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Entry
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- #604370 - BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1; BROVCA1
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- OMIM
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<p>
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<span class="h4">#604370</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/604370"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS604370"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div><a href="https://clinicaltrials.gov/search?cond=BREAST-OVARIAN CANCER, FAMILIAL" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div id="mimEuroGentestFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=3384&Typ=Pat" title="Hereditary breast and/or ovarian cancer syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Hereditary breast and/or o… </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=19054&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Hereditary breast cancer </a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1247/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/7865" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604370[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><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div id="mimOrphanetFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=145" title="Hereditary breast and/or ovarian cancer syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Hereditary breast and/or o…</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=227535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Hereditary breast cancer</a></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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<a id="title" class="mim-anchor"></a>
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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>ORPHA:</strong> 145, 227535<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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604370
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</span>
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</span>
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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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BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1; BROVCA1
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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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<a id="alternativeTitles" class="mim-anchor"></a>
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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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HBOC1
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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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<a id="includedTitles" class="mim-anchor"></a>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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BREAST CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, INCLUDED
|
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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|
OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, INCLUDED
|
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</span>
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</div>
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</div>
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<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="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene 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 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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</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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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/17/610?start=-3&limit=10&highlight=610">
|
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17q21.31
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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">
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{Breast-ovarian cancer, familial, 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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<a href="/entry/604370"> 604370 </a>
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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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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Multifactorial">Mu</abbr>
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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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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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BRCA1
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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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<a href="/entry/113705"> 113705 </a>
|
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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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<div class="btn-group ">
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<a href="/clinicalSynopsis/604370" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS604370" class="btn btn-info" role="button"> Phenotypic Series </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/604370" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/604370" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br /> -
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Multifactorial <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1837655&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1837655</a>]</span><br />
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</span>
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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 class="h5 mim-font">
|
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<strong> NEOPLASIA </strong>
|
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</span>
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</div>
|
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<div style="margin-left: 2em;">
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<div>
|
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<span class="mim-font">
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|
- Breast cancer <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254838004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254838004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/254837009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">254837009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C50-C50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C50-C50</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/C50" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C50</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0678222&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0678222</a>, <a href="https://bioportal.bioontology.org/search?q=C0006142&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0006142</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003002</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003002</a>]</span><br /> -
|
|
Ovarian cancer <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/363443007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">363443007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/123843001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">123843001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C56" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C56</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/183.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">183.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1140680&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1140680</a>, <a href="https://bioportal.bioontology.org/search?q=C0919267&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0919267</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100615" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100615</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100615" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100615</a>]</span><br />
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</span>
|
|
</div>
|
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</div>
|
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</div>
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Mutation carriers have an increased risk of developing breast and/or ovarian cancer at an earlier age<br /> -
|
|
Lifetime risk of breast cancer in mutation carriers is 80 to 90%<br /> -
|
|
Lifetime risk of ovarian cancer in mutation carriers is 40 to 50%<br /> -
|
|
Increased risk of bilateral breast cancer<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Susceptibility conferred by mutation in the breast cancer 1 gene (BRCA1, <a href="/entry/113705#0001">113705.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
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|
|
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|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Breast-ovarian cancer, familial, susceptibility to
|
|
- <a href="/phenotypicSeries/PS604370">PS604370</a>
|
|
- 5 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/13/83?start=-3&limit=10&highlight=83"> 13q13.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612555"> {Breast-ovarian cancer, familial, 2} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/612555"> 612555 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600185"> BRCA2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600185"> 600185 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/16/278?start=-3&limit=10&highlight=278"> 16p12.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620442"> {Breast-ovarian cancer, familial, susceptibility to, 5} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/620442"> 620442 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610355"> PALB2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610355"> 610355 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/17/415?start=-3&limit=10&highlight=415"> 17q12 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614291"> {Breast-ovarian cancer, familial, susceptibility to, 4} </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>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/614291"> 614291 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/602954"> RAD51D </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/602954"> 602954 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/17/610?start=-3&limit=10&highlight=610"> 17q21.31 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604370"> {Breast-ovarian cancer, familial, 1} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Multifactorial">Mu</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>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604370"> 604370 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/113705"> BRCA1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/113705"> 113705 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/17/792?start=-3&limit=10&highlight=792"> 17q22 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
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<a href="/entry/613399"> {Breast-ovarian cancer, familial, susceptibility to, 3} </a>
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<p>A number sign (#) is used with this entry because susceptibility to familial breast-ovarian cancer-1 (BROVCA1) is caused by heterozygous germline mutations in the BRCA1 (<a href="/entry/113705">113705</a>) gene on chromosomes 17q21.</p><p>See also susceptibility to familial breast-ovarian cancer-2 (BROVCA2; <a href="/entry/612555">612555</a>), caused by mutation in the BRCA2 gene (<a href="/entry/600185">600185</a>) on chromosome 13q13; BROVCA3 (<a href="/entry/613399">613399</a>), caused by mutation in the RAD51C gene (<a href="/entry/602774">602774</a>) on chromosome 17q22; BROVCA4 (<a href="/entry/614291">614291</a>), caused by mutation in the RAD51D gene (<a href="/entry/602954">602954</a>) on chromosome 17q12; and BROVCA5 (<a href="/entry/620442">620442</a>), caused by mutation in the PALB2 gene (<a href="/entry/610355">610355</a>) on chromosome 16p12.</p><p>For general discussions of breast cancer and ovarian cancer, see <a href="/entry/114480">114480</a> and <a href="/entry/167000">167000</a>, respectively.</p>
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<p><strong><em>Familial Breast Cancer</em></strong></p><p>
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Features characteristic of familial, versus sporadic, breast cancer are younger age at diagnosis, frequent bilateral disease, and frequent occurrence of disease among men (<a href="#31" class="mim-tip-reference" title="Hall, J. M., Lee, M. K., Newman, B., Morrow, J. E., Anderson, L. A., Huey, B., King, M.-C. <strong>Linkage of early-onset familial breast cancer to chromosome 17q21.</strong> Science 250: 1684-1689, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2270482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2270482</a>] [<a href="https://doi.org/10.1126/science.2270482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2270482">Hall et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2270482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>According to the conclusions of the <a href="#5" class="mim-tip-reference" title="Breast Cancer Linkage Consortium. <strong>Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 and BRCA2 mutations and sporadic cases.</strong> Lancet 349: 1505-1510, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9167459/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9167459</a>]" pmid="9167459">Breast Cancer Linkage Consortium (1997)</a>, the histology of breast cancers in women predisposed by reason of carrying BRCA1 and BRCA2 mutations differs from that in sporadic cases, and there are differences between breast cancers in carriers of BRCA1 and BRCA2 mutations. The findings were interpreted as suggesting that breast cancer due to BRCA1 has a different natural history from BRCA2 or apparently sporadic disease, which may have implications for screening and management. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9167459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Proliferative Breast Disease (PBD)</em></strong></p><p>
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In studies of 103 women from 20 kindreds that were selected for the presence of 2 first-degree relatives with breast cancer and of 31 control women, <a href="#71" class="mim-tip-reference" title="Skolnick, M. H., Cannon-Albright, L. A., Goldgar, D. E., Ward, J. H., Marshall, C. J., Schumann, G. B., Hogle, H., McWhorter, W. P., Wright, E. C., Tran, T. D., Bishop, D. T., Kushner, J. P., Eyre, H. J. <strong>Inheritance of proliferative breast disease in breast cancer kindreds.</strong> Science 250: 1715-1720, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2270486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2270486</a>] [<a href="https://doi.org/10.1126/science.2270486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2270486">Skolnick et al. (1990)</a> found, by 4-quadrant fine-needle breast aspirates, evidence of proliferative breast disease in 35% of clinically normal female first-degree relatives of breast cancer cases and in 13% of controls. Genetic analysis suggested that genetic susceptibility caused both PBD, a precursor lesion, and breast cancer in these kindreds. The study supported the hypothesis that this susceptibility is responsible for a considerable proportion of breast cancer, including unilateral and postmenopausal breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2270486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Ovarian Cancer</em></strong></p><p>
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<a href="#21" class="mim-tip-reference" title="Fraumeni, J. F., Jr., Grundy, G. W., Creagan, E. T., Everson, R. B. <strong>Six families prone to ovarian cancer.</strong> Cancer 36: 364-369, 1975.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1157008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1157008</a>] [<a href="https://doi.org/10.1002/1097-0142(197508)36:2<364::aid-cncr2820360211>3.0.co;2-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1157008">Fraumeni et al. (1975)</a> reported 6 families with multiple cases of ovarian cancer, mainly serous cystadenocarcinoma. Breast cancer also aggregated in 3 of the 6. Prophylactic oophorectomy was performed in 14 asymptomatic women from 4 of the families. Review of the microscopic sections from 8 women showed that 3, representing 2 families, had abnormalities of ovarian surface epithelium and mesothelial tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1157008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#61" class="mim-tip-reference" title="Nevo, S. <strong>Familial ovarian carcinoma: a problem in genetic counselling.</strong> Clin. Genet. 14: 219-222, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/699361/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">699361</a>]" pmid="699361">Nevo (1978)</a> described 2 families with multiple cases of ovarian papillary adenocarcinoma. In 1 family the tumor was detected in 4 females, of whom 2 had had breast cancer before the development of ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=699361" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 28 women in 16 families at high risk of ovarian carcinoma, in whom prophylactic oophorectomy was performed, 3 subsequently developed disseminated intraabdominal malignancy (<a href="#79" class="mim-tip-reference" title="Tobacman, J. K., Greene, M. H., Tucker, M. A., Costa, J., Kase, R., Fraumeni, J. F., Jr. <strong>Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian-cancer-prone families.</strong> Lancet 320: 795-797, 1982. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6126666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6126666</a>] [<a href="https://doi.org/10.1016/s0140-6736(82)92681-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6126666">Tobacman et al., 1982</a>). The primary site was uncertain despite extensive investigations, and the tumors were indistinguishable histopathologically from ovarian carcinoma. The authors concluded that in ovarian-cancer-prone families the susceptible tissue is not limited to the ovary, but includes other derivatives of the coelomic epithelium, from which primary peritoneal neoplasms may arise. <a href="#46" class="mim-tip-reference" title="Lynch, H. T., Bewtra, C., Lynch, J. F. <strong>Familial peritoneal ovarian carcinomatosis: a new clinical entity.</strong> Med. Hypotheses 21: 171-177, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3641031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3641031</a>] [<a href="https://doi.org/10.1016/0306-9877(86)90007-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3641031">Lynch et al. (1986)</a> expanded on this hypothesis and postulated that patients with hereditary predisposition to ovarian carcinoma harbor the first germinal hit in both the epithelial cells of the ovary as well as their derivatives in the coelomic mesothelium. These patients may then be inordinately susceptible to carcinogenesis from the second, somatic, hit in these same tissues. <a href="#46" class="mim-tip-reference" title="Lynch, H. T., Bewtra, C., Lynch, J. F. <strong>Familial peritoneal ovarian carcinomatosis: a new clinical entity.</strong> Med. Hypotheses 21: 171-177, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3641031/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3641031</a>] [<a href="https://doi.org/10.1016/0306-9877(86)90007-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3641031">Lynch et al. (1986)</a> referred to the condition as 'familial peritoneal ovarian carcinomatosis.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3641031+6126666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#67" class="mim-tip-reference" title="Schildkraut, J. M., Risch, N., Thompson, W. D. <strong>Evaluating genetic association among ovarian, breast, and endometrial cancer: evidence for a breast/ovarian cancer relationship.</strong> Am. J. Hum. Genet. 45: 521-529, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2491011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2491011</a>]" pmid="2491011">Schildkraut et al. (1989)</a> found a significant genetic correlation between ovarian and breast cancer. On the other hand, evidence for a significant genetic overlap between endometrial cancer (<a href="/entry/608089">608089</a>) and either ovarian or breast cancer was not found. In a multicenter population-based case-control study of 493 women aged 20 to 54 who had been newly diagnosed with epithelial ovarian cancer, <a href="#68" class="mim-tip-reference" title="Schildkraut, J. M., Thompson, W. D. <strong>Familial ovarian cancer: a population-based case-control study.</strong> Am. J. Epidemiol. 