generations, Khittoo et al. (2001) found that the 6503delTT mutation was associated with breast cancer. This mutation had been found in geographically diverse populations, and in some cases families that harbor this mutation had been shown to share intragenic polymorphisms (Neuhausen et al., 1998). The haplotype of the mutation found in the Mauritian family differed from that found in other populations harboring the same mutation, suggesting that it had arisen independently in that population. Mauritius, a small island situated in the Indian Ocean off the southeast coast of Africa, was colonized by the French in 1715 and was a British possession from 1810 to 1968, when it became independent. The present-day Mauritian population is composed of at least 4 major ethnic groups. </p>
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<span class="mim-font">
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<strong>.0003 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2</strong>
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BRCA2, 2-BP DEL
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SNP: rs80359605,
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gnomAD: rs80359605,
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ClinVar: RCV000009904, RCV000044989, RCV000131037, RCV000215210, RCV000735588, RCV002288479, RCV003128123, RCV003460446, RCV004771454
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<p>For discussion of the 2-bp deletion in the BRCA2 gene (6503delTT) that was found in compound heterozygous state in patients with early-onset breast cancer (BROVCA2; 612555) by Wooster et al. (1995), see 600185.0002. </p>
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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, 2</strong>
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</span>
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BRCA2, 2-BP DEL
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<br />
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SNP: rs80359530,
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gnomAD: rs80359530,
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|
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ClinVar: RCV000009905, RCV000044728, RCV000131120, RCV000160297, RCV000461157, RCV000735574, RCV001310125, RCV003162224, RCV004802926, RCV005003352
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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 family with breast-ovarian cancer (BROVCA2; 612555), Wooster et al. (1995) found a CT deletion which had arisen within a short repetitive sequence: CTCTCT. This feature is characteristic of deletion/insertion mutations in many genes and is presumed to be due to slippage during DNA synthesis. </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, 2</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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BRCA2, 1-BP DEL
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<br />
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SNP: rs80359550,
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gnomAD: rs80359550,
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ClinVar: RCV000009910, RCV000009911, RCV000009912, RCV000034451, RCV000044800, RCV000129627, RCV000212245, RCV000367838, RCV000414179, RCV000768632, RCV000785226, RCV001535431, RCV003128125, RCV004566711, RCV005007837
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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 2 families from Montreal with breast-ovarian cancer (BROVCA2; 612555), Wooster et al. (1995) found a T deletion and an AAAC deletion (600185.0006), respectively, in the BRCA2 gene. Both of these families included a male breast cancer case; previous analyses had indicated that the large majority of such families have BRCA2 mutations (Stratton et al., 1994). </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>.0006 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2</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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BRCA2, 4-BP DEL
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<br />
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SNP: rs80359351,
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gnomAD: rs80359351,
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ClinVar: RCV000009907, RCV000044064, RCV000131102, RCV000160273, RCV000210161, RCV000240755, RCV000458791, RCV000735443, RCV001354011, RCV001849261, RCV003128124, RCV003162225, RCV003483429, RCV004795387, RCV004802927
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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 4-bp AAAC deletion in the BRCA2 gene that was found in compound heterozygous state in patients with breast-ovarian cancer (BROVCA2; 612555) by Wooster et al. (1995), see 600185.0005. </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, 2</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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BRCA2, 1-BP DEL, 8525C
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<br />
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SNP: rs80359705,
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ClinVar: RCV000031732, RCV000034463, RCV000045466, RCV000163359, RCV000210122, RCV002477039, RCV003473217, RCV004532459
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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 10 of 18 breast cancer families (BROVCA2; 612555) selected on the basis of linkage analysis and/or the presence of 1 or more cases of male breast cancer, Tavtigian et al. (1996) identified microdeletions in the BRCA2 gene. One of the microdeletions involved nucleotide C8525 in codon 2766. This deletion caused a frameshift, generating a termination signal at codon 2776. </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>.0008 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2</strong>
|
|
</span>
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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BRCA2, 3-BP DEL, THR1302DEL
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<br />
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SNP: rs80359414,
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|
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ClinVar: RCV000009909
|
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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>One of the 10 breast cancer families (BROVCA2; 612555) with microdeletions studied by Tavtigian et al. (1996) had deletion of 3 nucleotides constituting codon 1302 for threonine. Except for a deletion of exon 2 in the mRNA in 1 family, all of the microdeletion families had frameshift mutations leading to premature termination. </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>.0009 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
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<span class="mim-text-font">
|
|
PANCREATIC CANCER, SUSCEPTIBILITY TO, 2, INCLUDED<br />
|
|
FANCONI ANEMIA, COMPLEMENTATION GROUP D1, 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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BRCA2, 1-BP DEL, 6174T
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<br />
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ClinVar: RCV000009910, RCV000009911, RCV000009912, RCV000034451, RCV000044800, RCV000129627, RCV000212245, RCV000367838, RCV000414179, RCV000768632, RCV000785226, RCV001535431, RCV003128125, RCV004566711, RCV005007837
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|
|
|
|
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Breast Cancer</em></strong></p><p>
|
|
Neuhausen et al. (1996) investigated the frequency of a 6174delT frameshift mutation in 200 women with early-onset breast cancer (BROVCA2; 612555). Six of 80 Ashkenazi Jewish women diagnosed with breast cancer before the age of 42 years were found to be heterozygous for the mutation, whereas the mutation was not detected in 93 non-Jewish women diagnosed with breast cancer at the same age. The mutation was detected in 2 of 27 additional Jewish families in which breast cancer occurred at age 42 to 50 years in the proband. The frequency of the 6174delT mutation in Ashkenazim was estimated to be 3 per 1000. </p><p>In a population-based study of approximately 3,000 Ashkenazi Jewish samples, Roa et al. (1996) determined that the BRCA1 185delAG mutation (113705.0003) and the BRCA2 6174delT mutation constitute the 2 most frequent mutant alleles predisposing to hereditary breast cancer among the Ashkenazim. The 6174delT mutation in BRCA2 appeared to have a relatively lower penetrance because it had a carrier frequency of 1.52% whereas the 185delAG mutation, which is a more frequent cause of breast cancer, had a frequency of 1.09%. </p><p>Oddoux et al. (1996) found a prevalence of approximately 1% for the del6174T mutation (confidence interval 0.6-1.5). Relative risk of developing breast cancer by age 42 is estimated to be 9.2 for the del6174T mutation, compared to 31 for the 185delAG mutation. </p><p>As indicated elsewhere, in Ashkenazi Jewish individuals, the BRCA1 185delAG and the BRCA2 6174delT mutations are estimated to be present in 1.05% and 1.36% of the population, respectively. Approximately 20% of Jewish breast cancer cases under age 42, and about 32% of Jewish breast cancer families, can be attributed to the BRCA1 185delAG mutation. In comparison, only about 8% of breast cancer cases less than age 42, and about 4% of breast cancer families can be attributed to the BRCA2 6174delT mutation. Cancers of male breast and several other sites are overrepresented in BRCA2 families (summary by Ozcelik et al., 1997). </p><p>In a patient who developed high-grade breast cancer with axillary nodal metastases before the age of 40 years, Tesoriero et al. (1999) identified a de novo mutation of BRCA1 (3888delGA; 113705.0028) and this mutation, 6174delT, of the BRCA2 gene. Although the 6174delT mutation of BRCA2 is frequent in individuals of Jewish descent (Neuhausen et al., 1996), there was no known Jewish ancestry in the family studied. The 3888delGA mutation of BRCA1 originated in the father's germline; the 6174delT mutation of BRCA2 was inherited from the father, who developed prostate carcinoma during his early fifties. </p><p><strong><em>Pancreatic Cancer</em></strong></p><p>
|
|
Ozcelik et al. (1997) investigated the contribution of germline BRCA2 mutations to the development of pancreatic cancer (PNCA2; 613347) in 41 patients seen over a 4-month period, and selected without regard for family history. Mutations were identified in 2 patients (4.9%); one had a previously undescribed 6076delGTTA mutation, and the other had a 6174delT mutation. The latter patient was 1 of 13 Jewish individuals in the cohort. In a subsequent study of 26 pancreatic cancers in Jewish individuals seen over a 15-year period, they found the 6174delT mutation in 3; no 6174delT mutations were identified in 55 non-Jewish pancreatic controls. The investigators suggested that the ability to identify a population at high risk for the development of pancreatic cancer might provide an opportunity to develop and evaluate prevention and early detection protocols aimed at reducing mortality. </p><p>Murphy et al. (2002) sequenced the BRCA2 gene in 29 kindreds with pancreatic cancer and found that 5 patients (17.2%) had mutations that had previously been reported to be deleterious. Three patients harbored the common 6174delT frameshift mutation, and 2 had splice site mutations. A family history of breast cancer was reported in 2 of the 5 BRCA2 mutation carriers; none reported a family history of ovarian cancer. These findings confirmed an increased risk of pancreatic cancer in individuals with BRCA2 mutations and identified germline BRCA2 mutations as the most common inherited genetic alteration in familial pancreatic cancer. </p><p><strong><em>Fanconi Anemia</em></strong></p><p>
|
|
Alter et al. (2007) described a female infant with Fanconi anemia of complementation group D1 (FANCD1; 605724) who carried the 6174delT mutation in compound heterozygosity with Q3066X (600185.0032). Hydrocephalus, fused kidneys, and growth retardation had been identified in utero. At birth, she had intrauterine growth retardation, corneal opacities (diagnosed as Peter anomaly; see 604229), an anteriorly placed anus, small kidneys, and long thumbs with increased laxity; this constellation led to a later diagnosis of VACTERL-H (276950). At age 3.1 years, she was diagnosed with medulloblastoma. Alter et al. (2007) described a strong family history of breast cancer and breast cancer-associated cancers. Alter et al. (2007) noted that 2 other FANCD1 patients with features of the VATER association (192350) carrying this mutation had been reported (Alter and Tenner, 1994; Offit et al., 2003). These patients, who were sibs, also had brain tumors. A third FANCD1 patient carrying this mutation and 886delGT (600185.0027) had medulloblastoma (Offit et al., 2003). </p><p>Edwards et al. (2008) found that resistance to poly(ADP-ribose) polymerase (PARP; 173870) inhibition can be acquired by deletion of a mutation in BRCA2. Edwards et al. (2008) derived PARP inhibitor-resistant clones from the human CAPAN1 pancreatic cancer cell line, which carries the 6174delT mutation in BRCA2. PARP inhibitor-resistant clones could form DNA damage-induced RAD51 (179617) nuclear foci and were able to limit genotoxin-induced genomic instability, both hallmarks of a competent homologous recombination pathway. New BRCA2 isoforms were expressed in the resistant lines as a result of intragenic deletion of the 6174delT mutation and restoration of the open reading frame (ORF). Reconstitution of BRCA2-deficient cells with these revertant BRCA2 alleles rescued PARP inhibitor sensitivity and homologous recombination deficiency. Most of the deletions in BRCA2 were associated with small tracts of homology, and possibly arose from error-prone repair caused by BRCA2 deficiency. Similar ORF-restoring mutations were present in carboplatin-resistant ovarian tumors from 6174delT mutation carriers. Edwards et al. (2008) concluded that their observations have implications for understanding drug resistance in BRCA mutation carriers as well as in defining functionally important domains within BRCA2. </p><p><strong><em>Prostate Cancer</em></strong></p><p>
|
|
In connection with the germline mutations of BRCA1 and BRCA2 that are frequent causes of hereditary breast cancer in Ashkenazi Jewish women, Nastiuk et al. (1999) studied the frequency of these mutations in Ashkenazi Jewish men with prostate cancer. They found no increased incidence and concluded that it is unlikely that either of these 2 mutations predispose men to prostate cancer. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
|
|
</div>
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|
|
</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, 5-BP DEL, NT999
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80359671,
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|
|
|
|
|
gnomAD: rs80359671,
|
|
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|
|
|
ClinVar: RCV000009913, RCV000056288, RCV000131848, RCV000195405, RCV000212208, RCV001310167, RCV001554244, RCV004732541, RCV004802928
|
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|
|
|
</span>
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|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Thorlacius et al. (1997) found a 5-bp deletion in exon 9 starting at nucleotide 999 (999del5) and leading to early protein termination, in 16 of 21 Icelandic breast cancer families (BROVCA2; 612555), indicating a founder effect. They detected a 999del5 germline mutation in 0.6% of the Icelandic population, in 7.7% of female breast cancer patients, and in 40% of males with breast cancer. The mutation was strongly associated with onset of female breast cancer at age less than 50 years. A number of cancers other than breast cancer were found to be increased in relatives of mutation carriers, including those with prostate and pancreatic cancer. Comparison of the age at onset for mother/daughter pairs with the 999del5 mutation in breast cancer indicated that age at onset was decreasing in the younger generation. Increasing breast cancer incidence and lower age at onset suggested a possible contributing environmental factor. </p><p>In Icelandic patients, Sigbjornsdottir et al. (2000) found loss of heterozygosity (LOH) at chromosome 8p in 50% of sporadic breast tumors and 78% of BRCA2-linked tumors carrying the 999del5 mutation. The pattern of LOH was different in the 2 groups with a high proportion of BRCA2 tumors having LOH in a large region of chromosome 8p. Patients with LOH at 8p have a worse prognosis than patients without this defect. Multivariate analysis suggested that LOH at 8p is an independent prognostic factor. Sigbjornsdottir et al. (2000) concluded that chromosome 8p carries a tumor suppressor gene(s), the loss of which results in growth advantage of breast tumor cells, especially in carriers of the BRCA2 999del5 mutation. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