128: 456-466, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3414654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3414654</a>] [<a href="https://doi.org/10.1093/oxfordjournals.aje.a114994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3414654">Schildkraut and Thompson (1988)</a> found that the odds ratios for ovarian cancer in first- and second-degree relatives were 3.6 and 2.9, respectively, compared with women with no family history of ovarian cancer. The null hypothesis of no association was excluded on both the maternal and paternal sides of the families studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2491011+3414654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 310 Israeli Jewish women with ovarian cancer of epithelial origin, <a href="#51" class="mim-tip-reference" title="Menczer, J., Ben-Baruch, G. <strong>Familial ovarian cancer in Israeli Jewish women.</strong> Obstet. Gynec. 77: 276-277, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1988892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1988892</a>] [<a href="https://doi.org/10.1097/00006250-199102000-00023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1988892">Menczer and Ben-Baruch (1991)</a> found 24 distributed in 8 families with multiple cases. Of first-degree relatives of these probands, 5 underwent prophylactic oophorectomy, and early ovarian carcinoma was found in 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1988892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Evans, D. G. R., Ribiero, G., Warrell, D., Donnai, D. <strong>Ovarian cancer family and prophylactic choices.</strong> J. Med. Genet. 29: 416-418, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1320125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1320125</a>] [<a href="https://doi.org/10.1136/jmg.29.6.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1320125">Evans et al. (1992)</a> reported a woman with ovarian cancer who developed bilateral medullary carcinoma of the breast after oophrectomy, all by age 40 years. Family history revealed 7 additional family members with ovarian cancer, 1 of whom also developed breast cancer. The mode of transmission was consistent with autosomal dominant inheritance. Twelve female family members had underwent bilateral prophylactic oophorectomy and been given hormone replacement therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1320125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 address whether or not there is an association between the presence of a BRCA1 mutation and the subtype of epithelial ovarian carcinoma, <a href="#58" class="mim-tip-reference" title="Narod, S., Tonin, P., Lynch, H., Watson, P., Feunteun, J., Lenoir, G. <strong>Histology of BRCA1-associated ovarian tumours. (Letter)</strong> Lancet 343: 236 only, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7904689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7904689</a>] [<a href="https://doi.org/10.1016/s0140-6736(94)91021-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7904689">Narod et al. (1994)</a> reviewed the histology of 49 ovarian cancers seen in 16 hereditary breast-ovarian cancer families shown to be linked to BRCA1 markers. Of the 49 cancers, 5 (10.2%) were mucinous. By haplotype analysis with 17q markers, they determined the BRCA1 carrier status of 40 of the cases; 36 occurred in women who were BRCA1 mutation carriers and 4 were sporadic in that they occurred in noncarriers. Only 2 of the 36 ovarian cancers found in BRCA1 carriers were mucinous, compared with 3 or 4 mucinous carcinomas observed in BRCA1 noncarriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7904689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#43" class="mim-tip-reference" title="Liede, A., Tonin, P. N., Sun, C. C., Serruya, C., Daly, M. B., Narod, S. A., Foulkes, W. D. <strong>Is hereditary site-specific ovarian cancer a distinct genetic condition?</strong> Am. J. Med. Genet. 75: 55-58, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9450858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9450858</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980106)75:1<55::aid-ajmg12>3.0.co;2-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9450858">Liede et al. (1998)</a> raised the question of the existence of hereditary site-specific ovarian cancer as a genetic entity distinct from hereditary breast-ovarian cancer syndrome. They identified a large Ashkenazi Jewish kindred with 8 cases of ovarian carcinoma and no cases of breast cancer. However, in all but 1 of the ovarian cancer cases, 185delAG mutation of the BRCA1 gene (<a href="/entry/113705#0003">113705.0003</a>) segregated with the cancer. <a href="#43" class="mim-tip-reference" title="Liede, A., Tonin, P. N., Sun, C. C., Serruya, C., Daly, M. B., Narod, S. A., Foulkes, W. D. <strong>Is hereditary site-specific ovarian cancer a distinct genetic condition?</strong> Am. J. Med. Genet. 75: 55-58, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9450858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9450858</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980106)75:1<55::aid-ajmg12>3.0.co;2-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9450858">Liede et al. (1998)</a> concluded that site-specific ovarian cancer families probably represent a variant of the breast-ovarian cancer syndrome, attributable to mutation in either BRCA1 or BRCA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9450858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Patients with germline BRCA1 mutations may develop papillary serous carcinoma of the peritoneum (PSCP), a malignancy that diffusely involves peritoneal surfaces, sparing or only superficially involving the ovaries. PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma, and it may develop years after oophorectomy. <a href="#69" class="mim-tip-reference" title="Schorge, J. O., Muto, M. G., Welch, W. R., Bandera, C. A., Rubin, S. C., Bell, D. A., Berkowitz, R. S., Mok, S. C. <strong>Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations.</strong> J. Nat. Cancer Inst. 90: 841-845, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9625172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9625172</a>] [<a href="https://doi.org/10.1093/jnci/90.11.841" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9625172">Schorge et al. (1998)</a> used the androgen receptor (AR; <a href="/entry/313700">313700</a>) gene locus to test the hypothesis that some cases of PSCP have a multifocal origin and to determine if patients with germline BRCA1 mutations develop multifocal PSCP. Specimens were studied from 22 women with PSCP. The AR gene locus was evaluated for patterns of loss of heterozygosity and X-chromosome inactivation. The methylation-sensitive HpaII restriction enzyme was used to differentiate the active and inactive X chromosomes. They found patterns of selective LOH at the AR locus in 5 (23%) of the 22 subjects, consistent with multifocal, polyclonal disease origin. Two patients with selective LOH also had alternating X-chromosome inactivation patterns. Patients with germline BRCA1 mutations were more likely to have evidence of multifocal disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9625172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By linkage analysis of 26 families including 146 patients with early-onset breast cancer, <a href="#31" class="mim-tip-reference" title="Hall, J. M., Lee, M. K., Newman, B., Morrow, J. E., Anderson, L. A., Huey, B., King, M.-C. <strong>Linkage of early-onset familial breast cancer to chromosome 17q21.</strong> Science 250: 1684-1689, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2270482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2270482</a>] [<a href="https://doi.org/10.1126/science.2270482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2270482">Hall et al. (1990)</a> identified a locus on chromosome 17q21 (lod score of 5.98 for linkage of breast cancer susceptibility to marker D17S74). There were negative lod scores at this locus for families with late-onset disease. The 329 participating relatives lived in 40 states of the United States, Puerto Rico, Canada, the United Kingdom, and Colombia. The families shared the epidemiologic features characteristic of familial, versus sporadic, breast cancer: younger age at diagnosis, frequent bilateral disease, and frequent occurrence of disease among men. Candidate genes in the region included HER2 (ERBB2; <a href="/entry/164870">164870</a>), estradiol-17-beta-dehydrogenase (HSD17B1; <a href="/entry/109684">109684</a>); a cluster of homeobox-2 genes (e.g., <a href="/entry/142960">142960</a>); retinoic acid receptor alpha (<a href="/entry/180240">180240</a>); and INT4 (<a href="/entry/165330">165330</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2270482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Linkage analyses in studies of 103 women from 20 kindreds failed to show linkage with D17S74 in either early- or late-age onset <a href="#71" class="mim-tip-reference" title="Skolnick, M. H., Cannon-Albright, L. A., Goldgar, D. E., Ward, J. H., Marshall, C. J., Schumann, G. B., Hogle, H., McWhorter, W. P., Wright, E. C., Tran, T. D., Bishop, D. T., Kushner, J. P., Eyre, H. J. <strong>Inheritance of proliferative breast disease in breast cancer kindreds.</strong> Science 250: 1715-1720, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2270486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2270486</a>] [<a href="https://doi.org/10.1126/science.2270486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2270486">Skolnick et al. (1990)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2270486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#56" class="mim-tip-reference" title="Narod, S., Feunteun, J., Lynch, H., Watson, P., Conway, T., Lynch, J., Lenoir, G. <strong>A breast-ovarian cancer locus on chromosome 17. (Abstract)</strong> Am. J. Hum. Genet. 49 (suppl.): 352, 1991."None>Narod et al. (1991)</a> investigated 5 large families with a hereditary predisposition to cancer of the breast and ovary. Three families showed linkage with the D17S74 marker used by <a href="#31" class="mim-tip-reference" title="Hall, J. M., Lee, M. K., Newman, B., Morrow, J. E., Anderson, L. A., Huey, B., King, M.-C. <strong>Linkage of early-onset familial breast cancer to chromosome 17q21.</strong> Science 250: 1684-1689, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2270482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2270482</a>] [<a href="https://doi.org/10.1126/science.2270482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2270482">Hall et al. (1990)</a>. For the largest family the lod score was 2.72 at a recombination fraction of 0.07. <a href="#56" class="mim-tip-reference" title="Narod, S., Feunteun, J., Lynch, H., Watson, P., Conway, T., Lynch, J., Lenoir, G. <strong>A breast-ovarian cancer locus on chromosome 17. (Abstract)</strong> Am. J. Hum. Genet. 49 (suppl.): 352, 1991."None>Narod et al. (1991)</a> suggested that about 60% of breast cancer families have linkage of the susceptibility to the chromosome 17q locus. <a href="#47" class="mim-tip-reference" title="Lynch, H. T., Watson, P. <strong>Genetic counselling and hereditary breast/ovarian cancer. (Letter)</strong> Lancet 339: 1181 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1349410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1349410</a>] [<a href="https://doi.org/10.1016/0140-6736(92)90787-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1349410">Lynch and Watson (1992)</a> reported extension of the linkage work to 19 families, most of which showed the hereditary breast-ovarian cancer syndrome. In 70% of families, linkage to 17q was demonstrated. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2270482+1349410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hall, J. M., Friedman, L., Guenther, C., Lee, M. K., Weber, J. L., Black, D. M., King, M.-C. <strong>Closing in on a breast cancer gene on chromosome 17q.</strong> Am. J. Hum. Genet. 50: 1235-1242, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1598904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1598904</a>]" pmid="1598904">Hall et al. (1992)</a> found that the most closely linked marker in their repertoire was D17S579, a highly informative CA repeat polymorphism located at 17q21. There were no recombinants with inherited breast or ovarian cancer in 79 informative meioses in the 7 families with early-onset disease; lod score = 9.12 at 0 recombination. <a href="#27" class="mim-tip-reference" title="Goldgar, D. E., Fields, P., Lewis, C. M., Cannon-Albright, L. A., Linker, G., Tran, T., Skolnick, M. <strong>A large kindred with 17q-linked susceptibility to breast and ovarian cancer: relationship between genotype and phenotype. (Abstract)</strong> Am. J. Hum. Genet. 51 (suppl.): A27, 1992."None>Goldgar et al. (1992)</a> identified a Utah kindred in which the BRCA1 locus was linked to 17q markers with odds in excess of a million to one. The kindred included 170 descendants of 2 Utah pioneers of 1847, containing a total of 24 cancer cases (16 breast, 8 ovarian). The median age of onset was 48 for breast cancer and 53 for ovarian cancer. The penetrance of the BRCA1 gene was estimated to be 0.92 by age 70. <a href="#13" class="mim-tip-reference" title="Easton, D. F., Bishop, D. T., Ford, D., Crockford, G. P., Breast Cancer Linkage Consortium. <strong>Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families.</strong> Am. J. Hum. Genet. 52: 678-701, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8460634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8460634</a>]" pmid="8460634">Easton et al. (1993)</a> reported the results of genetic linkage analysis in 214 families. In 15 accompanying papers, confirmatory evidence on the linkage was reported from Icelandic, Scottish, Dutch, Swedish, and other families including one African American family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8460634+1598904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>If the gene predisposing to breast cancer and ovarian cancer mapped to 17q12-q21 is a tumor suppressor gene, one would expect, based on the Knudson hypothesis, that tumors from affected family members would show loss of heterozygosity (LOH) affecting the wildtype chromosome. In 4 multiple-case breast-ovarian cancer families, <a href="#73" class="mim-tip-reference" title="Smith, S. A., Easton, D. F., Evans, D. G. R., Ponder, B. A. J. <strong>Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wild-type chromosome.</strong> Nature Genet. 2: 128-131, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303261</a>] [<a href="https://doi.org/10.1038/ng1092-128" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303261">Smith et al. (1992)</a> indeed found that in each of 9 tumors that showed allele loss, the losses were from the wildtype chromosome. <a href="#38" class="mim-tip-reference" title="Kelsell, D. P., Black, D. M., Bishop, D. T., Spurr, N. K. <strong>Genetic analysis of the BRCA1 region in a large breast/ovarian family: refinement of the minimal region containing BRCA1.</strong> Hum. Molec. Genet. 2: 1823-1828, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8281142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8281142</a>] [<a href="https://doi.org/10.1093/hmg/2.11.1823" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8281142">Kelsell et al. (1993)</a> found the same for each of 7 breast tumors from a single multi-affected breast/ovarian cancer pedigree. In the same family, they generated linkage data which, in combination with previously published information, suggested that the BRCA1 gene is contained in a region estimated to be 1 to 1.5 Mb long. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1303261+8281142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Cornelis, R. S., Vasen, H. F. A., Meijers-Heijboer, H., Ford, D., van Vliet, M., van Tilborg, A. A. G., Cleton, F. J., Klijn, J. G. M., Menko, F. H., Khan, P. M., Cornelisse, C. J., Devilee, P. <strong>Age at diagnosis as an indicator of eligibility for BRCA1 DNA testing in familial breast cancer.</strong> Hum. Genet. 95: 539-544, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7759075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7759075</a>] [<a href="https://doi.org/10.1007/BF00223866" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7759075">Cornelis et al. (1995)</a> performed linkage studies in 59 consecutively collected Dutch breast cancer families, including 16 families with at least 1 case of ovarian cancer. They used a family intake cutoff of at least 3 first-degree relatives with breast and/or ovarian cancer at any age. Significant evidence for linkage was found only among the 13 breast cancer families with a mean age at diagnosis of less than 45 years. An unexpectedly low proportion of breast-ovarian cancer families were estimated to be linked to BRCA1, which could have been due to a founder effect in the Dutch population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7759075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#80" class="mim-tip-reference" title="Tonin, P., Moslehi, R., Green, R., Rosen, B., Cole, D., Boyd, N., Cutler, C., Margolese, R., Carter, R., McGillivray, B., Ives, E., Labrie, F., Gilchrist, D., Morgan, K., Simard, J., Narod, S. A. <strong>Linkage analysis of 26 Canadian breast and breast-ovarian cancer families.</strong> Hum. Genet. 95: 545-550, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7759076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7759076</a>] [<a href="https://doi.org/10.1007/BF00223867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7759076">Tonin et al. (1995)</a> studied 26 Canadian families with hereditary breast or ovarian cancer for linkage to markers flanking BRCA1. Of the 15 families that contained cases of ovarian cancer, 94% were estimated to be linked to BRCA1. In contrast, there was no overall evidence of linkage in the group of 10 families with breast cancer without ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7759076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Narod, S. A., Ford, D., Devilee, P., Barkardottir, R. B., Lynch, H. T., Smith, S. A., Ponder, B. A. J., Weber, B. L., Garber, J. E., Birch, J. M., Cornelis, R. S., Kelsell, D. P., and 17 others. <strong>An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families.</strong> Am. J. Hum. Genet. 56: 254-264, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7825586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7825586</a>]" pmid="7825586">Narod et al. (1995)</a> reported the results of linkage analysis of 145 breast-ovarian families, each of which had 3 or more cases of early-onset breast cancer (age less than 60) or of ovarian cancer. All families had at least 1 case of ovarian cancer (there were 9 site-specific ovarian cancer families). Overall, they estimated that 76% of families were linked to the BRCA1 locus. At that time, the group stated that none of the 13 families with cases of male breast cancer appeared to be linked to BRCA1. In their letter, <a href="#57" class="mim-tip-reference" title="Narod, S., Ford, D., Devilee, P., Barkardottir, R. B., Eyfjord, J., Lenoir, G., Serova, O., Easton, D., Goldgar, D., Breast Cancer Linkage Consortium. <strong>Genetic heterogeneity of breast-ovarian cancer revisited. (Letter)</strong> Am. J. Hum. Genet. 57: 957-958, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7573057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7573057</a>]" pmid="7573057">Narod et al. (1995)</a> summarized their updated findings and reported a family with male breast cancer that showed a mutation (<a href="/entry/113705#0003">113705.0003</a>) in BRCA1; <a href="#75" class="mim-tip-reference" title="Struewing, J. P., Abeliovich, D., Peretz, T., Avishai, N., Kaback, M. M., Collins, F. S., Brody, L. C. <strong>The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals.</strong> Nature Genet. 11: 198-200, 1995. Note: Erratum: Nature Genet. 12: 110 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550349</a>] [<a href="https://doi.org/10.1038/ng1095-198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550349">Struewing et al. (1995)</a> had also reported such a family. Their final results indicated that BRCA1 and BRCA2 account for the most breast-ovarian cancer families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7573057+7825586+7550349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Linkage Heterogeneity</em></strong></p><p>
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<a href="#48" class="mim-tip-reference" title="Margaritte, P., Bonaiti-Pellie, C., King, M.-C., Clerget-Darpoux, F. <strong>Linkage of familial breast cancer to chromosome 17q21 may not be restricted to early-onset disease.</strong> Am. J. Hum. Genet. 50: 1231-1234, 1992. Note: Erratum: Am. J. Hum. Genet. 52: 654 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1598903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1598903</a>]" pmid="1598903">Margaritte et al. (1992)</a> found that when account is made for the higher relative probability of sporadic rather than inherited disease for late-onset cases of breast cancer, later-onset families are much less informative and linkage heterogeneity based on age at onset is no longer significant. Furthermore, for the sample of families as a whole, linkage is significant at a recombination fraction in the 17q21 region. Although there is probably more than one gene for inherited breast cancer, age at onset may not be a reflection of this heterogeneity. <a href="#74" class="mim-tip-reference" title="Sobol, H., Mazoyer, S., Narod, S. A., Smith, S. A., Black, D. M., Kerbrat, P., Jamot, B., Solomon, E., Ponder, B. A. J., Guerin, D. <strong>Genetic heterogeneity of early-onset familial breast cancer.</strong> Hum. Genet. 89: 381-383, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1352270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1352270</a>] [<a href="https://doi.org/10.1007/BF00194307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1352270">Sobol et al. (1992)</a> also pointed to genetic heterogeneity of early-onset familial breast cancer; in an extensively affected family they found no evidence of linkage to markers on 17q. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1352270+1598903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#7" class="mim-tip-reference" title="Claus, E. B., Risch, N., Thompson, W. D. <strong>Genetic analysis of breast cancer in the cancer and steroid hormone study.</strong> Am. J. Hum. Genet. 48: 232-242, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1990835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1990835</a>]" pmid="1990835">Claus et al. (1991)</a> presented evidence for the existence of a rare autosomal dominant allele (q = 0.0033) leading to increased susceptibility to breast cancer in a dataset based on 4,730 histologically confirmed breast cancer patients aged 20 to 54 years and 4,688 controls. The cumulative lifetime risk of breast cancer for women who carried the susceptibility allele was predicted to be approximately 92%, while the cumulative lifetime risk for noncarriers was estimated to be about 10%. <a href="#30" class="mim-tip-reference" title="Hall, J. M., Friedman, L., Guenther, C., Lee, M. K., Weber, J. L., Black, D. M., King, M.-C. <strong>Closing in on a breast cancer gene on chromosome 17q.</strong> Am. J. Hum. Genet. 50: 1235-1242, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1598904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1598904</a>]" pmid="1598904">Hall et al. (1992)</a> indicated that the proportion of older-onset breast cancer attributable to BRCA1 was not yet determinable, because both inherited and sporadic cases occur in older-onset families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1990835+1598904" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Rebbeck, T. R., Couch, F. J., Kant, J., Calzone, K., DeShano, M., Peng, Y., Chen, K., Garber, J. E., Weber, B. L. <strong>Genetic heterogeneity in hereditary breast cancer: role of BRCA1 and BRCA2.</strong> Am. J. Hum. Genet. 59: 547-553, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8751855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8751855</a>]" pmid="8751855">Rebbeck et al. (1996)</a> performed specific studies of 23 families identified through 2 high-risk breast cancer research programs. In 14 (61%) it was possible to attribute the pattern of hereditary cancer to BRCA1 by a combination of linkage and mutation analyses. No families were attributed to BRCA2. In 5 families (22%), evidence against linkage to both BRCA1 and BRCA2 was found; no BRCA1 or BRCA2 mutations were detected in these 5 families. The BRCA1 or BRCA2 status of the 4 remaining families (17%) could not be determined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8751855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Ford, D., Easton, D. F., Stratton, M., Narod, S., Goldgar, D., Devilee, P., Bishop, D. T., Weber, B., Lenoir, G., Chang-Claude, J., Sobol, H., Teare, M. D., and 27 others. <strong>Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families.</strong> Am. J. Hum. Genet. 62: 676-689, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9497246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9497246</a>] [<a href="https://doi.org/10.1086/301749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9497246">Ford et al. (1998)</a> assessed the contribution of BRCA1 and BRCA2 to inherited breast cancer by linkage and mutation analysis in 237 families, each with at least 4 cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16%, suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority (76%) of families with both male and female breast cancer were due to BRCA2. The largest proportion (67%) of families due to other genes were families with 4 or 5 cases of female breast cancer only. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63%. The estimated sensitivity was identical for direct sequencing and other techniques. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9497246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 estimate the average magnitude of risks of breast and ovarian cancer associated with germline mutations in BRCA1 and BRCA2, <a href="#2" class="mim-tip-reference" title="Antoniou, A., Pharoah, P. D. P., Narod, S., Risch, H. A., Eyfjord, J. E., Hopper, J. L., Loman, N., Olsson, H., Johannsson, O., Borg, A., Pasini, B., Radice, P., and 21 others. <strong>Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies.</strong> Am. J. Hum. Genet. 72: 1117-1130, 2003. Note: Erratum: Am. J. Hum. Genet. 73: 709 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12677558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12677558</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12677558[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/10.1086/375033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12677558">Antoniou et al. (2003)</a> pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% for breast cancer and 39% for ovarian cancer. The corresponding estimates for BRCA2 were 45% and 11%. Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed under the age of 35 years of age. They found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk according to mutation position for both genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12677558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 515 women with invasive ovarian cancer in Ontario, Canada, <a href="#65" 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 39 mutations in the BRCA1 gene and 21 in the BRCA2 gene, for a total mutation frequency of 11.7%. Hereditary ovarian cancers diagnosed at less than 50 years of age were mostly (83%) due to BRCA1, whereas the majority (60%) of those diagnosed at more than 60 years of age were due to BRCA2. Mutations were found in 19% of women reporting first-degree relatives with breast or ovarian cancer and in 6.5% of women with no affected first-degree relatives. For carriers of BRCA1 mutations, the estimated penetrance by age 80 years was 36% for ovarian cancer and 68% for breast cancer. In breast cancer risk for first-degree relatives, there was a strong trend according to mutation location along the coding sequence of BRCA1, with little evidence of increased risk for mutations in the 5-prime fifth, but 8.8-fold increased risk for mutations in the 3-prime fifth, corresponding to a carrier penetrance of essentially 100%. 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 (OCCR) 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%. <a href="#65" 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> suggested that the trend in breast cancer penetrance, according to mutation location along the BRCA1 coding sequence, may have an impact on management decisions for carriers of BRCA1 mutations. <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><a href="#75" class="mim-tip-reference" title="Struewing, J. P., Abeliovich, D., Peretz, T., Avishai, N., Kaback, M. M., Collins, F. S., Brody, L. C. <strong>The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals.</strong> Nature Genet. 11: 198-200, 1995. Note: Erratum: Nature Genet. 12: 110 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550349</a>] [<a href="https://doi.org/10.1038/ng1095-198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550349">Struewing et al. (1995)</a> stated that more than 50 unique mutations had been detected in the BRCA1 gene in the germline of individuals with breast and ovarian cancer. In high-risk pedigrees, female carriers of a BRCA1 mutation had an 80 to 90% lifetime risk of breast cancer and a 40 to 50% risk of ovarian cancer. <a href="#9" class="mim-tip-reference" title="Couch, F. J., DeShano, M. L., Blackwood, M. A., Calzone, K., Stopfer, J., Campeau, L., Ganguly, A., Rebbeck, T., Weber, B. L. <strong>BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer.</strong> New Eng. J. Med. 336: 1409-1415, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9145677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9145677</a>] [<a href="https://doi.org/10.1056/NEJM199705153362002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9145677">Couch et al. (1997)</a> identified BRCA1 mutations in 16% of women with a family history of breast cancer. Only 76% of women from families with a history of breast cancer but not ovarian cancer had BRCA1 mutations. They concluded that even in a referral clinic specializing in screening women from high-risk families, most tests for BRCA1 mutations will be negative and, therefore, uninformative. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9145677+7550349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#60" class="mim-tip-reference" title="Nathanson, K. N., Wooster, R., Weber, B. L. <strong>Breast cancer genetics: what we know and what we need.</strong> Nature Med. 7: 552-556, 2001. Note: Erratum: Nature Med. 7: 749 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11329055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11329055</a>] [<a href="https://doi.org/10.1038/87876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11329055">Nathanson et al. (2001)</a> reviewed breast cancer genetics. They stated that germline mutations in BRCA1 had been identified in 15 to 20% of women with a family history of breast cancer and 60 to 80% of women with a family history of both breast and ovarian cancer. They cited a lifetime breast cancer risk of 60 to 80% for female BRCA1 mutation carriers, although penetrance estimates as low as 36% had been reported in a series of Jewish breast cancer cases selected without regard to family history (<a href="#17" class="mim-tip-reference" title="Fodor, F. H., Weston, A., Bleiweiss, I. J., McCurdy, L. D., Walsh, M. M., Tartter, P. I., Brower, S. T., Eng, C. M. <strong>Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients.</strong> Am. J. Hum. Genet. 63: 45-51, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634504</a>] [<a href="https://doi.org/10.1086/301903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634504">Fodor et al., 1998</a>). For carriers of BRCA2 mutations, they cited a lifetime breast cancer risk of 60 to 85% and a lifetime ovarian cancer risk of 10 to 20%. Men with germline mutations in BRCA2, unlike those with germline mutations in BRCA1, had an estimated 6% lifetime risk of breast cancer, a 100-fold increase over the male population risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9634504+11329055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Genetic Counseling</em></strong></p><p>
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<a href="#47" class="mim-tip-reference" title="Lynch, H. T., Watson, P. <strong>Genetic counselling and hereditary breast/ovarian cancer. (Letter)</strong> Lancet 339: 1181 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1349410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1349410</a>] [<a href="https://doi.org/10.1016/0140-6736(92)90787-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1349410">Lynch and Watson (1992)</a> reported the first experience with genetic counseling and targeted management of patients demonstrated to be at risk for hereditary breast-ovarian cancer by use of multipoint linkage analysis in the largest and most informative of the kindreds studied to date. The single family provided a lod score of 3.03. In those persons shown by linkage to be at risk, they recommended completing their families before the age of 35 so that prophylactic oophorectomy could be performed at an early age. <a href="#8" class="mim-tip-reference" title="Cornelis, R. S., Vasen, H. F. A., Meijers-Heijboer, H., Ford, D., van Vliet, M., van Tilborg, A. A. G., Cleton, F. J., Klijn, J. G. M., Menko, F. H., Khan, P. M., Cornelisse, C. J., Devilee, P. <strong>Age at diagnosis as an indicator of eligibility for BRCA1 DNA testing in familial breast cancer.</strong> Hum. Genet. 95: 539-544, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7759075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7759075</a>] [<a href="https://doi.org/10.1007/BF00223866" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7759075">Cornelis et al. (1995)</a> proposed that, during an interim period, BRCA1 mutation testing be offered only to families with a strong positive family history for early-onset breast and/or ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1349410+7759075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Friedman, E., Bar-Sade Bruchim, R., 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> suggested that identification of additional carriers of more than one mutation will increase our understanding between various mutations and will improve genetic counseling. <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="#49" class="mim-tip-reference" title="Meijers-Heijboer, E. J., Verhoog, L. C., Brekelmans, C. T. M., Seynaeve, C., Tilanus-Linthorst, M. M. A., Wagner, A., Dukel, L., Devilee, P., van den Ouweland, A. M. W., van Geel, A. N., Klijn, J. G. M. <strong>Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation.</strong> Lancet 355: 2015-2020, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10885351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10885351</a>] [<a href="https://doi.org/10.1016/s0140-6736(00)02347-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10885351">Meijers-Heijboer et al. (2000)</a> studied a large cohort of Dutch individuals at 50% or 25% risk of BRCA1 or BRCA2 mutation. Presymptomatic DNA testing was requested by 48% (198 of 411) of women and 22% (59 of 271) of men. In women, DNA testing was significantly more frequent at young age, in those who had children, and at high pretest genetic risk for a mutation. Of the unaffected women with an identified mutation who were eligible for prophylactic surgery, 51% (35 of 68) opted for bilateral mastectomy and 64% (29 of 45) for oophorectomy. Age was significantly associated with prophylactic oophorectomy, but not with prophylactic mastectomy, although there was a tendency toward mastectomy at younger ages. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10885351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#83" class="mim-tip-reference" title="Watson, P., Narod, S. A., Fodde, R., Wagner, A., Lynch, J. F., Tinley, S. T., Snyder, C. L., Coronel, S. A., Riley, B., Kinarsky, Y., Lynch, H. T. <strong>Carrier risk status changes resulting from mutation testing in hereditary non-polyposis colorectal cancer and hereditary breast-ovarian cancer.</strong> J. Med. Genet. 40: 591-596, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920070</a>] [<a href="https://doi.org/10.1136/jmg.40.8.591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920070">Watson et al. (2003)</a> studied the change in distribution of carrier risk status resulting from molecular testing in 75 families with hereditary breast-ovarian cancer and 47 families with hereditary nonpolyposis colorectal cancer (HNPCC; <a href="/entry/120435">120435</a>). Carrier risk status changes from uncertainty to certainty (i.e., to carrier or to noncarrier) accounted for 89% of risk changes resulting from testing. These risk changes affect cancer prevention recommendations, most commonly reducing their burden. <a href="#83" class="mim-tip-reference" title="Watson, P., Narod, S. A., Fodde, R., Wagner, A., Lynch, J. F., Tinley, S. T., Snyder, C. L., Coronel, S. A., Riley, B., Kinarsky, Y., Lynch, H. T. <strong>Carrier risk status changes resulting from mutation testing in hereditary non-polyposis colorectal cancer and hereditary breast-ovarian cancer.</strong> J. Med. Genet. 40: 591-596, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920070</a>] [<a href="https://doi.org/10.1136/jmg.40.8.591" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920070">Watson et al. (2003)</a> found that 60% of persons with a carrier risk status change were not themselves tested; their risk status changed because of a relative's test result. They noted that practices in use at the time did not ensure that untested family members were informed about changes in their carrier risk status resulting from mutation testing of their relatives. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Women in familial BRCA1/BRCA2 breast cancer kindreds who test negative for the family mutation are usually reassured and additional breast cancer surveillance is discontinued. However, <a href="#72" class="mim-tip-reference" title="Smith, A., Moran, A., Boyd, M. C., Bulman, M., Shenton, A., Smith, L., Iddenden, R., Woodward, E. R., Lalloo, F., Maher, E. R., Evans, D. G. R. <strong>Phenocopies in BRCA1 and BRCA2 families; evidence for modifier genes and implications for screening.</strong> J. Med. Genet. 44: 10-15, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17079251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17079251</a>] [<a href="https://doi.org/10.1136/jmg.2006.043091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17079251">Smith et al. (2007)</a> postulated that in high-risk families, such as those seen in clinical genetic centers, the risk of breast cancer may be influenced not only by the BRCA1/BRCA2 mutation but also by modifier genes. One manifestation of this would be the presence of phenocopies in BRCA1/BRCA2 kindreds. They reviewed 277 families with pathogenic BRCA1/BRCA2 mutations and identified 28 breast cancer phenocopies. Phenocopies constituted up to 24% of tests on women with breast cancer after the identification of the mutation in the proband. The standardized incidence ratio for women who tested negative for the BRCA1/BRCA2 family mutation was 5.3 for all relatives, 5.0 for all first-degree relatives, and 3.2 (95% confidence interval 2.0-4.9) for first-degree relatives in whose family all other cases of breast and ovarian cancer could be explained by the identified mutation. Thirteen of 107 (12.1%) first-degree relatives with breast cancer and no unexplained family history tested negative. Thus, in high-risk families, women who test negative for the familial BRCA1/BRCA2 mutation have an increased risk of breast cancer consistent with genetic modifiers. In light of this, <a href="#72" class="mim-tip-reference" title="Smith, A., Moran, A., Boyd, M. C., Bulman, M., Shenton, A., Smith, L., Iddenden, R., Woodward, E. R., Lalloo, F., Maher, E. R., Evans, D. G. R. <strong>Phenocopies in BRCA1 and BRCA2 families; evidence for modifier genes and implications for screening.</strong> J. Med. Genet. 44: 10-15, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17079251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17079251</a>] [<a href="https://doi.org/10.1136/jmg.2006.043091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17079251">Smith et al. (2007)</a> suggested that such women should be considered for continued surveillance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17079251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of 5 of 8 kindreds with hereditary breast-ovarian cancer syndrome, <a href="#52" class="mim-tip-reference" title="Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P. A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L. M., Ding, W., Bell, R., Rosenthal, J., and 33 others. <strong>A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.</strong> Science 266: 66-71, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7545954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7545954</a>] [<a href="https://doi.org/10.1126/science.7545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7545954">Miki et al. (1994)</a> identified 5 different heterozygous pathogenic mutations in the BRCA1 gene (see, e.g., <a href="/entry/113705#0035">113705.0035</a>). The mutations included an 11-bp deletion, a 1-bp insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Castilla, L. H., Couch, F. J., Erdos, M. R., Hoskins, K. F., Calzone, K., Garber, J. E., Boyd, J., Lubin, M. B., Deshano, M. L., Brody, L. C., Collins, F. S., Weber, B. L. <strong>Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer.</strong> Nature Genet. 8: 387-391, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894491</a>] [<a href="https://doi.org/10.1038/ng1294-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894491">Castilla et al. (1994)</a> found 8 putative disease-causing mutations in the BRCA1 gene (see, e.g., <a href="/entry/113705#0001">113705.0001</a>; <a href="/entry/113705#0006">113705.0006</a>; <a href="/entry/113705#0013">113705.0013</a>; <a href="/entry/113705#0014">113705.0014</a>) in 50 probands with a family history of breast and/or ovarian cancer. The authors used single-strand conformation polymorphism (SSCP) analysis on PCR-amplified genomic DNA. The data were considered consistent with a tumor suppressor model. The heterogeneity of mutations, coupled with the large size of the gene, indicated that clinical application of BRCA1 mutation testing would be technically challenging. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 10 families with breast-ovarian cancer, <a href="#24" class="mim-tip-reference" title="Friedman, L. S., Ostermeyer, E. A., Szabo, C. I., Dowd, P., Lynch, E. D., Rowell, S. E., King, M.-C. <strong>Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.</strong> Nature Genet. 8: 399-404, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7894493/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7894493</a>] [<a href="https://doi.org/10.1038/ng1294-399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7894493">Friedman et al. (1994)</a> used SSCP analysis and direct sequencing to identify 9 different heterozygous BRCA1 mutations (see, e.g., <a href="/entry/113705#0004">113705.0004</a>; <a href="/entry/113705#0007">113705.0007</a>-<a href="/entry/113705#0009">113705.0009</a>). The mutations in 7 instances led to protein truncation at sites throughout the gene. A missense mutation, which occurred independently in 2 families, led to loss of a cysteine in the zinc-binding domain. An intronic single basepair substitution destroyed an acceptor site and activated a cryptic splice site, leading to a 59-bp insertion and chain termination. In 4 families with both breast and ovarian cancer, chain termination mutations were found in the N-terminal half of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7894493" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a population-based series of 54 breast cancer cases from southern California, <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> found no instance of germline mutation in the BRCA1 gene but found 2 male breast cancer patients who carried novel truncating mutations in the BRCA2 gene. Only 1 of the 2 had a family history of cancer, namely, 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><strong><em>Modifier Genes</em></strong></p><p>