|
|
BRCA2, 1-BP INS, 3295A
|
|
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|
|
|
<br />
|
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|
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SNP: rs80359368,
|
|
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|
|
ClinVar: RCV000113129, RCV000496220
|
|
|
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|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a breast cancer patient (BROVCA2; 612555) of Scottish descent, Liede et al. (1998) found double heterozygosity for 2 high-penetrance breast cancer mutations: 2508G-T in BRCA1 (113705.0023) and 3295insA, resulting in an in-frame stop codon 1025, in BRCA2. </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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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, 2-BP DEL, 8765AG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80359714,
|
|
|
|
|
|
gnomAD: rs80359714,
|
|
|
|
|
|
ClinVar: RCV000009915, RCV000045550, RCV000131085, RCV000160308, RCV000735482, RCV001353461, RCV003460447, RCV004802929
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Phelan et al. (1996) identified an 8765delAG mutation in the BRCA2 gene in 2 French Canadian patients whose families included 22 females with breast cancer (BROVCA2; 612555) only, with mean age of diagnosis of 49.2 years. Lerer et al. (1998) found the same mutation in 3 Yemenite Jewish families with breast cancer; haplotype analysis indicated that the mutation was derived from a common ancestor. </p>
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|
</span>
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</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 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
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BRCA2, ASN372HIS
|
|
|
|
|
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<br />
|
|
|
|
SNP: rs144848,
|
|
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|
|
|
gnomAD: rs144848,
|
|
|
|
|
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ClinVar: RCV000009916, RCV000034427, RCV000120303, RCV000130720, RCV000207052, RCV000260146, RCV000320173, RCV000468776, RCV000768560, RCV002476952, RCV004802930
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|
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|
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</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>This variant, formerly titled BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2, has been reclassified based on the findings of Guidugli et al. (2014). </p><p>Healey et al. (2000) described a polymorphism of the BRCA2 gene, asn372 to his (N372H), located in exon 10 and associated not only with an increased risk of breast cancer (BROVCA2; 612555) but also with an effect on prenatal viability with increased fitness of males and decreased fitness of females. The rarer allele (372H) had a frequency of 0.221 in Finnish, 0.285 in German, and a frequency intermediate between these 2 in British populations. HH homozygotes were found to have a 1.31-fold (95% confidence interval, 1.07-1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there was a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there was an excess of homozygotes: the HH group had an estimated fitness of 0.82 in females and 1.38 in males. The authors suggested that the differences in genotype may be due to selection, and concluded that this variant of BRCA2 may also affect fetal survival in a sex-dependent manner. </p><p>Using a mathematical model to analyze the BRCA2 N372H polymorphism data reported by Healey et al. (2000) as well as data from 8 other populations, Teare et al. (2004) found significant evidence consistent with a heterozygote advantage in females, but no evidence of genotype-specific selection in males. </p><p>Functional assays used to assess the impact of the N372H variant indicated that N372H is a class 1 variant (not pathogenic or of no clinical significance), according to the International Agency for Research on Cancer (IARC) class system (Guidugli et al., 2014). </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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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2</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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BRCA2, IVS23AS, A-G, -2
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<br />
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SNP: rs81002862,
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gnomAD: rs81002862,
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ClinVar: RCV000077460, RCV000212285, RCV000496786, RCV000771399
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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>Sarantaus et al. (2000) studied a recurrent BRCA2 mutation in Finnish breast cancer families (BROVCA2; 612555), an A-to-G transition at position -2 in the splice donor site of intron 23. In 9 Finnish families carrying this mutation, Sarantaus et al. (2000) found by haplotype analysis that the spread of the mutation was estimated to have started 7 to 11 generations (150-200 years) ago. This was also supported by the distribution of the origins of the families in the northern and eastern parts of the country that were settled after the 15th century, followed by regional population expansions in the 17th century. </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>.0015 PROSTATE CANCER</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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BRCA2, 1-BP DEL, 6051A
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<br />
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SNP: rs80359540,
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ClinVar: RCV000009918, RCV000113489, RCV000217033, RCV001269662, RCV001852945
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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>Gronberg et al. (2001) described a family in which the father and 4 of his sons had prostate cancer (176807) at an early age: 51, 52, 56, 58, and 63 years, respectively. In addition, 3 daughters had breast cancer between the ages of 47 and 61. In this family, a truncating mutation, 6051delA, was identified in exon 11 of the BRCA2 gene, leading to an early termination of the protein at codon 1962. In addition, loss of heterozygosity indicating a change in the other allele supported the role of the BRCA2 gene in this family as a tumor suppressor gene. </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>.0016 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2</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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BRCA2, 4-BP DEL, NT3034
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<br />
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ClinVar: RCV000009907, RCV000044064, RCV000131102, RCV000160273, RCV000210161, RCV000240755, RCV000458791, RCV000735443, RCV001354011, RCV001849261, RCV003128124, RCV003162225, RCV003483429, RCV004795387, RCV004802927
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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 patient with early-onset breast cancer (BROVCA2; 612555) and no strong family history of the disease, van der Luijt et al. (2001) found a 4-bp deletion in exon 11 of the BRCA2 gene (3034del4) as a de novo mutation in genomic DNA from peripheral lymphocytes. Paternity was established using highly polymorphic markers. Van der Luijt et al. (2001) believed this to be the first report of a de novo germline mutation in the BRCA2 gene. In an international study of recurrent BRCA2 mutations, Neuhausen et al. (1998) had investigated 11 families from 7 different western European and North American countries carrying this 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">
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<strong>.0017 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</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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BRCA2, IVS19AS, G-A, -1
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<br />
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SNP: rs397507404,