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Women who carry a mutation in the BRCA1 gene have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 years. <a href="#62" class="mim-tip-reference" title="Phelan, C. M., Rebbeck, T. R., Weber, B. L., Devilee, P., Ruttledge, M. H., Lynch, H. T., Lenoir, G. M., Stratton, M. R., Easton, D. F., Ponder, B. A. J., Cannon-Albright, L., Larsson, C., Goldgar, D. E., Narod, S. A. <strong>Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus.</strong> Nature Genet. 12: 309-311, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589723</a>] [<a href="https://doi.org/10.1038/ng0396-309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589723">Phelan et al. (1996)</a> demonstrated that a modifier of this risk is the HRAS1 (<a href="/entry/190020">190020</a>) variable number of tandem repeats (VNTR) polymorphism, located 1 kb downstream of the HRAS1 oncogene. Individuals who have rare alleles of this VNTR had been found to have an increased risk of certain types of cancer, including breast cancer. <a href="#62" class="mim-tip-reference" title="Phelan, C. M., Rebbeck, T. R., Weber, B. L., Devilee, P., Ruttledge, M. H., Lynch, H. T., Lenoir, G. M., Stratton, M. R., Easton, D. F., Ponder, B. A. J., Cannon-Albright, L., Larsson, C., Goldgar, D. E., Narod, S. A. <strong>Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus.</strong> Nature Genet. 12: 309-311, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589723</a>] [<a href="https://doi.org/10.1038/ng0396-309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589723">Phelan et al. (1996)</a> claimed that this was the first study to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#59" class="mim-tip-reference" title="Nathanson, K. L., Shugart, Y. Y., Omaruddin, R., Szabo, C., Goldgar, D., Rebbeck, T. R., Weber, B. L. <strong>CGH-targeted linkage analysis reveals a possible BRCA1 modifier locus on chromosome 5q.</strong> Hum. Molec. Genet. 11: 1327-1332, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019214</a>] [<a href="https://doi.org/10.1093/hmg/11.11.1327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019214">Nathanson et al. (2002)</a> used nonparametric linkage analysis to determine whether allele sharing of chromosomes 4p, 4q, and 5q was observed preferentially within 16 BRCA1 mutation families in women with BRCA1 mutations and breast cancer. No significant linkage on chromosome 4p or 4q was observed associated with breast cancer risk in BRCA1 mutation carriers. However, the authors observed a significant linkage signal at D5S1471 on chromosome 5q (P = 0.009) in all the families analyzed together. The significance of this observation increased in the subset of families with an average of breast cancer diagnosis less than 45 years (P = 0.003). The authors suggested that one or more genes on chromosome 5q33-q34 modify breast cancer risk in BRCA1 mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019214" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 sample of 10,358 carriers of BRCA1 or BRCA2 gene mutations from 23 studies, <a href="#1" class="mim-tip-reference" title="Antoniou, A. C., Spurdle, A. B., Sinilnikova, O. M., Healey, S., Pooley, K. A., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Hofmann, W., Sutter, C., and 80 others. <strong>Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.</strong> Am. J. Hum. Genet. 82: 937-948, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18355772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18355772</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18355772[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.02.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18355772">Antoniou et al. (2008)</a> observed an association between breast cancer and a SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3803662;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3803662</a>) in the TNRC9 gene (TOX3; <a href="/entry/611416">611416</a>) (per allele hazard ratio of 1.13, p(trend) = 5 x 10(-5)). The authors postulated a multiplicative effect for the SNP on breast cancer risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18355772" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The risk of ovarian cancer is reduced by 50% or more in unselected women with long-term use of oral contraceptives (<a href="#20" class="mim-tip-reference" title="Franceschi, S., Parazzini, F., Negri, E., Booth, M., La Vecchia, C., Beral, V., Tzonov, A., Trichopoulos, D. <strong>Pooled analysis of 3 European case-control studies of epithelial ovarian cancer. III. Oral contraceptive use.</strong> Int. J. Cancer 49: 61-65, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1874572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1874572</a>] [<a href="https://doi.org/10.1002/ijc.2910490112" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1874572">Franceschi et al., 1991</a>; <a href="#85" class="mim-tip-reference" title="Whittemore, A. S., Harris, R., Itnyre, J., Collaborative Ovarian Cancer Group. <strong>Characteristics relating to ovarian cancer risk: collaborative analysis of 12 U.S. case-control studies. II. Invasive epithelial ovarian cancers in white women.</strong> Am. J. Epidemiol. 136: 1184-1203, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1476141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1476141</a>] [<a href="https://doi.org/10.1093/oxfordjournals.aje.a116427" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1476141">Whittemore et al., 1992</a>). To evaluate the potential benefit of oral contraceptive use in women at high risk for ovarian cancer, <a href="#55" class="mim-tip-reference" title="Narod, S. A., Risch, H., Moslehi, R., Dorum, A., Neuhausen, S., Olsson, H., Provencher, D., Radice, P., Evans, G., Bishop, S., Brunet, J.-S., Ponder, B. A. J., Hereditary Ovarian Cancer Clinical Study Group. <strong>Oral contraceptives and the risk of hereditary ovarian cancer.</strong> New Eng. J. Med. 339: 424-428, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700175</a>] [<a href="https://doi.org/10.1056/NEJM199808133390702" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9700175">Narod et al. (1998)</a> studied 207 patients with BRCA1 or BRCA2 mutations and ovarian cancer and 161 of their sisters, who served as controls. Their findings suggested that oral contraceptive use protects against ovarian cancer in carriers of either the BRCA1 or BRCA2 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1874572+1476141+9700175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#50" class="mim-tip-reference" title="Meijers-Heijboer, H., van Geel, B., van Putten, W. L. J., Henzen-Logmans, S. C., Seynaeve, C., Menke-Pluymers, M. B. E., Bartels, C. C. M., Verhoog, L. C., van den Ouweland, A. M. W., Niermeijer, M. F., Brekelmans, C. T. M., Klijn, J. G. M. <strong>Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.</strong> New Eng. J. Med. 345: 159-164, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11463009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11463009</a>] [<a href="https://doi.org/10.1056/NEJM200107193450301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11463009">Meijers-Heijboer et al. (2001)</a> conducted a prospective study of 139 women with pathogenic BRCA1 or BRCA2 mutations without a history of breast cancer; 76 underwent prophylactic mastectomy and 63 remained under regular surveillance. They found that prophylactic bilateral total mastectomy reduced the incidence of breast cancer at 3 years of follow-up. <a href="#15" class="mim-tip-reference" title="Eisen, A., Weber, B. L. <strong>Prophylactic mastectomy for women with BRCA1 and BRCA2 mutations--facts and controversy. (Editorial)</strong> New Eng. J. Med. 345: 207-208, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11463017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11463017</a>] [<a href="https://doi.org/10.1056/NEJM200107193450309" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11463017">Eisen and Weber (2001)</a> stated that prophylactic mastectomy is 'clearly the right choice for some women. For the remainder, oophorectomy and tamoxifen in conjunction with intensive screening that includes breast MRI is a viable alternative.' They noted the need for underlying and novel prospective studies to define the role of prophylactic surgery, new chemopreventive agents, and optimal screening strategies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11463009+11463017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kauff, N. D., Satagopan, J. M., Robson, M. E., Scheuer, L., Hensley, M., Hudis, C. A., Ellis, N. A., Boyd, J., Borgen, P. I., Barakat, R. R., Norton, L., Offit, K. <strong>Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation.</strong> New Eng. J. Med. 346: 1609-1615, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12023992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12023992</a>] [<a href="https://doi.org/10.1056/NEJMoa020119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12023992">Kauff et al. (2002)</a> and <a href="#64" class="mim-tip-reference" title="Rebbeck, T. R., Lynch, H. T., Neuhausen, S. L., Narod, S. A., van't Veer, L., Garber, J. E., Evans, G., Isaacs, C., Daly, M. B., Matloff, E., Olopade, O. I., Weber, B. L. <strong>Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations.</strong> New Eng. J. Med. 346: 1616-1622, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12023993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12023993</a>] [<a href="https://doi.org/10.1056/NEJMoa012158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12023993">Rebbeck et al. (2002)</a> reported the results of studies indicating that prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer. In the study of <a href="#37" class="mim-tip-reference" title="Kauff, N. D., Satagopan, J. M., Robson, M. E., Scheuer, L., Hensley, M., Hudis, C. A., Ellis, N. A., Boyd, J., Borgen, P. I., Barakat, R. R., Norton, L., Offit, K. <strong>Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation.</strong> New Eng. J. Med. 346: 1609-1615, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12023992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12023992</a>] [<a href="https://doi.org/10.1056/NEJMoa020119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12023992">Kauff et al. (2002)</a>, of 98 women who had salpingo-oophorectomy, 3 developed breast cancer and 1 developed peritoneal cancer. Among the 72 women who chose surveillance alone, breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal cancer in 1. In the study of <a href="#64" class="mim-tip-reference" title="Rebbeck, T. R., Lynch, H. T., Neuhausen, S. L., Narod, S. A., van't Veer, L., Garber, J. E., Evans, G., Isaacs, C., Daly, M. B., Matloff, E., Olopade, O. I., Weber, B. L. <strong>Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations.</strong> New Eng. J. Med. 346: 1616-1622, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12023993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12023993</a>] [<a href="https://doi.org/10.1056/NEJMoa012158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12023993">Rebbeck et al. (2002)</a>, 6 of 259 women who underwent prophylactic oophorectomy (2.3%) received a diagnosis of stage I ovarian cancer at the time of the procedure; 2 women (0.8%) received a diagnosis of papillary serous peritoneal carcinoma 3.8 and 8.6 years after bilateral prophylactic oophorectomy. Among the controls, 58 women (19.9%) received a diagnosis of ovarian cancer, after a mean follow-up of 8.8 years. With the exclusion of the 6 women whose cancer was diagnosed at surgery, prophylactic oophorectomy significantly reduced the risk of coelomic epithelial cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12023992+12023993" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>'Synthetic lethality' as a treatment for cancer refers to an event in which tumor cell death results from lethal synergy of 2 otherwise nonlethal events. <a href="#18" class="mim-tip-reference" title="Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M. J., Ashworth, A., Carmichael, J., Kaye, S. B., Schellens, J. H. M., de Bono, J. S. <strong>Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.</strong> New Eng. J. Med. 361: 123-134, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19553641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19553641</a>] [<a href="https://doi.org/10.1056/NEJMoa0900212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19553641">Fong et al. (2009)</a> used this model to treat breast cancer cells that have homozygous loss of the tumor suppressor genes BRCA1 or BRCA2 with a PARP (<a href="/entry/173870">173870</a>) inhibitor, resulting in the induction of selective tumor cytotoxicity and the sparing of normal cells. The method aims at inhibiting PARP-mediated single-strand DNA repair in cells with deficient homologous-recombination double-strand DNA repair, which leads to unrepaired DNA breaks, the accumulation of DNA defects, and cell death. Heterozygous BRCA mutant cells retain homologous-recombination function and are not affected by PARP inhibition. In vitro, BRCA1-deficient and BRCA2-deficient cells were up to 1,000-fold more sensitive to PARP inhibition than wildtype cells, and tumor growth inhibition was also demonstrated in BRCA2-deficient xenografts. <a href="#18" class="mim-tip-reference" title="Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M. J., Ashworth, A., Carmichael, J., Kaye, S. B., Schellens, J. H. M., de Bono, J. S. <strong>Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.</strong> New Eng. J. Med. 361: 123-134, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19553641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19553641</a>] [<a href="https://doi.org/10.1056/NEJMoa0900212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19553641">Fong et al. (2009)</a> reported a phase 1 clinical trial of an orally active PARP inhibitor olaparib (AZD2281 or KU-0059436) in 60 patients with mainly breast or ovarian cancer, including 22 BRCA mutation carriers and 1 who was likely a mutation carrier but declined genetic testing. Durable objective antitumor activity was observed only in confirmed carriers of a BRCA1 or BRCA2 mutation; no objective antitumor responses were observed in patients without known BRCA mutations. Twelve (63%) of 19 BRCA carriers with ovarian, breast, or prostate cancers showed a clinical benefit from treatment with olaparib, with radiologic or tumor-marker responses or meaningful disease stabilization. The drug had an acceptable side-effect profile and did not have the toxic effects commonly associated with conventional chemotherapy. <a href="#18" class="mim-tip-reference" title="Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M. J., Ashworth, A., Carmichael, J., Kaye, S. B., Schellens, J. H. M., de Bono, J. S. <strong>Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.</strong> New Eng. J. Med. 361: 123-134, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19553641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19553641</a>] [<a href="https://doi.org/10.1056/NEJMoa0900212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19553641">Fong et al. (2009)</a> concluded that PARP inhibition has antitumor activity in BRCA mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19553641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Litton, J. K., Rugo, H. S., Ettl, J., Hurvitz, S. A., Goncalves, A., Lee, K.-H., Fehrenbacher, L., Yerushalmi, R., Mina, L. A., Martin, M., Roche, H., Im, Y.-H., Quek, R. G. W., Markova, D., Tudor, I. C., Hannah, A. L., Eiermann, W., Blum, J. L. <strong>Talazoparib in patients with advanced breast cancer and a germline BRCA mutation.</strong> New Eng. J. Med. 379: 753-763, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30110579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30110579</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30110579[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/NEJMoa1802905" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30110579">Litton et al. (2018)</a> conducted a randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physician's choice. Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs 5.6 months; hazard ratio for disease progression or death, 0.54; 95% CI, 0.41 to 0.71; p less than 0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; p = 0.11; 57% of projected events). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs 27.2%; OR, 5.0; 95% CI, 2.9 to 8.8; p less than 0.001). Hematologic grade 3-4 adverse events, primarily anemia, occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events were not different in the 2 groups. Patient-reported outcomes favored talazoparib. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30110579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Using immunohistochemical staining of human breast specimens, <a href="#86" class="mim-tip-reference" title="Wilson, C. A., Ramos, L., Villasenor, M. R., Anders, K. H., Press, M. F., Clarke, K., Karlan, B., Chen, J.-J., Scully, R., Livingston, D., Zuch, R. H., Kanter, M. H., Cohen, S., Calzone, F. J., Slamon, D. J. <strong>Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas.</strong> Nature Genet. 21: 236-240, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9988281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9988281</a>] [<a href="https://doi.org/10.1038/6029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9988281">Wilson et al. (1999)</a> demonstrated discrete nuclear foci of BRCA1 proteins in benign breast, invasive lobular cancers, and low-grade ductal carcinomas. Conversely, BRCA1 expression was reduced or undetectable in the majority of high-grade, ductal carcinomas, suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9988281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="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>Germline mutations in the BRCA1 gene are associated with a higher risk of developing basal-like breast cancer. Using immunohistochemical studies, <a href="#44" class="mim-tip-reference" title="Lim, E., Vaillant, F., Wu, D., Forrest, N. C., Pal, B., Hart, A. H., Asselin-Labat, M.-L., Gyorki, D. E., Ward, T., Partanen, A., Feleppa, F., Huschtscha, L. I., and 9 others. <strong>Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers.</strong> Nature Med. 15: 907-913, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19648928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19648928</a>] [<a href="https://doi.org/10.1038/nm.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19648928">Lim et al. (2009)</a> identified 3 different epithelial cell subsets within mammary tissue: basal stem/progenitor, luminal progenitor, and mature luminal cells. Breast cancer from BRCA1 carriers showed an expanded luminal progenitor population that displayed factor-independent growth in vitro. Gene expression profiling showed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than to any other subset. The findings suggested that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19648928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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In a study of 37 families with 4 or more cases of breast cancer or breast and ovarian cancer, <a href="#25" class="mim-tip-reference" title="Friedman, L. S., Szabo, C. I., Ostermeyer, E. A., Dowd, P., Butler, L., Park, T., Lee, M. K., Goode, E. L., Rowell, S. E., King, M.-C. <strong>Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.</strong> Am. J. Hum. Genet. 57: 1284-1297, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8533757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8533757</a>]" pmid="8533757">Friedman et al. (1995)</a> found that 5 families of Ashkenazi Jewish descent carried the BRCA1 185delAG mutation (<a href="/entry/113705#0003">113705.0003</a>) and shared the same haplotype at 8 polymorphic markers spanning approximately 850 kb. Expressivity of 185delAG in these families varied from early-onset bilateral breast cancer and ovarian cancer to late-onset breast cancer without ovarian cancer. Overall, BRCA1 mutations were detected in 26 of the families: 16 with positive BRCA1 linkage lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8533757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Following the finding of a 185delAG frameshift mutation in several Ashkenazi Jewish breast/ovarian families, <a href="#75" class="mim-tip-reference" title="Struewing, J. P., Abeliovich, D., Peretz, T., Avishai, N., Kaback, M. M., Collins, F. S., Brody, L. C. <strong>The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals.</strong> Nature Genet. 11: 198-200, 1995. Note: Erratum: Nature Genet. 12: 110 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550349</a>] [<a href="https://doi.org/10.1038/ng1095-198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550349">Struewing et al. (1995)</a> determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and in 815 reference persons not selected for ethnic origin. They found the 185delAG mutation in 0.9% of Ashkenazim (95% confidence limit, 0.4%-1.8%) and in none of the reference samples. The results suggested that 1 in 100 women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an editorial, <a href="#28" class="mim-tip-reference" title="Goldgar, D. E., Reilly, P. R. <strong>A common BRCA1 mutation in the Ashkenazim.</strong> Nature Genet. 11: 113-114, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550331</a>] [<a href="https://doi.org/10.1038/ng1095-113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550331">Goldgar and Reilly (1995)</a> raised the possibility that a high frequency of mortality from breast cancer in Nassau County, New York, in the previous 2 decades might be related to the high proportion of Ashkenazim (roughly 16%) in that population; the pathogenetic collaboration of exposure to an environmental pollutant was raised. Ethical, legal, and social issues raised by these findings were also discussed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 5,318 Jewish subjects, <a href="#77" class="mim-tip-reference" title="Struewing, J. P., Hartge, P., Wacholder, S., Baker, S. M., Berlin, M., McAdams, M., Timmerman, M. M., Brody, L. C., Tucker, M. A. <strong>The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.</strong> New Eng. J. Med. 336: 1401-1408, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9145676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9145676</a>] [<a href="https://doi.org/10.1056/NEJM199705153362001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9145676">Struewing et al. (1997)</a> found 120 carriers of a BRCA1 or BRCA2 mutation. The BRCA1 mutations studied were 185delAG and 5382insC (<a href="/entry/113705#0018">113705.0018</a>); the BRCA2 mutation studied was 6174delT (<a href="/entry/600185#0009">600185.0009</a>). By the age of 70, the estimated risk of breast cancer among carriers was 56%; of ovarian cancer, 16%; and of prostate cancer, 16%. There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated. They concluded that over 2% of Ashkenazi Jews carried mutations in BRCA1 or BRCA2 that conferred increased risks of breast, ovarian, and prostate cancer. <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+9145676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 series of 268 Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset, <a href="#17" class="mim-tip-reference" title="Fodor, F. H., Weston, A., Bleiweiss, I. J., McCurdy, L. D., Walsh, M. M., Tartter, P. I., Brower, S. T., Eng, C. M. <strong>Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients.</strong> Am. J. Hum. Genet. 63: 45-51, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634504</a>] [<a href="https://doi.org/10.1086/301903" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634504">Fodor et al. (1998)</a> determined the frequency of the common BRCA1 and BRCA2 mutations: 185delAG, 5382insC, and 6174delT. DNA was analyzed for the 3 mutations by allele-specific oligonucleotide (ASO) hybridization. Eight patients (3%) were heterozygous for the 185delAG mutation, 2 (0.75%) for the 5382insC mutation, and 8 (3%) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was estimated to be 36%, approximately 3 times the overall risk for the general population (relative risk 2.9). The results differed markedly from previous estimates based on high-risk breast cancer families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9634504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Friedman, E., Bar-Sade Bruchim, R., 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 were 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>In Australia, <a href="#4" class="mim-tip-reference" title="Bahar, A. Y., Taylor, P. J., Andrews, L., Proos, A., Burnett, L., Tucker, K., Friedlander, M., Buckley, M. F. <strong>The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data.</strong> Cancer 92: 440-445, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11466700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11466700</a>] [<a href="https://doi.org/10.1002/1097-0142(20010715)92:2<440::aid-cncr1340>3.0.co;2-o" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11466700">Bahar et al. (2001)</a> found in Ashkenazi Jews the same high prevalence of 4 founder mutations as found in Ashkenazi Jews in the United States and Israel. The 4 mutations analyzed were 185delAG and 5382insC in BRCA1; 6174delT in BRCA2; and I1307K (<a href="/entry/611731#0029">611731.0029</a>) in APC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11466700" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#39" class="mim-tip-reference" title="King, M.-C., Marks, J. H., Mandell, J. B. <strong>Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.</strong> Science 302: 643-646, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14576434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14576434</a>] [<a href="https://doi.org/10.1126/science.1088759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14576434">King et al. (2003)</a> determined the risks of breast and ovarian cancer for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. They selected 1,008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appeared to be increasing with time: breast cancer risk by age 50 years among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset. <a href="#14" class="mim-tip-reference" title="Easton, D. F., Hopper, J. L., Thomas, D. C., Antoniou, A., Pharoah, P. D. P., Whittemore, A. S., Haile, R. W. <strong>Breast cancer risks for BRCA1/2 carriers. (Letter)</strong> Science 306: 2187-2188, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15622557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15622557</a>] [<a href="https://doi.org/10.1126/science.306.5705.2187c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15622557">Easton et al. (2004)</a> and <a href="#82" class="mim-tip-reference" title="Wacholder, S., Struewing, J. P., Hartge, P., Greene, M. H., Tucker, M. A. <strong>Breast cancer risks for BRCA1/2 carriers. (Letter)</strong> Science 306: 2188 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15622558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15622558</a>]" pmid="15622558">Wacholder et al. (2004)</a> disputed the conclusions of the report by <a href="#39" class="mim-tip-reference" title="King, M.-C., Marks, J. H., Mandell, J. B. <strong>Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.</strong> Science 302: 643-646, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14576434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14576434</a>] [<a href="https://doi.org/10.1126/science.1088759" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14576434">King et al. (2003)</a> estimating a breast cancer risk by age 70 to be 71%, irrespective of mutation. Both groups suggested bias of ascertainment. <a href="#40" class="mim-tip-reference" title="King, M.-C. <strong>Response to Breast cancer risks for BRCA1/2 carriers. (Letter)</strong> Science 306: 2188-2191, 2004."None>King (2004)</a> rebutted these comments, suggesting that their penetrance estimates, at least to age 60, were comparable to those of other reported studies and that only the risk above age 70 was higher in their study, which may reflect a small sample size in that age group. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15622557+15622558+14576434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 1,098 Ashkenazi Jewish women with breast and/or ovarian cancer, <a href="#36" class="mim-tip-reference" title="Kadouri, L., Hubert, A., Rotenberg, Y., Hamburger, T., Sagi, M., Nechushtan, C., Abeliovich, D., Peretz, T. <strong>Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations. (Letter)</strong> J. Med. Genet. 44: 467-471, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17307836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17307836</a>] [<a href="https://doi.org/10.1136/jmg.2006.048173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17307836">Kadouri et al. (2007)</a> found that those with BRCA1 or BRCA2 founder mutations (329 patients) had a 2.5-fold increased risk of other cancers compared to those without BRCA1/2 mutations. Among specific cancers, BRCA1 carriers had a 3.9-fold increased risk for colon cancer and BRCA2 carriers had an 11.9-fold increased risk for lymphoma, the latter of which may have been related to treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17307836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Populations</em></strong></p><p>
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<a href="#35" class="mim-tip-reference" title="Johannsson, O., Ostermeyer, E. A., Hakansson, S., Friedman, L. S., Johansson, U., Sellberg, G., Brondum-Nielsen, K., Sele, V., Olsson, H., King, M.-C., Borg, A. <strong>Founding BRCA1 mutations in hereditary breast and ovarian cancer in Southern Sweden.</strong> Am. J. Hum. Genet. 58: 441-450, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644702</a>]" pmid="8644702">Johannsson et al. (1996)</a> identified 9 different germline mutations in the BRCA1 gene in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations were predicted to give rise to premature translation termination and included 7 frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation. The remaining mutation was a missense mutation (cys61-to-gly) in the zinc-binding motif. They also identified 4 novel Swedish founding mutations: deletion of 2595A in 5 families, the C-to-T nonsense mutation of nt1806 in 3 families, the insertion of TGAGA after nt3166 in 3 families, and the deletion of 11 nucleotides after nt1201 in 2 families. Analysis of the intragenic polymorphism D17S855 supported common origins of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of which had a predominant ovarian cancer phenotype. Among the 32 families in which no BRCA1 alteration was detected, there was 1 breast-ovarian cancer kindred showing clear linkage to the BRCA1 region and loss of the wildtype chromosome in associated tumors. Other tumor types found in BRCA1 mutation or haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma. In all, 12 of the 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8644702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Gayther, S. A., Harrington, P., Russell, P., Kharkevich, G., Garkavtseva, R. F., Ponder, B. A. J. <strong>Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia. (Letter)</strong> Am. J. Hum. Genet. 60: 1239-1242, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150173</a>]" pmid="9150173">Gayther et al. (1997)</a> found that the 5382insC and 4153delA (<a href="/entry/113705#0030">113705.0030</a>) mutations in the BRCA1 gene may account for 86% of cases of familial ovarian cancer in Russia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Hamann, U., Haner, M., Stosiek, U., Bastert, G., Scott, R. J. <strong>Low frequency of BRCA1 germline mutations in 45 German breast/ovarian cancer families.</strong> J. Med. Genet. 34: 884-888, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9391879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9391879</a>] [<a href="https://doi.org/10.1136/jmg.34.11.884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9391879">Hamann et al. (1997)</a> studied 45 German breast/ovarian cancer families for germline mutations in the BRCA1 gene. They identified 4 germline mutations in 3 breast cancer families and in 1 breast/ovarian cancer family. One of these, a missense mutation, was also found in 2.8% of the general population, suggesting that this was not disease associated. <a href="#33" class="mim-tip-reference" title="Hamann, U., Haner, M., Stosiek, U., Bastert, G., Scott, R. J. <strong>Low frequency of BRCA1 germline mutations in 45 German breast/ovarian cancer families.</strong> J. Med. Genet. 34: 884-888, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9391879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9391879</a>] [<a href="https://doi.org/10.1136/jmg.34.11.884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9391879">Hamann et al. (1997)</a> concluded that the low incidence of BRCA1 germline mutations in these families suggests the involvement of other susceptibility genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9391879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Szabo, C. I., King, M.-C. <strong>Population genetics of BRCA1 and BRCA2. (Editorial)</strong> Am. J. Hum. Genet. 60: 1013-1020, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9150148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9150148</a>]" pmid="9150148">Szabo and King (1997)</a> collated information on the population genetics of BRCA1 and BRCA2 in populations from many countries of Europe as well as the U.S., Canada, and Japan. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9150148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#81" class="mim-tip-reference" title="Tonin, P. N., Mes-Masson, A.-M., Futreal, P. A., Morgan, K., Mahon, M., Foulkes, W. D., Cole, D. E. C., Provencher, D., Ghadirian, P., Narod, S. A. <strong>Founder BRCA1 and BRCA2 mutations in French Canadian breast ovarian cancer families.</strong> Am. J. Hum. Genet. 63: 1341-1351, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792861</a>] [<a href="https://doi.org/10.1086/302099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9792861">Tonin et al. (1998)</a> noted that 4 mutations in BRCA1 and 4 mutations in BRCA2 had been identified in French Canadian breast cancer and breast/ovarian cancer families from Quebec. To identify founder effects, they examined independently ascertained French Canadian cancer families for the distribution of these 8 mutations. Mutations were found in 41 of 97 families. Six of 8 mutations were observed at least twice. The 4446C-T mutation (arg1443 to ter; <a href="/entry/113705#0016">113705.0016</a>) was the most common mutation found, followed by the BRCA2 8765delAG mutation (<a href="/entry/600185#0012">600185.0012</a>). Together, these mutations were found in 28 of 41 families identified as having the mutation. The odds of detection of any of the 4 BRCA1 mutations was 18.7 times greater if one or more cases of ovarian cancer were also present in the family. The odds of detection of any of the 4 BRCA2 mutations was 5.3 times greater if there were at least 5 cases of breast cancer in the family. Interestingly, the presence of a breast cancer case less than 36 years of age was strongly predictive of the presence of any of the 8 mutations screened. Carriers of the same mutation, from different families, shared similar haplotypes, indicating that the mutant alleles were likely to be identical by descent for a mutation in the founder population. The identification of common BRCA1 and BRCA2 mutations could facilitate carrier detection in French Canadian breast cancer and breast/ovarian cancer families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9792861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#29" class="mim-tip-reference" title="Gorski, B., Byrski, T., Huzarski, T., Jakubowska, A., Menkiszak, J., Gronwald, J., Pluzanska, A., Bebenek, M., Fischer-Maliszewska, L., Grzybowska, E., Narod, S. A., Lubinski, J. <strong>Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.</strong> Am. J. Hum. Genet. 66: 1963-1968, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10788334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10788334</a>] [<a href="https://doi.org/10.1086/302922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10788334">Gorski et al. (2000)</a> studied 66 Polish families in each of which at least 3 related females had breast or ovarian cancer and at least 1 of these 3 had been diagnosed with cancer before the age of 50 years. A total of 26 families had both breast and ovarian cancers, 4 had ovarian cancers only, and 36 families had breast cancers only. Using SSCP followed by direct sequencing of observed variants, they screened the entire coding region of BRCA1 and BRCA2 for germline mutations. Mutations were found in 35 (53%) of the 66 families. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all 4 families with ovarian cancer only, and 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; 5 of these occurred in 2 or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. <a href="#29" class="mim-tip-reference" title="Gorski, B., Byrski, T., Huzarski, T., Jakubowska, A., Menkiszak, J., Gronwald, J., Pluzanska, A., Bebenek, M., Fischer-Maliszewska, L., Grzybowska, E., Narod, S. A., Lubinski, J. <strong>Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer.</strong> Am. J. Hum. Genet. 66: 1963-1968, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10788334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10788334</a>] [<a href="https://doi.org/10.1086/302922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10788334">Gorski et al. (2000)</a> found that 3 BRCA1 abnormalities, 5382insC, cys61 to gly (<a href="/entry/113705#0002">113705.0002</a>), and 4153delA, accounted for 51%, 20%, and 11% of the identified mutations, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10788334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="De Los Rios, P., Jack, E., Kuperstein, G., Lynch, H., Lubinski, J., Narod, S. A. <strong>Founder mutations in BRCA1 and BRCA2 in North American families of Polish origin that are affected with breast cancer. (Letter)</strong> Am. J. Hum. Genet. 68: 546 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11170903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11170903</a>] [<a href="https://doi.org/10.1086/318211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11170903">De Los Rios et al. (2001)</a> reported findings in Canadian families suggesting that most of the mutation-carrying families of Polish ancestry have the BRCA1 5382insC mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11170903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#66" class="mim-tip-reference" title="Sarantaus, L., Vahteristo, P., Bloom, E., Tamminen, A., Unkila-Kallio, L., Butzow, R., Nevanlinna, H. <strong>BRCA1 and BRCA2 mutations among 233 unselected Finnish ovarian carcinoma patients.</strong> Europ. J. Hum. Genet. 9: 424-430, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11436123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11436123</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200652" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11436123">Sarantaus et al. (2001)</a> studied 233 unselected Finnish ovarian carcinoma patients treated at the Helsinki University Central Hospital during the years 1989 to 1998. The patients were screened for 12 BRCA1 and 8 BRCA2 mutations identified previously in the Finnish population. Germline mutations of BRCA1/BRCA2 were detected in 13 of the patients (11 in BRCA1 and 2 in BRCA2) and 7 recurrent founder mutations accounted for 12 of the 13 mutations detected. All mutation-positive patients but one had serous or poorly differentiated carcinoma. The presence of breast and ovarian cancer in the same woman and/or early onset (under 50 years of age) breast cancer was characteristic of the majority (77%) of the mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11436123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution of genetic factors to these high rates, <a href="#42" class="mim-tip-reference" title="Liede, A., Malik, I. A., Aziz, Z., de los Rios, P., Kwan, E., Narod, S. A. <strong>Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan.</strong> Am. J. Hum. Genet. 