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ClinVar: RCV000009920, RCV000031747, RCV000160152, RCV000213906, RCV000231355, RCV000763329, RCV002221480, RCV003162283, RCV003473221, RCV004803081
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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 the Fanconi anemia complementation group D1 (FANCD1; 605724) reference cell line HSC62, Howlett et al. (2002) identified homozygosity for an intron 19 mutation, IVS19-1G-A, in the BRCA2 gene. This mutation results in deletion of 12 nucleotides or 4 amino acids in exon 20. Howlett et al. (2002) suggested that the mutant protein may have partial activity since the HSC62 patient has a relatively mild clinical Fanconi anemia phenotype and HSC62 cells have only modest mitomycin C sensitivity. </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>.0018 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</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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|
|
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BRCA2, 2-BP INS, 7691AT
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<br />
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|
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SNP: rs886038169,
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|
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ClinVar: RCV000009921, RCV000241322
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|
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|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In the Fanconi anemia complementation group D1 (FANCD1; 605724) cell line EUFA423, Howlett et al. (2002) identified 2 BRCA2 mutations. One was an insertion of AT at nucleotide 7691 in exon 15, and the other was an insertion of A at nucleotide 9900 in exon 27 (600185.0019). Both mutations created frameshifts that were predicted to encode carboxy-terminal truncated BRCA2 proteins. </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>.0019 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, 1-BP INS, 9900A
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|
|
<br />
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|
|
SNP: rs80359773,
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|
|
ClinVar: RCV000009922, RCV000114151, RCV000130631, RCV000197712, RCV000372727, RCV001353641, RCV003460795, RCV004529911, RCV004804111
|
|
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|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the Fanconi anemia complementation group D1 (FANCD1; 605724) reference cell line EUFA423, Howlett et al. (2002) found a 9900insA mutation in the BRCA2 gene in compound heterozygosity with 7691insAT (600185.0018). The 9900insA mutant allele was previously identified in a breast cancer kindred (Breast Cancer Linkage Consortium, 1999). </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>.0020 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
|
|
</span>
|
|
</h4>
|
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</div>
|
|
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|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, 7235G-A
|
|
|
|
|
|
<br />
|
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|
|
SNP: rs28897743,
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|
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|
|
|
gnomAD: rs28897743,
|
|
|
|
|
|
ClinVar: RCV000009923, RCV000031659, RCV000045112, RCV000131031, RCV000174440, RCV000475925, RCV000735595, RCV002496486, RCV004732575
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the Fanconi anemia (FANCD1; 605724) cell line EUFA579, Howlett et al. (2002) identified a G-to-A transition at nucleotide 7235 in exon 13 on 1 allele of the BRCA2 gene, and a 5837TC to AG mutation on the other allele (600185.0021). </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>.0021 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, 5837TC-AG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs276174859,
|
|
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|
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|
|
|
ClinVar: RCV000009924, RCV000044694, RCV000113449, RCV000129595, RCV000214770, RCV000255347, RCV001310124, RCV003473362
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the EUFA579 cell line from a patient with Fanconi anemia (FANCD1; 605724), Howlett et al. (2002) identified compound heterozygosity for 2 BRCA2 mutations: 7235G-A in exon 13 (600185.0020) and 5837TC to AG in exon 11. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, 8415G-T
|
|
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|
|
|
<br />
|
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|
|
SNP: rs80359065,
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|
|
|
|
|
gnomAD: rs80359065,
|
|
|
|
|
|
ClinVar: RCV000009925, RCV000045445, RCV000113885, RCV000120363, RCV000129090, RCV000735610, RCV001353739, RCV002250493, RCV003476912
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In the Fanconi anemia (FANCD1; 605724) cell line AP37P, Howlett et al. (2002) identified a G-to-T transversion at nucleotide 8415 in exon 18 of the BRCA2 gene. This mutation was in compound heterozygosity with a C-to-A transversion at nucleotide 8732 in exon 20 (600185.0023). </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>.0023 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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|
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|
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<div>
|
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<span class="mim-text-font">
|
|
|
|
BRCA2, 8732C-A
|
|
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|
<br />
|
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|
|
SNP: rs80359130,
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|
|
|
|
|
gnomAD: rs80359130,
|
|
|
|
|
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ClinVar: RCV000009926, RCV003114180
|
|
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|
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</span>
|
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</div>
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the C-to-A transversion at nucleotide 8732 in exon 20 in the BRCA2 gene that was found in compound heterozygous state in the Fanconi anemia (FANCD1; 605724) cell line AP37P by Howlett et al. (2002), see 600185.0022. </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>.0024 REMOVED FROM DATABASE</strong>
|
|
</span>
|
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</h4>
|
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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>.0025 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, THR2722ARG
|
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|
|
|
|
<br />
|
|
|
|
SNP: rs80359062,
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|
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|
|
|
|
|
ClinVar: RCV000031723, RCV000163026, RCV000405476, RCV000414368, RCV001193120, RCV003460448
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, formerly titled BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2, has been reclassified based on findings discussed in an erratum pertaining to Fackenthal et al. (2002). </p><p>By examining several BRCA2 mutations for potential exon splicing enhancer (ESE) disruption mutations, Fackenthal et al. (2002) found a C-to-G transition at nucleotide 8393 at exon 18 of the BRCA2 gene. The transition caused a thr2722-to-arg (T2722R) mutation which segregated with affected individuals in a family with breast cancer (612555) and disrupted 3 potential ESE sites. RT-PCR analysis confirmed that this mutation caused exon skipping, leading to an out-of-frame fusion of BRCA2 exons 17 and 19. The mutation caused deleterious protein truncation. </p><p>In an erratum, the authors of Fackenthal et al. (2002) stated that they and others had sequenced the full-length T2722R RT-PCR product and found on several occasions that both mutant and wildtype alleles were detectable. Thus, the putative T2722R-specific exon skipping event is not complete. As this evidence suggested that exon skipping may not be fully penetrant in blood cells, the authors recommended that the BRCA2 T2722R allele be regarded as an unclassified variant until further analysis can provide definitive evidence of clinically deleterious behavior in breast epithelial cells. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 PROSTATE CANCER</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, 1-BP INS, 2558A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80359328,