71: 595-606, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12181777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12181777</a>] [<a href="https://doi.org/10.1086/342506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12181777">Liede et al. (2002)</a> conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from 2 major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7%, and that among case subjects with ovarian cancer was 15.8%. Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. Most of the detected mutations were unique to Pakistan. Five BRCA1 mutations and 1 BRCA2 mutation were found in multiple case subjects and may represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 was comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1 mutation-positive case subjects was 48%, and it was 37% for first-degree relatives of the BRCA2 mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio = 2.1). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age less than 40 years) (odds ratio = 2.7) and case subjects with ovarian cancer (odds ratio = 2.4). These results suggested that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12181777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Diez, O., Osorio, A., Duran, M., Martinez-Ferrandis, J. I., de la Hoya, M., Salazar, R., Vega, A., Campos, B., Rodriguez-Lopez, R., Velasco, E., Chaves, J., Diaz-Rubio, E., and 13 others. <strong>Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects.</strong> Hum. Mutat. 22: 301-312, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12955716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12955716</a>] [<a href="https://doi.org/10.1002/humu.10260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12955716">Diez et al. (2003)</a> screened index cases from 410 Spanish breast/ovarian cancer families and 214 patients (19 of them males) with breast cancer for germline mutations in the BRCA1 and BRCA2 genes. They identified 60 mutations in BRCA1 and 53 in BRCA2. Of the 53 distinct mutations observed, 11 were novel and 12 had been reported only in Spanish families (41.5%); the prevalence of mutations in this set of families was 26.3%. The percentage was higher in families with breast and ovarian cancer (52.1%). Of the families with male breast cancer cases, 59.1% presented mutations in the BRCA2 gene. They found a higher frequency of ovarian cancer associated with mutations localized in the 5-prime end of the BRCA1 gene, but there was no association between the prevalence of this type of cancer and mutations situated in the OCCR of exon 11 of the BRCA2 gene. Five mutations accounted for 46.6% of BRCA1 detected mutations, whereas 4 mutations accounted for 56.6% of the BRCA2 mutations. The BRCA1 330A-G substitution (<a href="/entry/113705#0034">113705.0034</a>) had a Galician origin (northwest Spain). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12955716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Hartikainen, J. M., Kataja, V., Pirskanen, M., Arffman, A., Ristonmaa, U., Vahteristo, P., Ryynanen, M., Heinonen, S., Kosma, V.-M., Mannermaa, A. <strong>Screening for BRCA1 and BRCA2 mutations in Eastern Finnish breast/ovarian cancer families.</strong> Clin. Genet. 72: 311-320, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17850627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17850627</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00866.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17850627">Hartikainen et al. (2007)</a> identified 5 different mutations in the BRCA1 or BRCA2 genes in 7 (19.4%) of 36 families with breast/ovarian cancer from eastern Finland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17850627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hall, M. J., Reid, J. E., Burbidge, L. A., Pruss, D., Deffenbaugh, A. M., Frye, C., Wenstrup, R. J., Ward, B. E., Scholl, T. A., Noll, W. W. <strong>BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer.</strong> Cancer 115: 2222-2233, 2009. Note: Erratum: Cancer 115: 2804 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19241424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19241424</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19241424[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/cncr.24200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19241424">Hall et al. (2009)</a> examined a comprehensive database of BRCA1/BRCA2 testing in the United States compiled over about 10 years (1996 to 2006). Full-sequence testing of the genes was performed in 46,276 women who met eligibility criteria. The largest ethnic subgroup was of Western or Central European ancestry (87.1%), followed by Latin American (4.2%), African (3.8%), Asian (2.6%), Native American (1.3%), and Middle Eastern (1.1%) ancestry. Individuals of Ashkenazi Jewish origin were excluded. Women of non-European descent were younger (mean age of 45.9 years) than European women (mean age of 50 years) at age of testing. Mutations were identified in 12.5% of women overall, but those of African and Latin American ancestries had significantly higher prevalences of deleterious BRCA1 and BRCA2 mutations (15.6% and 14.8%, respectively) compared with women of Western European ancestry (12.1%), primarily because of an increased prevalence of BRCA1 mutations in the former 2 groups. Overall, BRCA1 mutations were more common than BRCA2 mutations for every ethnicity except Asian, in which the frequency was equal (about 6.3% for each gene). The most common recurrent mutations per group were 5385insC (also known as 5382insC; <a href="/entry/113705#0018">113705.0018</a>) in BRCA1, accounting for 5.2% of all mutations among Western Europeans and 14.9% of all mutations among Central Europeans; 943ins10 (<a href="/entry/113705#0029">113705.0029</a>) in BRCA1, accounting for 10% of all mutations among Africans; and 187delAG (also known as 185delAG; <a href="/entry/113705#0003">113705.0003</a>) in BRCA1, accounting for 6.7% of all mutations among Native Americans, 12.2% of all mutations among Latin Americans, and 15.2% of all mutations among Middle Eastern women. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19241424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#70" class="mim-tip-reference" title="Simard, J., Feunteun, J., Lenoir, G., Tonin, P., Normand, T., The, V. L., Vivier, A., Lasko, D., Morgan, K., Rouleau, G. A., Lynch, H., Labrie, F., Narod, S. A. <strong>Genetic mapping of the breast-ovarian cancer syndrome to a small interval on chromosome 17q12-21: exclusion of candidate genes EDH17B2 and RARA.</strong> Hum. Molec. Genet. 2: 1193-1199, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401501</a>] [<a href="https://doi.org/10.1093/hmg/2.8.1193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401501">Simard et al. (1993)</a> were able to exclude the RARA gene (<a href="/entry/180240">180240</a>) as a candidate disease gene by genetic recombination. Although BRCA1 and the gene for estradiol 17-beta-hydroxysteroid dehydrogenase II (HSD17B2; <a href="/entry/109685">109685</a>) map to a 6-cM interval and no recombination was observed between the 2 genes, direct sequencing of overlapping PCR products containing the entire EDH17B2 gene in 4 unrelated affected woman did not uncover any pathogenic sequence variations, thus excluding the EDH17B2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8401501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kelsell, D. P., Black, D. M., Bishop, D. T., Spurr, N. K. <strong>Genetic analysis of the BRCA1 region in a large breast/ovarian family: refinement of the minimal region containing BRCA1.</strong> Hum. Molec. Genet. 2: 1823-1828, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8281142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8281142</a>] [<a href="https://doi.org/10.1093/hmg/2.11.1823" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8281142">Kelsell et al. (1993)</a> did not identify pathogenic variations in the EDH17B1 or EDH17B2 gene in 4 affected members of a family with breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8281142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#Arason1993" class="mim-tip-reference" title="Arason, A., Barkardottir, R. B., Egilsson, V. <strong>Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer.</strong> Am. J. Hum. Genet. 52: 711-717, 1993.">Arason et al. (1993)</a>; <a href="#Donnai1983" class="mim-tip-reference" title="Donnai, D., Warrell, D. W. <strong>Familial ovarian cancer: gynaecological and genetic management.</strong> J. Med. Genet. 20: 300 only, 1983.">Donnai and Warrell (1983)</a>; <a href="#Narod1991" class="mim-tip-reference" title="Narod, S., Feunteun, J., Lynch, H., Watson, P., Conway, T., Lynch, J., Lenoir, G. <strong>A breast-ovarian cancer locus on chromosome 17. (Abstract)</strong> Am. J. Hum. Genet. 49 (suppl.): 352, 1991.">Narod et al. (1991)</a>; <a href="#Struewing1995" class="mim-tip-reference" title="Struewing, J. P., Brody, L. C., Erdos, M. R., Kase, R. G., Giambarresi, T. R., Smith, S. A., Collins, F. S., Tucker, M.A. <strong>Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer.</strong> Am. J. Hum. Genet. 57: 1-7, 1995.">Struewing et al. (1995)</a>
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Antoniou, A. C., Spurdle, A. B., Sinilnikova, O. M., Healey, S., Pooley, K. A., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Hofmann, W., Sutter, C., and 80 others.
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<strong>Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.</strong>
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Am. J. Hum. Genet. 82: 937-948, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18355772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18355772</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18355772[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=18355772" 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.ajhg.2008.02.008" target="_blank">Full Text</a>]
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Antoniou, A., Pharoah, P. D. P., Narod, S., Risch, H. A., Eyfjord, J. E., Hopper, J. L., Loman, N., Olsson, H., Johannsson, O., Borg, A., Pasini, B., Radice, P., and 21 others.
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<strong>Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies.</strong>
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Am. J. Hum. Genet. 72: 1117-1130, 2003. Note: Erratum: Am. J. Hum. Genet. 73: 709 only, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12677558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12677558</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12677558[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=12677558" 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/10.1086/375033" target="_blank">Full Text</a>]
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<strong>Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer.</strong>
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Am. J. Hum. Genet. 52: 711-717, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8460636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8460636</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8460636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bahar, A. Y., Taylor, P. J., Andrews, L., Proos, A., Burnett, L., Tucker, K., Friedlander, M., Buckley, M. F.
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<strong>The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data.</strong>
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Cancer 92: 440-445, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11466700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11466700</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11466700" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/1097-0142(20010715)92:2<440::aid-cncr1340>3.0.co;2-o" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302040" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1352270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1352270</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1352270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/BF00194307" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM199705153362001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(82)92681-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00223867" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/302099" target="_blank">Full Text</a>]
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Watson, P., Narod, S. A., Fodde, R., Wagner, A., Lynch, J. F., Tinley, S. T., Snyder, C. L., Coronel, S. A., Riley, B., Kinarsky, Y., Lynch, H. T.
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[<a href="https://doi.org/10.1136/jmg.40.8.591" target="_blank">Full Text</a>]
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Welcsh, P. L., King, M.-C.
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Whittemore, A. S., Harris, R., Itnyre, J., Collaborative Ovarian Cancer Group.
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<strong>Characteristics relating to ovarian cancer risk: collaborative analysis of 12 U.S. case-control studies. II. Invasive epithelial ovarian cancers in white women.</strong>
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Wilson, C. A., Ramos, L., Villasenor, M. R., Anders, K. H., Press, M. F., Clarke, K., Karlan, B., Chen, J.-J., Scully, R., Livingston, D., Zuch, R. H., Kanter, M. H., Cohen, S., Calzone, F. J., Slamon, D. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9988281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9988281</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9988281" 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/10.1038/6029" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 10/16/2018
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Cassandra L. Kniffin - updated : 12/16/2009<br>Cassandra L. Kniffin - updated : 9/3/2009<br>Cassandra L. Kniffin - updated : 8/4/2009<br>Cassandra L. Kniffin - reorganized : 2/6/2009<br>Cassandra L. Kniffin - updated : 1/30/2009<br>Marla J. F. O'Neill - updated : 11/16/2006<br>Patricia A. Hartz - updated : 8/7/2006<br>Marla J. F. O'Neill - updated : 3/22/2005<br>Victor A. McKusick - updated : 7/1/2003
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Victor A. McKusick : 12/27/1999
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carol : 07/21/2023<br>carol : 05/23/2022<br>carol : 05/20/2022<br>carol : 11/04/2021<br>carol : 10/06/2021<br>alopez : 10/16/2018<br>carol : 05/22/2018<br>carol : 04/30/2018<br>carol : 04/25/2018<br>carol : 02/21/2014<br>carol : 8/19/2013<br>terry : 12/20/2012<br>terry : 11/28/2012<br>terry : 9/7/2012<br>alopez : 5/12/2010<br>ckniffin : 5/10/2010<br>carol : 4/5/2010<br>terry : 1/20/2010<br>wwang : 1/8/2010<br>ckniffin : 12/16/2009<br>wwang : 9/15/2009<br>ckniffin : 9/3/2009<br>wwang : 8/28/2009<br>ckniffin : 8/4/2009<br>terry : 6/3/2009<br>ckniffin : 3/6/2009<br>carol : 2/6/2009<br>terry : 2/6/2009<br>ckniffin : 1/30/2009<br>carol : 12/9/2008<br>alopez : 8/31/2007<br>wwang : 11/17/2006<br>terry : 11/16/2006<br>wwang : 8/7/2006<br>joanna : 12/2/2005<br>mgross : 4/14/2005<br>tkritzer : 3/22/2005<br>tkritzer : 2/11/2005<br>tkritzer : 7/24/2003<br>alopez : 7/2/2003<br>terry : 7/1/2003<br>carol : 6/18/2003<br>carol : 12/27/1999
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BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1; BROVCA1
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<em>Alternative titles; symbols</em>
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HBOC1
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Other entities represented in this entry:
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BREAST CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, INCLUDED
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OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1, INCLUDED
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<strong>ORPHA:</strong> 145, 227535;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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17q21.31
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<span class="mim-font">
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{Breast-ovarian cancer, familial, 1}
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<span class="mim-font">
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604370
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Autosomal dominant; Multifactorial
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<span class="mim-font">
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3
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BRCA1
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113705
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because susceptibility to familial breast-ovarian cancer-1 (BROVCA1) is caused by heterozygous germline mutations in the BRCA1 (113705) gene on chromosomes 17q21.</p><p>See also susceptibility to familial breast-ovarian cancer-2 (BROVCA2; 612555), caused by mutation in the BRCA2 gene (600185) on chromosome 13q13; BROVCA3 (613399), caused by mutation in the RAD51C gene (602774) on chromosome 17q22; BROVCA4 (614291), caused by mutation in the RAD51D gene (602954) on chromosome 17q12; and BROVCA5 (620442), caused by mutation in the PALB2 gene (610355) on chromosome 16p12.</p><p>For general discussions of breast cancer and ovarian cancer, see 114480 and 167000, respectively.</p>
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<strong>Clinical Features</strong>
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<p><strong><em>Familial Breast Cancer</em></strong></p><p>
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Features characteristic of familial, versus sporadic, breast cancer are younger age at diagnosis, frequent bilateral disease, and frequent occurrence of disease among men (Hall et al., 1990). </p><p>According to the conclusions of the Breast Cancer Linkage Consortium (1997), the histology of breast cancers in women predisposed by reason of carrying BRCA1 and BRCA2 mutations differs from that in sporadic cases, and there are differences between breast cancers in carriers of BRCA1 and BRCA2 mutations. The findings were interpreted as suggesting that breast cancer due to BRCA1 has a different natural history from BRCA2 or apparently sporadic disease, which may have implications for screening and management. </p><p><strong><em>Proliferative Breast Disease (PBD)</em></strong></p><p>
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In studies of 103 women from 20 kindreds that were selected for the presence of 2 first-degree relatives with breast cancer and of 31 control women, Skolnick et al. (1990) found, by 4-quadrant fine-needle breast aspirates, evidence of proliferative breast disease in 35% of clinically normal female first-degree relatives of breast cancer cases and in 13% of controls. Genetic analysis suggested that genetic susceptibility caused both PBD, a precursor lesion, and breast cancer in these kindreds. The study supported the hypothesis that this susceptibility is responsible for a considerable proportion of breast cancer, including unilateral and postmenopausal breast cancer. </p><p><strong><em>Ovarian Cancer</em></strong></p><p>
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Fraumeni et al. (1975) reported 6 families with multiple cases of ovarian cancer, mainly serous cystadenocarcinoma. Breast cancer also aggregated in 3 of the 6. Prophylactic oophorectomy was performed in 14 asymptomatic women from 4 of the families. Review of the microscopic sections from 8 women showed that 3, representing 2 families, had abnormalities of ovarian surface epithelium and mesothelial tissue. </p><p>Nevo (1978) described 2 families with multiple cases of ovarian papillary adenocarcinoma. In 1 family the tumor was detected in 4 females, of whom 2 had had breast cancer before the development of ovarian cancer. </p><p>Among 28 women in 16 families at high risk of ovarian carcinoma, in whom prophylactic oophorectomy was performed, 3 subsequently developed disseminated intraabdominal malignancy (Tobacman et al., 1982). The primary site was uncertain despite extensive investigations, and the tumors were indistinguishable histopathologically from ovarian carcinoma. The authors concluded that in ovarian-cancer-prone families the susceptible tissue is not limited to the ovary, but includes other derivatives of the coelomic epithelium, from which primary peritoneal neoplasms may arise. Lynch et al. (1986) expanded on this hypothesis and postulated that patients with hereditary predisposition to ovarian carcinoma harbor the first germinal hit in both the epithelial cells of the ovary as well as their derivatives in the coelomic mesothelium. These patients may then be inordinately susceptible to carcinogenesis from the second, somatic, hit in these same tissues. Lynch et al. (1986) referred to the condition as 'familial peritoneal ovarian carcinomatosis.' </p><p>Schildkraut et al. (1989) found a significant genetic correlation between ovarian and breast cancer. On the other hand, evidence for a significant genetic overlap between endometrial cancer (608089) and either ovarian or breast cancer was not found. In a multicenter population-based case-control study of 493 women aged 20 to 54 who had been newly diagnosed with epithelial ovarian cancer, Schildkraut and Thompson (1988) found that the odds ratios for ovarian cancer in first- and second-degree relatives were 3.6 and 2.9, respectively, compared with women with no family history of ovarian cancer. The null hypothesis of no association was excluded on both the maternal and paternal sides of the families studied. </p><p>Among 310 Israeli Jewish women with ovarian cancer of epithelial origin, Menczer and Ben-Baruch (1991) found 24 distributed in 8 families with multiple cases. Of first-degree relatives of these probands, 5 underwent prophylactic oophorectomy, and early ovarian carcinoma was found in 1. </p><p>Evans et al. (1992) reported a woman with ovarian cancer who developed bilateral medullary carcinoma of the breast after oophrectomy, all by age 40 years. Family history revealed 7 additional family members with ovarian cancer, 1 of whom also developed breast cancer. The mode of transmission was consistent with autosomal dominant inheritance. Twelve female family members had underwent bilateral prophylactic oophorectomy and been given hormone replacement therapy. </p><p>To address whether or not there is an association between the presence of a BRCA1 mutation and the subtype of epithelial ovarian carcinoma, Narod et al. (1994) reviewed the histology of 49 ovarian cancers seen in 16 hereditary breast-ovarian cancer families shown to be linked to BRCA1 markers. Of the 49 cancers, 5 (10.2%) were mucinous. By haplotype analysis with 17q markers, they determined the BRCA1 carrier status of 40 of the cases; 36 occurred in women who were BRCA1 mutation carriers and 4 were sporadic in that they occurred in noncarriers. Only 2 of the 36 ovarian cancers found in BRCA1 carriers were mucinous, compared with 3 or 4 mucinous carcinomas observed in BRCA1 noncarriers. </p><p>Liede et al. (1998) raised the question of the existence of hereditary site-specific ovarian cancer as a genetic entity distinct from hereditary breast-ovarian cancer syndrome. They identified a large Ashkenazi Jewish kindred with 8 cases of ovarian carcinoma and no cases of breast cancer. However, in all but 1 of the ovarian cancer cases, 185delAG mutation of the BRCA1 gene (113705.0003) segregated with the cancer. Liede et al. (1998) concluded that site-specific ovarian cancer families probably represent a variant of the breast-ovarian cancer syndrome, attributable to mutation in either BRCA1 or BRCA2. </p><p>Patients with germline BRCA1 mutations may develop papillary serous carcinoma of the peritoneum (PSCP), a malignancy that diffusely involves peritoneal surfaces, sparing or only superficially involving the ovaries. PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma, and it may develop years after oophorectomy. Schorge et al. (1998) used the androgen receptor (AR; 313700) gene locus to test the hypothesis that some cases of PSCP have a multifocal origin and to determine if patients with germline BRCA1 mutations develop multifocal PSCP. Specimens were studied from 22 women with PSCP. The AR gene locus was evaluated for patterns of loss of heterozygosity and X-chromosome inactivation. The methylation-sensitive HpaII restriction enzyme was used to differentiate the active and inactive X chromosomes. They found patterns of selective LOH at the AR locus in 5 (23%) of the 22 subjects, consistent with multifocal, polyclonal disease origin. Two patients with selective LOH also had alternating X-chromosome inactivation patterns. Patients with germline BRCA1 mutations were more likely to have evidence of multifocal disease. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>By linkage analysis of 26 families including 146 patients with early-onset breast cancer, Hall et al. (1990) identified a locus on chromosome 17q21 (lod score of 5.98 for linkage of breast cancer susceptibility to marker D17S74). There were negative lod scores at this locus for families with late-onset disease. The 329 participating relatives lived in 40 states of the United States, Puerto Rico, Canada, the United Kingdom, and Colombia. The families shared the epidemiologic features characteristic of familial, versus sporadic, breast cancer: younger age at diagnosis, frequent bilateral disease, and frequent occurrence of disease among men. Candidate genes in the region included HER2 (ERBB2; 164870), estradiol-17-beta-dehydrogenase (HSD17B1; 109684); a cluster of homeobox-2 genes (e.g., 142960); retinoic acid receptor alpha (180240); and INT4 (165330). </p><p>Linkage analyses in studies of 103 women from 20 kindreds failed to show linkage with D17S74 in either early- or late-age onset Skolnick et al. (1990). </p><p>Narod et al. (1991) investigated 5 large families with a hereditary predisposition to cancer of the breast and ovary. Three families showed linkage with the D17S74 marker used by Hall et al. (1990). For the largest family the lod score was 2.72 at a recombination fraction of 0.07. Narod et al. (1991) suggested that about 60% of breast cancer families have linkage of the susceptibility to the chromosome 17q locus. Lynch and Watson (1992) reported extension of the linkage work to 19 families, most of which showed the hereditary breast-ovarian cancer syndrome. In 70% of families, linkage to 17q was demonstrated. </p><p>Hall et al. (1992) found that the most closely linked marker in their repertoire was D17S579, a highly informative CA repeat polymorphism located at 17q21. There were no recombinants with inherited breast or ovarian cancer in 79 informative meioses in the 7 families with early-onset disease; lod score = 9.12 at 0 recombination. Goldgar et al. (1992) identified a Utah kindred in which the BRCA1 locus was linked to 17q markers with odds in excess of a million to one. The kindred included 170 descendants of 2 Utah pioneers of 1847, containing a total of 24 cancer cases (16 breast, 8 ovarian). The median age of onset was 48 for breast cancer and 53 for ovarian cancer. The penetrance of the BRCA1 gene was estimated to be 0.92 by age 70. Easton et al. (1993) reported the results of genetic linkage analysis in 214 families. In 15 accompanying papers, confirmatory evidence on the linkage was reported from Icelandic, Scottish, Dutch, Swedish, and other families including one African American family. </p><p>If the gene predisposing to breast cancer and ovarian cancer mapped to 17q12-q21 is a tumor suppressor gene, one would expect, based on the Knudson hypothesis, that tumors from affected family members would show loss of heterozygosity (LOH) affecting the wildtype chromosome. In 4 multiple-case breast-ovarian cancer families, Smith et al. (1992) indeed found that in each of 9 tumors that showed allele loss, the losses were from the wildtype chromosome. Kelsell et al. (1993) found the same for each of 7 breast tumors from a single multi-affected breast/ovarian cancer pedigree. In the same family, they generated linkage data which, in combination with previously published information, suggested that the BRCA1 gene is contained in a region estimated to be 1 to 1.5 Mb long. </p><p>Cornelis et al. (1995) performed linkage studies in 59 consecutively collected Dutch breast cancer families, including 16 families with at least 1 case of ovarian cancer. They used a family intake cutoff of at least 3 first-degree relatives with breast and/or ovarian cancer at any age. Significant evidence for linkage was found only among the 13 breast cancer families with a mean age at diagnosis of less than 45 years. An unexpectedly low proportion of breast-ovarian cancer families were estimated to be linked to BRCA1, which could have been due to a founder effect in the Dutch population. </p><p>Tonin et al. (1995) studied 26 Canadian families with hereditary breast or ovarian cancer for linkage to markers flanking BRCA1. Of the 15 families that contained cases of ovarian cancer, 94% were estimated to be linked to BRCA1. In contrast, there was no overall evidence of linkage in the group of 10 families with breast cancer without ovarian cancer. </p><p>Narod et al. (1995) reported the results of linkage analysis of 145 breast-ovarian families, each of which had 3 or more cases of early-onset breast cancer (age less than 60) or of ovarian cancer. All families had at least 1 case of ovarian cancer (there were 9 site-specific ovarian cancer families). Overall, they estimated that 76% of families were linked to the BRCA1 locus. At that time, the group stated that none of the 13 families with cases of male breast cancer appeared to be linked to BRCA1. In their letter, Narod et al. (1995) summarized their updated findings and reported a family with male breast cancer that showed a mutation (113705.0003) in BRCA1; Struewing et al. (1995) had also reported such a family. Their final results indicated that BRCA1 and BRCA2 account for the most breast-ovarian cancer families. </p><p><strong><em>Linkage Heterogeneity</em></strong></p><p>
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Margaritte et al. (1992) found that when account is made for the higher relative probability of sporadic rather than inherited disease for late-onset cases of breast cancer, later-onset families are much less informative and linkage heterogeneity based on age at onset is no longer significant. Furthermore, for the sample of families as a whole, linkage is significant at a recombination fraction in the 17q21 region. Although there is probably more than one gene for inherited breast cancer, age at onset may not be a reflection of this heterogeneity. Sobol et al. (1992) also pointed to genetic heterogeneity of early-onset familial breast cancer; in an extensively affected family they found no evidence of linkage to markers on 17q. </p>
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<span class="mim-font">
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<strong>Inheritance</strong>
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<p>Claus et al. (1991) presented evidence for the existence of a rare autosomal dominant allele (q = 0.0033) leading to increased susceptibility to breast cancer in a dataset based on 4,730 histologically confirmed breast cancer patients aged 20 to 54 years and 4,688 controls. The cumulative lifetime risk of breast cancer for women who carried the susceptibility allele was predicted to be approximately 92%, while the cumulative lifetime risk for noncarriers was estimated to be about 10%. Hall et al. (1992) indicated that the proportion of older-onset breast cancer attributable to BRCA1 was not yet determinable, because both inherited and sporadic cases occur in older-onset families. </p><p>Rebbeck et al. (1996) performed specific studies of 23 families identified through 2 high-risk breast cancer research programs. In 14 (61%) it was possible to attribute the pattern of hereditary cancer to BRCA1 by a combination of linkage and mutation analyses. No families were attributed to BRCA2. In 5 families (22%), evidence against linkage to both BRCA1 and BRCA2 was found; no BRCA1 or BRCA2 mutations were detected in these 5 families. The BRCA1 or BRCA2 status of the 4 remaining families (17%) could not be determined. </p><p>Ford et al. (1998) assessed the contribution of BRCA1 and BRCA2 to inherited breast cancer by linkage and mutation analysis in 237 families, each with at least 4 cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16%, suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority (76%) of families with both male and female breast cancer were due to BRCA2. The largest proportion (67%) of families due to other genes were families with 4 or 5 cases of female breast cancer only. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63%. The estimated sensitivity was identical for direct sequencing and other techniques. </p><p>To estimate the average magnitude of risks of breast and ovarian cancer associated with germline mutations in BRCA1 and BRCA2, Antoniou et al. (2003) pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% for breast cancer and 39% for ovarian cancer. The corresponding estimates for BRCA2 were 45% and 11%. Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed under the age of 35 years of age. They found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk according to mutation position for both genes. </p><p>In a study of 515 women with invasive ovarian cancer in Ontario, Canada, Risch et al. (2001) found 39 mutations in the BRCA1 gene and 21 in the BRCA2 gene, for a total mutation frequency of 11.7%. Hereditary ovarian cancers diagnosed at less than 50 years of age were mostly (83%) due to BRCA1, whereas the majority (60%) of those diagnosed at more than 60 years of age were due to BRCA2. Mutations were found in 19% of women reporting first-degree relatives with breast or ovarian cancer and in 6.5% of women with no affected first-degree relatives. For carriers of BRCA1 mutations, the estimated penetrance by age 80 years was 36% for ovarian cancer and 68% for breast cancer. In breast cancer risk for first-degree relatives, there was a strong trend according to mutation location along the coding sequence of BRCA1, with little evidence of increased risk for mutations in the 5-prime fifth, but 8.8-fold increased risk for mutations in the 3-prime fifth, corresponding to a carrier penetrance of essentially 100%. 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 (OCCR) 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%. Risch et al. (2001) suggested that the trend in breast cancer penetrance, according to mutation location along the BRCA1 coding sequence, may have an impact on management decisions for carriers of BRCA1 mutations. </p><p>Struewing et al. (1995) stated that more than 50 unique mutations had been detected in the BRCA1 gene in the germline of individuals with breast and ovarian cancer. In high-risk pedigrees, female carriers of a BRCA1 mutation had an 80 to 90% lifetime risk of breast cancer and a 40 to 50% risk of ovarian cancer. Couch et al. (1997) identified BRCA1 mutations in 16% of women with a family history of breast cancer. Only 76% of women from families with a history of breast cancer but not ovarian cancer had BRCA1 mutations. They concluded that even in a referral clinic specializing in screening women from high-risk families, most tests for BRCA1 mutations will be negative and, therefore, uninformative. </p><p>Nathanson et al. (2001) reviewed breast cancer genetics. They stated that germline mutations in BRCA1 had been identified in 15 to 20% of women with a family history of breast cancer and 60 to 80% of women with a family history of both breast and ovarian cancer. They cited a lifetime breast cancer risk of 60 to 80% for female BRCA1 mutation carriers, although penetrance estimates as low as 36% had been reported in a series of Jewish breast cancer cases selected without regard to family history (Fodor et al., 1998). For carriers of BRCA2 mutations, they cited a lifetime breast cancer risk of 60 to 85% and a lifetime ovarian cancer risk of 10 to 20%. Men with germline mutations in BRCA2, unlike those with germline mutations in BRCA1, had an estimated 6% lifetime risk of breast cancer, a 100-fold increase over the male population risk. </p><p><strong><em>Genetic Counseling</em></strong></p><p>
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Lynch and Watson (1992) reported the first experience with genetic counseling and targeted management of patients demonstrated to be at risk for hereditary breast-ovarian cancer by use of multipoint linkage analysis in the largest and most informative of the kindreds studied to date. The single family provided a lod score of 3.03. In those persons shown by linkage to be at risk, they recommended completing their families before the age of 35 so that prophylactic oophorectomy could be performed at an early age. Cornelis et al. (1995) proposed that, during an interim period, BRCA1 mutation testing be offered only to families with a strong positive family history for early-onset breast and/or ovarian cancer. </p><p>Friedman et al. (1998) suggested that identification of additional carriers of more than one mutation will increase our understanding between various mutations and will improve genetic counseling. </p><p>Meijers-Heijboer et al. (2000) studied a large cohort of Dutch individuals at 50% or 25% risk of BRCA1 or BRCA2 mutation. Presymptomatic DNA testing was requested by 48% (198 of 411) of women and 22% (59 of 271) of men. In women, DNA testing was significantly more frequent at young age, in those who had children, and at high pretest genetic risk for a mutation. Of the unaffected women with an identified mutation who were eligible for prophylactic surgery, 51% (35 of 68) opted for bilateral mastectomy and 64% (29 of 45) for oophorectomy. Age was significantly associated with prophylactic oophorectomy, but not with prophylactic mastectomy, although there was a tendency toward mastectomy at younger ages. </p><p>Watson et al. (2003) studied the change in distribution of carrier risk status resulting from molecular testing in 75 families with hereditary breast-ovarian cancer and 47 families with hereditary nonpolyposis colorectal cancer (HNPCC; 120435). Carrier risk status changes from uncertainty to certainty (i.e., to carrier or to noncarrier) accounted for 89% of risk changes resulting from testing. These risk changes affect cancer prevention recommendations, most commonly reducing their burden. Watson et al. (2003) found that 60% of persons with a carrier risk status change were not themselves tested; their risk status changed because of a relative's test result. They noted that practices in use at the time did not ensure that untested family members were informed about changes in their carrier risk status resulting from mutation testing of their relatives. </p><p>Women in familial BRCA1/BRCA2 breast cancer kindreds who test negative for the family mutation are usually reassured and additional breast cancer surveillance is discontinued. However, Smith et al. (2007) postulated that in high-risk families, such as those seen in clinical genetic centers, the risk of breast cancer may be influenced not only by the BRCA1/BRCA2 mutation but also by modifier genes. One manifestation of this would be the presence of phenocopies in BRCA1/BRCA2 kindreds. They reviewed 277 families with pathogenic BRCA1/BRCA2 mutations and identified 28 breast cancer phenocopies. Phenocopies constituted up to 24% of tests on women with breast cancer after the identification of the mutation in the proband. The standardized incidence ratio for women who tested negative for the BRCA1/BRCA2 family mutation was 5.3 for all relatives, 5.0 for all first-degree relatives, and 3.2 (95% confidence interval 2.0-4.9) for first-degree relatives in whose family all other cases of breast and ovarian cancer could be explained by the identified mutation. Thirteen of 107 (12.1%) first-degree relatives with breast cancer and no unexplained family history tested negative. Thus, in high-risk families, women who test negative for the familial BRCA1/BRCA2 mutation have an increased risk of breast cancer consistent with genetic modifiers. In light of this, Smith et al. (2007) suggested that such women should be considered for continued surveillance. </p>
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<h4>
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<strong>Molecular Genetics</strong>
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<p>In affected members of 5 of 8 kindreds with hereditary breast-ovarian cancer syndrome, Miki et al. (1994) identified 5 different heterozygous pathogenic mutations in the BRCA1 gene (see, e.g., 113705.0035). The mutations included an 11-bp deletion, a 1-bp insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. </p><p>Castilla et al. (1994) found 8 putative disease-causing mutations in the BRCA1 gene (see, e.g., 113705.0001; 113705.0006; 113705.0013; 113705.0014) in 50 probands with a family history of breast and/or ovarian cancer. The authors used single-strand conformation polymorphism (SSCP) analysis on PCR-amplified genomic DNA. The data were considered consistent with a tumor suppressor model. The heterogeneity of mutations, coupled with the large size of the gene, indicated that clinical application of BRCA1 mutation testing would be technically challenging. </p><p>In 10 families with breast-ovarian cancer, Friedman et al. (1994) used SSCP analysis and direct sequencing to identify 9 different heterozygous BRCA1 mutations (see, e.g., 113705.0004; 113705.0007-113705.0009). The mutations in 7 instances led to protein truncation at sites throughout the gene. A missense mutation, which occurred independently in 2 families, led to loss of a cysteine in the zinc-binding domain. An intronic single basepair substitution destroyed an acceptor site and activated a cryptic splice site, leading to a 59-bp insertion and chain termination. In 4 families with both breast and ovarian cancer, chain termination mutations were found in the N-terminal half of the protein. </p><p>In a population-based series of 54 breast cancer cases from southern California, Friedman et al. (1997) found no instance of germline mutation in the BRCA1 gene but found 2 male breast cancer patients who carried novel truncating mutations in the BRCA2 gene. Only 1 of the 2 had a family history of cancer, namely, ovarian cancer in a first-degree relative. </p><p><strong><em>Modifier Genes</em></strong></p><p>