|
|
|
|
|
|
|
|
ClinVar: RCV000009928, RCV000077683, RCV000160270, RCV000163933, RCV000206474, RCV000735532, RCV001353737, RCV002272056, RCV004804074
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>One of 6 truncating mutations of the BRCA2 gene identified by Edwards et al. (2003) in 6 men with prostate cancer (176807) was a 1-bp insertion of an adenine after nucleotide 2558. </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 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</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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WILMS TUMOR, INCLUDED<br />
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GLIOMA SUSCEPTIBILITY 3, INCLUDED<br />
|
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MEDULLOBLASTOMA, 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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BRCA2, 2-BP DEL, 886GT
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<br />
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SNP: rs80359604,
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ClinVar: RCV000009929, RCV000009930, RCV000009931, RCV000009932, RCV000031637, RCV000044988, RCV000074548, RCV000131858, RCV000210073, RCV000466729, RCV000735587, RCV001356991, RCV001843452, RCV002496316, RCV003128126, RCV003162226, RCV003335024, RCV004802931
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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>Fanconi Anemia</em></strong></p><p>
|
|
In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 gene: a 2-bp deletion in exon 8 (886delGT), inherited from the father, and an 8447T-A transversion in exon 18, resulting in a leu2740-to-ter substitution (L2740X; 600185.0028), inherited from the mother. </p><p><strong><em>Wilms Tumor/Medulloblastoma/Glioblastoma</em></strong></p><p>
|
|
In 2 brothers who developed Wilms tumor (WT1; 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: a paternally inherited 886delGT, predicted to truncate the protein at codon 223 before the 8 BRC repeats, and a maternally inherited 5873C-A transversion in exon 11, resulting in a ser1882-to-ter substitution (S1882X; 600185.0031) predicted to truncate the protein such that BRC7 and BRC8 would be missing. One boy developed a glioblastoma (GLM3; 613029); the other had recurrent medulloblastoma (MDB; 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48. </p><p>Alter et al. (2007) included this mutation in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. They noted that the 886delGT mutation is associated with brain tumors. They also concluded that small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, with early onset and high rates of leukaemia and specific solid tumours. These features may comprise an extreme variant of Fanconi anemia. </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 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</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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BRCA2, LEU2740TER
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<br />
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SNP: rs80359070,
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ClinVar: RCV000009934, RCV000113889, RCV000236578, RCV001380789
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|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the leu274-to-ter (L274X) mutation in the BRCA2 gene that was found in compound heterozygous state in patients with Fanconi anemia complementation group D1 (FANCD1; 605724) by Hirsch et al. (2004), see 600185.0027. </p>
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|
</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>.0029 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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BRCA2, GLU1550TER
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<br />
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|
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SNP: rs80358695,
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|
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gnomAD: rs80358695,
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|
|
|
ClinVar: RCV000009935, RCV000044460, RCV000113326, RCV000571951, RCV001530923, RCV003473074
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 gene: a 4876G-T transversion, resulting in a glu1550-to-ter (E1550X) substitution, and a 7757T-C transition, resulting in a leu2510-to-pro substitution (L2510P; 600185.0030). </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>.0030 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
BRCA2, LEU2510PRO
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|
|
<br />
|
|
|
|
SNP: rs80358979,
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|
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|
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|
|
ClinVar: RCV000009936, RCV000113772, RCV000478444, RCV000509658, RCV001290186
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the leu2510-to-pro (L2510P) mutation in the BRCA2 gene that was found in compound heterozygous state in patients with Fanconi anemia complementation group D1 (FANCD1; 605724) by Hirsch et al. (2004), see 600185.0029. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 WILMS TUMOR</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
GLIOMA SUSCEPTIBILITY 3, INCLUDED<br />
|
|
MEDULLOBLASTOMA, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, SER1882TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80358785,
|
|
|
|
|
|
gnomAD: rs80358785,
|
|
|
|
|
|
ClinVar: RCV000009937, RCV000009938, RCV000009939, RCV000113452, RCV000496664, RCV000568762, RCV001284577
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the ser1882-to-ter (S1882X) mutation in the BRCA2 gene that was found in compound heterozygous state in patients with Wilms tumor (WT1; 194070) and brain tumors by Reid et al. (2005), see 600185.0027. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, GLN3066TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80359180,
|
|
|
|
|
|
|
|
ClinVar: RCV000009941, RCV000077463, RCV000131052, RCV000210196, RCV000235644, RCV000257912, RCV001357808, RCV003460449, RCV004802932
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the gln3066-to-ter (Q3066X) mutation in the BRCA2 gene that was found in compound heterozygous state in a patient with Fanconi anemia of complementation group D1 (FANCD1; 605724) by Alter et al. (2007), see 600185.0009. This mutation arises from a 9424C-T transition. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, IVS7DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs81002897,
|
|
|
|
|
|
|
|
ClinVar: RCV000009942, RCV000044895, RCV000113913, RCV000131851, RCV000985563, RCV001310166
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters with Fanconi anemia complementation group D1 (FANCD1; 605724), Wagner et al. (2004) found a splice site mutation in intron 7 of the BRCA2 gene, IVS7+1G-A, in compound heterozygosity with a premature termination mutation. Both sisters developed acute myeloblastic leukemia, at 3 and 1.8 years of age, respectively. Alter et al. (2007) included these patients in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 FANCONI ANEMIA, COMPLEMENTATION GROUP D1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BRCA2, IVS7DS, T-G, +2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs81002899,
|
|
|
|
|
|
|
|
ClinVar: RCV000009943, RCV000031615, RCV000044897, RCV000129071, RCV000195357, RCV000769680, RCV000826135, RCV001353557, RCV003147279, RCV004802933
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Wagner et al. (2004) found a splice site mutation in intron 7 of the BRCA2 gene, IVS7+2T-G, in compound heterozygosity with a 4-bp deletion. One of the brothers developed acute myeloblastic leukemia and the other Wilms tumor, both before 1 year of age. An unrelated patient identified by Meyer et al. (2005) also carried this mutation; he developed acute myeloblastic leukemia as well. Alter et al. (2007) included these patients in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Mazoyer et al. (1996)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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|
|
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<div>
|
|
<ol>
|
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Alter, B. P., Rosenberg, P. S., Brody, L. C.
|
|
<strong>Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.</strong>
|
|
J. Med. Genet. 44: 1-9, 2007.
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|
|
[PubMed: 16825431]
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|
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|
|
[Full Text: https://doi.org/10.1136/jmg.2006.043257]
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</p>
|
|
</li>
|
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Alter, B. P., Tenner, M. S.
|
|
<strong>Brain tumors in patients with Fanconi's anemia.</strong>
|
|
Arch. Pediat. Adolesc. Med. 148: 661-663, 1994.
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|
|
|
|
|
[PubMed: 8193701]
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|
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|
|
[Full Text: https://doi.org/10.1001/archpedi.1994.02170060115027]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Antoniou, A. C., Sinilnikova, O. M., McGuffog, L., Healey, S., Nevanlinna, H., Heikkinen, T., Simard, J., Spurdle, A. B., Beesley, J., Chen, X., Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Neuhausen, S. L., and 131 others.
|
|
<strong>Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers.</strong>
|
|
Hum. Molec. Genet. 18: 4442-4456, 2009.
|
|
|
|
|
|
[PubMed: 19656774]
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddp372]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Bhatia, V., Barroso, S. I., Garcia-Rubio, M. L., Tumini, E., Herrera-Moyano, E., Aguilera, A.
|
|
<strong>BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2.</strong>
|
|
Nature 511: 362-365, 2014.
|
|
|
|
|
|
[PubMed: 24896180]
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|
|
[Full Text: https://doi.org/10.1038/nature13374]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bolgi, O., Silva-Garcia, M., Ross, B., Pilla, E., Kari, V., Killisch, M., Spitzner, M., Stark, N., Lenz, C., Weiss, K., Donzelli, L., Gorrell, M. D., Grade, M., Riemer, J., Urlaub, H., Dobbelstein, M., Huber, R., Geiss-Friedlander, R.
|
|
<strong>Dipeptidyl peptidase 9 triggers BRCA2 degradation and promotes DNA damage repair.</strong>
|
|
EMBO Rep. 23: e54136, 2022.
|
|
|
|
|
|
[PubMed: 35912982]
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|
[Full Text: https://doi.org/10.15252/embr.202154136]
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</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Breast Cancer Linkage Consortium.
|
|
<strong>Cancer risks in BRCA2 mutation carriers.</strong>
|
|
J. Nat. Cancer Inst. 91: 1310-1316, 1999.
|
|
|
|
|
|
[PubMed: 10433620]
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|
|
[Full Text: https://doi.org/10.1093/jnci/91.15.1310]
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</p>
|
|
</li>
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., Kyle, S., Meuth, M., Curtin, N. J., Helleday, T.
|
|
<strong>Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.</strong>
|
|
Nature 434: 913-916, 2005. Note: Erratum: Nature 447: 346 only, 2007.
|
|
|
|
|
|
[PubMed: 15829966]
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|
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|
|
[Full Text: https://doi.org/10.1038/nature03443]
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</p>
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|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Casilli, F., Tournier, I., Sinilnikova, O. M., Coulet, F., Soubrier, F., Houdayer, C., Hardouin, A., Berthet, P., Sobol, H., Bourdon, V., Muller, D., Fricker, J. P., and 23 others.
|
|
<strong>The contribution of germline rearrangements to the spectrum of BRCA2 mutations.</strong>
|
|
J. Med. Genet. 43: e49, 2006. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 16950820]
|
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|
|
[Full Text: https://doi.org/10.1136/jmg.2005.040212]
|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
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Bao Lige - updated : 05/10/2023<br>Ada Hamosh - updated : 03/27/2020<br>Ada Hamosh - updated : 07/31/2019<br>Ada Hamosh - updated : 11/28/2017<br>Ada Hamosh - updated : 02/04/2016<br>Carol A. Bocchini - updated : 11/10/2015<br>Ada Hamosh - updated : 7/17/2014<br>George E. Tiller - updated : 9/5/2013<br>Ada Hamosh - updated : 7/26/2011<br>Ada Hamosh - updated : 10/27/2010<br>George E. Tiller - updated : 10/4/2010<br>Patricia A. Hartz - updated : 8/12/2010<br>Patricia A. Hartz - updated : 7/14/2009<br>Cassandra L. Kniffin - updated : 4/28/2008<br>Ada Hamosh - updated : 3/18/2008<br>Cassandra L. Kniffin - updated : 1/8/2008<br>Ada Hamosh - updated : 11/28/2007<br>Cassandra L. Kniffin - updated : 8/27/2007<br>Ada Hamosh - updated : 5/30/2007<br>Victor A. McKusick - updated : 2/21/2007<br>Cassandra L. Kniffin - updated : 2/15/2007<br>Patricia A. Hartz - updated : 12/5/2006<br>George E. Tiller - updated : 9/7/2006<br>Victor A. McKusick - updated : 8/23/2006<br>Victor A. McKusick - updated : 12/20/2005<br>George E. Tiller - updated : 9/12/2005<br>Ada Hamosh - updated : 5/25/2005<br>Ada Hamosh - updated : 4/15/2005<br>Marla J. F. O'Neill - updated : 3/1/2005<br>Ada Hamosh - updated : 1/14/2005<br>Ada Hamosh - updated : 11/11/2004<br>Tyler D. Kritzer - updated : 9/3/2004<br>Victor A. McKusick - updated : 9/3/2004<br>Marla J. F. O'Neill - updated : 8/27/2004<br>Patricia A. Hartz - updated : 3/10/2004<br>Victor A. McKusick - updated : 1/13/2004<br>Cassandra L. Kniffin - updated : 11/11/2003<br>Victor A. McKusick - updated : 10/23/2003<br>Cassandra L. Kniffin - reorganized : 9/12/2003<br>Victor A. McKusick - updated : 6/3/2003<br>Victor A. McKusick - updated : 1/22/2003<br>Ada Hamosh - updated : 11/12/2002<br>George E. Tiller - updated : 10/29/2002<br>Victor A. McKusick - updated : 10/9/2002<br>Victor A. McKusick - updated : 10/1/2002<br>Ada Hamosh - updated : 9/30/2002<br>Victor A. McKusick - updated : 9/19/2002<br>Victor A. McKusick - updated : 9/17/2002<br>Anne M. Stumpf - updated : 8/7/2002<br>Ada Hamosh - updated : 8/6/2002<br>Victor A. McKusick - updated : 6/12/2002<br>Michael B. Petersen - updated : 3/4/2002<br>Michael B. Petersen - updated : 11/19/2001<br>Ada Hamosh - updated : 11/13/2001<br>Victor A. McKusick - updated : 9/26/2001<br>Victor A. McKusick - updated : 9/13/2001<br>Michael J. Wright - updated : 7/20/2001<br>George E. Tiller - updated : 6/18/2001<br>Michael J. Wright - updated : 6/6/2001<br>Victor A. McKusick - updated : 4/10/2001<br>Victor A. McKusick - updated : 3/16/2001<br>Victor A. McKusick - updated : 3/15/2001<br>Stylianos E. Antonarakis - updated : 3/12/2001<br>Victor A. McKusick - updated : 3/8/2001<br>Victor A. McKusick - updated : 10/26/2000<br>Ada Hamosh - updated : 8/18/2000<br>Ada Hamosh - updated : 7/20/2000<br>Victor A. McKusick - updated : 1/11/2000<br>Victor A. McKusick - updated : 12/8/1999<br>Victor A. McKusick - updated : 11/1/1999<br>Stylianos E. Antonarakis - updated : 8/3/1999<br>Ada Hamosh - updated : 3/25/1999<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>Stylianos E. Antonarakis - updated : 10/8/1998<br>Victor A. McKusick - updated : 7/20/1998<br>Victor A. McKusick - updated : 6/23/1998<br>Victor A. McKusick - updated : 2/11/1998<br>Victor A. McKusick - updated : 1/10/1998<br>Victor A. McKusick - updated : 8/20/1997<br>Victor A. McKusick - updated : 6/16/1997<br>Victor A. McKusick - updated : 5/2/1997<br>Victor A. McKusick - updated : 4/23/1997<br>Victor A. McKusick - updated : 4/8/1997<br>Victor A. McKusick - updated : 2/26/1997<br>Moyra Smith - updated : 11/9/1996<br>Moyra Smith - updated : 4/29/1996
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Victor A. McKusick : 11/9/1994
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Edit History:
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mgross : 05/10/2023<br>carol : 10/06/2021<br>carol : 10/06/2021<br>alopez : 03/27/2020<br>alopez : 03/27/2020<br>carol : 01/14/2020<br>alopez : 07/31/2019<br>alopez : 11/28/2017<br>carol : 01/27/2017<br>carol : 09/12/2016<br>carol : 09/12/2016<br>carol : 09/09/2016<br>alopez : 02/04/2016<br>carol : 11/11/2015<br>carol : 11/11/2015<br>carol : 11/10/2015<br>mcolton : 6/3/2015<br>alopez : 4/23/2015<br>mcolton : 4/14/2015<br>alopez : 7/17/2014<br>alopez : 4/8/2014<br>carol : 2/25/2014<br>alopez : 9/5/2013<br>terry : 11/9/2012<br>terry : 10/3/2012<br>terry : 9/4/2012<br>alopez : 8/7/2012<br>carol : 5/10/2012<br>alopez : 3/8/2012<br>alopez : 8/8/2011<br>alopez : 8/8/2011<br>terry : 7/26/2011<br>carol : 6/17/2011<br>terry : 11/30/2010<br>alopez : 11/10/2010<br>alopez : 10/27/2010<br>alopez : 10/26/2010<br>terry : 10/4/2010<br>wwang : 9/21/2010<br>terry : 8/12/2010<br>alopez : 5/12/2010<br>alopez : 4/8/2010<br>carol : 11/23/2009<br>ckniffin : 10/2/2009<br>alopez : 9/25/2009<br>mgross : 7/15/2009<br>terry : 7/14/2009<br>ckniffin : 2/11/2009<br>carol : 2/9/2009<br>carol : 2/6/2009<br>ckniffin : 1/30/2009<br>wwang : 5/1/2008<br>ckniffin : 4/28/2008<br>alopez : 3/26/2008<br>terry : 3/18/2008<br>ckniffin : 2/5/2008<br>wwang : 1/28/2008<br>ckniffin : 1/8/2008<br>carol : 12/26/2007<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>terry : 5/30/2007<br>alopez : 2/23/2007<br>terry : 2/21/2007<br>wwang : 2/19/2007<br>ckniffin : 2/15/2007<br>mgross : 12/5/2006<br>terry : 11/16/2006<br>wwang : 10/16/2006<br>alopez : 9/7/2006<br>alopez : 8/28/2006<br>terry : 8/23/2006<br>wwang : 1/3/2006<br>wwang : 12/28/2005<br>terry : 12/20/2005<br>alopez : 10/11/2005<br>alopez : 10/11/2005<br>alopez : 10/3/2005<br>terry : 9/12/2005<br>wwang : 5/27/2005<br>wwang : 5/25/2005<br>terry : 5/25/2005<br>alopez : 4/22/2005<br>alopez : 4/22/2005<br>terry : 4/15/2005<br>carol : 3/17/2005<br>wwang : 3/17/2005<br>terry : 3/1/2005<br>alopez : 1/18/2005<br>terry : 1/14/2005<br>alopez : 11/29/2004<br>tkritzer : 11/11/2004<br>carol : 9/3/2004<br>tkritzer : 9/3/2004<br>carol : 9/2/2004<br>carol : 8/27/2004<br>terry : 8/27/2004<br>ckniffin : 3/23/2004<br>alopez : 3/17/2004<br>mgross : 3/10/2004<br>tkritzer : 2/6/2004<br>terry : 1/13/2004<br>alopez : 11/21/2003<br>tkritzer : 11/17/2003<br>ckniffin : 11/11/2003<br>cwells : 10/24/2003<br>terry : 10/23/2003<br>carol : 9/12/2003<br>ckniffin : 9/9/2003<br>tkritzer : 6/3/2003<br>terry : 6/3/2003<br>tkritzer : 1/31/2003<br>tkritzer : 1/22/2003<br>terry : 1/22/2003<br>alopez : 12/3/2002<br>tkritzer : 11/19/2002<br>alopez : 11/13/2002<br>terry : 11/12/2002<br>terry : 11/12/2002<br>cwells : 10/29/2002<br>carol : 10/11/2002<br>tkritzer : 10/10/2002<br>terry : 10/9/2002<br>alopez : 10/1/2002<br>alopez : 9/30/2002<br>tkritzer : 9/30/2002<br>tkritzer : 9/30/2002<br>tkritzer : 9/25/2002<br>tkritzer : 9/20/2002<br>carol : 9/19/2002<br>mgross : 9/17/2002<br>alopez : 8/7/2002<br>alopez : 8/7/2002<br>terry : 8/6/2002<br>cwells : 6/24/2002<br>terry : 6/12/2002<br>mgross : 3/4/2002<br>mgross : 3/4/2002<br>alopez : 12/5/2001<br>cwells : 11/29/2001<br>cwells : 11/19/2001<br>alopez : 11/13/2001<br>terry : 11/13/2001<br>carol : 10/9/2001<br>mcapotos : 9/26/2001<br>mcapotos : 9/18/2001<br>mcapotos : 9/13/2001<br>alopez : 7/26/2001<br>terry : 7/20/2001<br>cwells : 6/20/2001<br>cwells : 6/18/2001<br>alopez : 6/6/2001<br>mcapotos : 4/11/2001<br>mcapotos : 4/10/2001<br>terry : 4/10/2001<br>mcapotos : 3/27/2001<br>terry : 3/26/2001<br>mcapotos : 3/23/2001<br>terry : 3/16/2001<br>terry : 3/15/2001<br>mgross : 3/12/2001<br>mgross : 3/12/2001<br>terry : 3/8/2001<br>alopez : 10/31/2000<br>terry : 10/26/2000<br>alopez : 8/18/2000<br>mcapotos : 8/1/2000<br>mcapotos : 7/28/2000<br>terry : 7/20/2000<br>mgross : 2/15/2000<br>mcapotos : 2/7/2000<br>terry : 1/11/2000<br>carol : 12/10/1999<br>mcapotos : 12/10/1999<br>mcapotos : 12/10/1999<br>terry : 12/8/1999<br>carol : 11/9/1999<br>carol : 11/8/1999<br>terry : 11/1/1999<br>mgross : 8/3/1999<br>mgross : 3/29/1999<br>mgross : 3/25/1999<br>alopez : 2/17/1999<br>carol : 12/14/1998<br>dkim : 12/14/1998<br>terry : 12/7/1998<br>carol : 11/10/1998<br>terry : 10/29/1998<br>carol : 10/27/1998<br>terry : 10/27/1998<br>terry : 10/23/1998<br>carol : 10/8/1998<br>terry : 8/20/1998<br>carol : 7/22/1998<br>terry : 7/20/1998<br>terry : 7/20/1998<br>carol : 7/1/1998<br>terry : 6/23/1998<br>terry : 6/23/1998<br>mark : 2/11/1998<br>mark : 1/10/1998<br>jenny : 8/22/1997<br>terry : 8/20/1997<br>alopez : 7/10/1997<br>mark : 6/18/1997<br>terry : 6/16/1997<br>terry : 6/5/1997<br>mark : 5/2/1997<br>terry : 4/29/1997<br>alopez : 4/23/1997<br>terry : 4/23/1997<br>jenny : 4/8/1997<br>terry : 4/4/1997<br>mark : 2/26/1997<br>terry : 2/24/1997<br>terry : 1/2/1997<br>jamie : 12/18/1996<br>terry : 12/5/1996<br>mark : 11/9/1996<br>mark : 11/9/1996<br>mark : 10/5/1996<br>terry : 10/1/1996<br>terry : 9/12/1996<br>terry : 9/12/1996<br>terry : 9/5/1996<br>mark : 5/30/1996<br>carol : 5/30/1996<br>terry : 5/29/1996<br>carol : 5/22/1996<br>mark : 5/21/1996<br>carol : 4/29/1996<br>mark : 4/26/1996<br>terry : 4/19/1996<br>mark : 2/29/1996<br>terry : 2/27/1996<br>terry : 2/7/1996<br>mark : 1/5/1996<br>terry : 1/3/1996<br>mark : 11/2/1995<br>mimadm : 9/23/1995<br>carol : 12/6/1994<br>terry : 11/9/1994
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