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Women who carry a mutation in the BRCA1 gene have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 years. Phelan et al. (1996) demonstrated that a modifier of this risk is the HRAS1 (190020) variable number of tandem repeats (VNTR) polymorphism, located 1 kb downstream of the HRAS1 oncogene. Individuals who have rare alleles of this VNTR had been found to have an increased risk of certain types of cancer, including breast cancer. Phelan et al. (1996) claimed that this was the first study to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome. </p><p>Nathanson et al. (2002) used nonparametric linkage analysis to determine whether allele sharing of chromosomes 4p, 4q, and 5q was observed preferentially within 16 BRCA1 mutation families in women with BRCA1 mutations and breast cancer. No significant linkage on chromosome 4p or 4q was observed associated with breast cancer risk in BRCA1 mutation carriers. However, the authors observed a significant linkage signal at D5S1471 on chromosome 5q (P = 0.009) in all the families analyzed together. The significance of this observation increased in the subset of families with an average of breast cancer diagnosis less than 45 years (P = 0.003). The authors suggested that one or more genes on chromosome 5q33-q34 modify breast cancer risk in BRCA1 mutation carriers. </p><p>In a sample of 10,358 carriers of BRCA1 or BRCA2 gene mutations from 23 studies, Antoniou et al. (2008) observed an association between breast cancer and a SNP (rs3803662) in the TNRC9 gene (TOX3; 611416) (per allele hazard ratio of 1.13, p(trend) = 5 x 10(-5)). The authors postulated a multiplicative effect for the SNP on breast cancer risk. </p>
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<strong>Clinical Management</strong>
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<p>The risk of ovarian cancer is reduced by 50% or more in unselected women with long-term use of oral contraceptives (Franceschi et al., 1991; Whittemore et al., 1992). To evaluate the potential benefit of oral contraceptive use in women at high risk for ovarian cancer, Narod et al. (1998) studied 207 patients with BRCA1 or BRCA2 mutations and ovarian cancer and 161 of their sisters, who served as controls. Their findings suggested that oral contraceptive use protects against ovarian cancer in carriers of either the BRCA1 or BRCA2 mutation. </p><p>Meijers-Heijboer et al. (2001) conducted a prospective study of 139 women with pathogenic BRCA1 or BRCA2 mutations without a history of breast cancer; 76 underwent prophylactic mastectomy and 63 remained under regular surveillance. They found that prophylactic bilateral total mastectomy reduced the incidence of breast cancer at 3 years of follow-up. Eisen and Weber (2001) stated that prophylactic mastectomy is 'clearly the right choice for some women. For the remainder, oophorectomy and tamoxifen in conjunction with intensive screening that includes breast MRI is a viable alternative.' They noted the need for underlying and novel prospective studies to define the role of prophylactic surgery, new chemopreventive agents, and optimal screening strategies. </p><p>Kauff et al. (2002) and Rebbeck et al. (2002) reported the results of studies indicating that prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer. In the study of Kauff et al. (2002), of 98 women who had salpingo-oophorectomy, 3 developed breast cancer and 1 developed peritoneal cancer. Among the 72 women who chose surveillance alone, breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal cancer in 1. In the study of Rebbeck et al. (2002), 6 of 259 women who underwent prophylactic oophorectomy (2.3%) received a diagnosis of stage I ovarian cancer at the time of the procedure; 2 women (0.8%) received a diagnosis of papillary serous peritoneal carcinoma 3.8 and 8.6 years after bilateral prophylactic oophorectomy. Among the controls, 58 women (19.9%) received a diagnosis of ovarian cancer, after a mean follow-up of 8.8 years. With the exclusion of the 6 women whose cancer was diagnosed at surgery, prophylactic oophorectomy significantly reduced the risk of coelomic epithelial cancer. </p><p>'Synthetic lethality' as a treatment for cancer refers to an event in which tumor cell death results from lethal synergy of 2 otherwise nonlethal events. Fong et al. (2009) used this model to treat breast cancer cells that have homozygous loss of the tumor suppressor genes BRCA1 or BRCA2 with a PARP (173870) inhibitor, resulting in the induction of selective tumor cytotoxicity and the sparing of normal cells. The method aims at inhibiting PARP-mediated single-strand DNA repair in cells with deficient homologous-recombination double-strand DNA repair, which leads to unrepaired DNA breaks, the accumulation of DNA defects, and cell death. Heterozygous BRCA mutant cells retain homologous-recombination function and are not affected by PARP inhibition. In vitro, BRCA1-deficient and BRCA2-deficient cells were up to 1,000-fold more sensitive to PARP inhibition than wildtype cells, and tumor growth inhibition was also demonstrated in BRCA2-deficient xenografts. Fong et al. (2009) reported a phase 1 clinical trial of an orally active PARP inhibitor olaparib (AZD2281 or KU-0059436) in 60 patients with mainly breast or ovarian cancer, including 22 BRCA mutation carriers and 1 who was likely a mutation carrier but declined genetic testing. Durable objective antitumor activity was observed only in confirmed carriers of a BRCA1 or BRCA2 mutation; no objective antitumor responses were observed in patients without known BRCA mutations. Twelve (63%) of 19 BRCA carriers with ovarian, breast, or prostate cancers showed a clinical benefit from treatment with olaparib, with radiologic or tumor-marker responses or meaningful disease stabilization. The drug had an acceptable side-effect profile and did not have the toxic effects commonly associated with conventional chemotherapy. Fong et al. (2009) concluded that PARP inhibition has antitumor activity in BRCA mutation carriers. </p><p>Litton et al. (2018) conducted a randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physician's choice. Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs 5.6 months; hazard ratio for disease progression or death, 0.54; 95% CI, 0.41 to 0.71; p less than 0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; p = 0.11; 57% of projected events). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs 27.2%; OR, 5.0; 95% CI, 2.9 to 8.8; p less than 0.001). Hematologic grade 3-4 adverse events, primarily anemia, occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events were not different in the 2 groups. Patient-reported outcomes favored talazoparib. </p>
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<span class="mim-font">
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<strong>Pathogenesis</strong>
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<p>Using immunohistochemical staining of human breast specimens, Wilson et al. (1999) demonstrated discrete nuclear foci of BRCA1 proteins in benign breast, invasive lobular cancers, and low-grade ductal carcinomas. Conversely, BRCA1 expression was reduced or undetectable in the majority of high-grade, ductal carcinomas, suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers. </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>Germline mutations in the BRCA1 gene are associated with a higher risk of developing basal-like breast cancer. Using immunohistochemical studies, Lim et al. (2009) identified 3 different epithelial cell subsets within mammary tissue: basal stem/progenitor, luminal progenitor, and mature luminal cells. Breast cancer from BRCA1 carriers showed an expanded luminal progenitor population that displayed factor-independent growth in vitro. Gene expression profiling showed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than to any other subset. The findings suggested that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors. </p>
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<strong>Population Genetics</strong>
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<p><strong><em>Ashkenazi Jewish Population</em></strong></p><p>
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In a study of 37 families with 4 or more cases of breast cancer or breast and ovarian cancer, Friedman et al. (1995) found that 5 families of Ashkenazi Jewish descent carried the BRCA1 185delAG mutation (113705.0003) and shared the same haplotype at 8 polymorphic markers spanning approximately 850 kb. Expressivity of 185delAG in these families varied from early-onset bilateral breast cancer and ovarian cancer to late-onset breast cancer without ovarian cancer. Overall, BRCA1 mutations were detected in 26 of the families: 16 with positive BRCA1 linkage lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. </p><p>Following the finding of a 185delAG frameshift mutation in several Ashkenazi Jewish breast/ovarian families, Struewing et al. (1995) determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and in 815 reference persons not selected for ethnic origin. They found the 185delAG mutation in 0.9% of Ashkenazim (95% confidence limit, 0.4%-1.8%) and in none of the reference samples. The results suggested that 1 in 100 women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer. </p><p>In an editorial, Goldgar and Reilly (1995) raised the possibility that a high frequency of mortality from breast cancer in Nassau County, New York, in the previous 2 decades might be related to the high proportion of Ashkenazim (roughly 16%) in that population; the pathogenetic collaboration of exposure to an environmental pollutant was raised. Ethical, legal, and social issues raised by these findings were also discussed. </p><p>Among 5,318 Jewish subjects, Struewing et al. (1997) found 120 carriers of a BRCA1 or BRCA2 mutation. The BRCA1 mutations studied were 185delAG and 5382insC (113705.0018); the BRCA2 mutation studied was 6174delT (600185.0009). By the age of 70, the estimated risk of breast cancer among carriers was 56%; of ovarian cancer, 16%; and of prostate cancer, 16%. There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated. They concluded that over 2% of Ashkenazi Jews carried mutations in BRCA1 or BRCA2 that conferred increased risks of breast, ovarian, and prostate cancer. 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>In a series of 268 Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset, Fodor et al. (1998) determined the frequency of the common BRCA1 and BRCA2 mutations: 185delAG, 5382insC, and 6174delT. DNA was analyzed for the 3 mutations by allele-specific oligonucleotide (ASO) hybridization. Eight patients (3%) were heterozygous for the 185delAG mutation, 2 (0.75%) for the 5382insC mutation, and 8 (3%) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was estimated to be 36%, approximately 3 times the overall risk for the general population (relative risk 2.9). The results differed markedly from previous estimates based on high-risk breast cancer families. </p><p>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 were 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>In Australia, Bahar et al. (2001) found in Ashkenazi Jews the same high prevalence of 4 founder mutations as found in Ashkenazi Jews in the United States and Israel. The 4 mutations analyzed were 185delAG and 5382insC in BRCA1; 6174delT in BRCA2; and I1307K (611731.0029) in APC. </p><p>King et al. (2003) determined the risks of breast and ovarian cancer for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. They selected 1,008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appeared to be increasing with time: breast cancer risk by age 50 years among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset. Easton et al. (2004) and Wacholder et al. (2004) disputed the conclusions of the report by King et al. (2003) estimating a breast cancer risk by age 70 to be 71%, irrespective of mutation. Both groups suggested bias of ascertainment. King (2004) rebutted these comments, suggesting that their penetrance estimates, at least to age 60, were comparable to those of other reported studies and that only the risk above age 70 was higher in their study, which may reflect a small sample size in that age group. </p><p>Among 1,098 Ashkenazi Jewish women with breast and/or ovarian cancer, Kadouri et al. (2007) found that those with BRCA1 or BRCA2 founder mutations (329 patients) had a 2.5-fold increased risk of other cancers compared to those without BRCA1/2 mutations. Among specific cancers, BRCA1 carriers had a 3.9-fold increased risk for colon cancer and BRCA2 carriers had an 11.9-fold increased risk for lymphoma, the latter of which may have been related to treatment. </p><p><strong><em>Other Populations</em></strong></p><p>
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Johannsson et al. (1996) identified 9 different germline mutations in the BRCA1 gene in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations were predicted to give rise to premature translation termination and included 7 frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation. The remaining mutation was a missense mutation (cys61-to-gly) in the zinc-binding motif. They also identified 4 novel Swedish founding mutations: deletion of 2595A in 5 families, the C-to-T nonsense mutation of nt1806 in 3 families, the insertion of TGAGA after nt3166 in 3 families, and the deletion of 11 nucleotides after nt1201 in 2 families. Analysis of the intragenic polymorphism D17S855 supported common origins of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of which had a predominant ovarian cancer phenotype. Among the 32 families in which no BRCA1 alteration was detected, there was 1 breast-ovarian cancer kindred showing clear linkage to the BRCA1 region and loss of the wildtype chromosome in associated tumors. Other tumor types found in BRCA1 mutation or haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma. In all, 12 of the 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families. </p><p>Gayther et al. (1997) found that the 5382insC and 4153delA (113705.0030) mutations in the BRCA1 gene may account for 86% of cases of familial ovarian cancer in Russia. </p><p>Hamann et al. (1997) studied 45 German breast/ovarian cancer families for germline mutations in the BRCA1 gene. They identified 4 germline mutations in 3 breast cancer families and in 1 breast/ovarian cancer family. One of these, a missense mutation, was also found in 2.8% of the general population, suggesting that this was not disease associated. Hamann et al. (1997) concluded that the low incidence of BRCA1 germline mutations in these families suggests the involvement of other susceptibility genes. </p><p>Szabo and King (1997) collated information on the population genetics of BRCA1 and BRCA2 in populations from many countries of Europe as well as the U.S., Canada, and Japan. </p><p>Tonin et al. (1998) noted that 4 mutations in BRCA1 and 4 mutations in BRCA2 had been identified in French Canadian breast cancer and breast/ovarian cancer families from Quebec. To identify founder effects, they examined independently ascertained French Canadian cancer families for the distribution of these 8 mutations. Mutations were found in 41 of 97 families. Six of 8 mutations were observed at least twice. The 4446C-T mutation (arg1443 to ter; 113705.0016) was the most common mutation found, followed by the BRCA2 8765delAG mutation (600185.0012). Together, these mutations were found in 28 of 41 families identified as having the mutation. The odds of detection of any of the 4 BRCA1 mutations was 18.7 times greater if one or more cases of ovarian cancer were also present in the family. The odds of detection of any of the 4 BRCA2 mutations was 5.3 times greater if there were at least 5 cases of breast cancer in the family. Interestingly, the presence of a breast cancer case less than 36 years of age was strongly predictive of the presence of any of the 8 mutations screened. Carriers of the same mutation, from different families, shared similar haplotypes, indicating that the mutant alleles were likely to be identical by descent for a mutation in the founder population. The identification of common BRCA1 and BRCA2 mutations could facilitate carrier detection in French Canadian breast cancer and breast/ovarian cancer families. </p><p>Gorski et al. (2000) studied 66 Polish families in each of which at least 3 related females had breast or ovarian cancer and at least 1 of these 3 had been diagnosed with cancer before the age of 50 years. A total of 26 families had both breast and ovarian cancers, 4 had ovarian cancers only, and 36 families had breast cancers only. Using SSCP followed by direct sequencing of observed variants, they screened the entire coding region of BRCA1 and BRCA2 for germline mutations. Mutations were found in 35 (53%) of the 66 families. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all 4 families with ovarian cancer only, and 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; 5 of these occurred in 2 or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Gorski et al. (2000) found that 3 BRCA1 abnormalities, 5382insC, cys61 to gly (113705.0002), and 4153delA, accounted for 51%, 20%, and 11% of the identified mutations, respectively. </p><p>De Los Rios et al. (2001) reported findings in Canadian families suggesting that most of the mutation-carrying families of Polish ancestry have the BRCA1 5382insC mutation. </p><p>Sarantaus et al. (2001) studied 233 unselected Finnish ovarian carcinoma patients treated at the Helsinki University Central Hospital during the years 1989 to 1998. The patients were screened for 12 BRCA1 and 8 BRCA2 mutations identified previously in the Finnish population. Germline mutations of BRCA1/BRCA2 were detected in 13 of the patients (11 in BRCA1 and 2 in BRCA2) and 7 recurrent founder mutations accounted for 12 of the 13 mutations detected. All mutation-positive patients but one had serous or poorly differentiated carcinoma. The presence of breast and ovarian cancer in the same woman and/or early onset (under 50 years of age) breast cancer was characteristic of the majority (77%) of the mutation carriers. </p><p>The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution of genetic factors to these high rates, Liede et al. (2002) conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from 2 major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7%, and that among case subjects with ovarian cancer was 15.8%. Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. Most of the detected mutations were unique to Pakistan. Five BRCA1 mutations and 1 BRCA2 mutation were found in multiple case subjects and may represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 was comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1 mutation-positive case subjects was 48%, and it was 37% for first-degree relatives of the BRCA2 mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio = 2.1). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age less than 40 years) (odds ratio = 2.7) and case subjects with ovarian cancer (odds ratio = 2.4). These results suggested that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan. </p><p>Diez et al. (2003) screened index cases from 410 Spanish breast/ovarian cancer families and 214 patients (19 of them males) with breast cancer for germline mutations in the BRCA1 and BRCA2 genes. They identified 60 mutations in BRCA1 and 53 in BRCA2. Of the 53 distinct mutations observed, 11 were novel and 12 had been reported only in Spanish families (41.5%); the prevalence of mutations in this set of families was 26.3%. The percentage was higher in families with breast and ovarian cancer (52.1%). Of the families with male breast cancer cases, 59.1% presented mutations in the BRCA2 gene. They found a higher frequency of ovarian cancer associated with mutations localized in the 5-prime end of the BRCA1 gene, but there was no association between the prevalence of this type of cancer and mutations situated in the OCCR of exon 11 of the BRCA2 gene. Five mutations accounted for 46.6% of BRCA1 detected mutations, whereas 4 mutations accounted for 56.6% of the BRCA2 mutations. The BRCA1 330A-G substitution (113705.0034) had a Galician origin (northwest Spain). </p><p>Hartikainen et al. (2007) identified 5 different mutations in the BRCA1 or BRCA2 genes in 7 (19.4%) of 36 families with breast/ovarian cancer from eastern Finland. </p><p>Hall et al. (2009) examined a comprehensive database of BRCA1/BRCA2 testing in the United States compiled over about 10 years (1996 to 2006). Full-sequence testing of the genes was performed in 46,276 women who met eligibility criteria. The largest ethnic subgroup was of Western or Central European ancestry (87.1%), followed by Latin American (4.2%), African (3.8%), Asian (2.6%), Native American (1.3%), and Middle Eastern (1.1%) ancestry. Individuals of Ashkenazi Jewish origin were excluded. Women of non-European descent were younger (mean age of 45.9 years) than European women (mean age of 50 years) at age of testing. Mutations were identified in 12.5% of women overall, but those of African and Latin American ancestries had significantly higher prevalences of deleterious BRCA1 and BRCA2 mutations (15.6% and 14.8%, respectively) compared with women of Western European ancestry (12.1%), primarily because of an increased prevalence of BRCA1 mutations in the former 2 groups. Overall, BRCA1 mutations were more common than BRCA2 mutations for every ethnicity except Asian, in which the frequency was equal (about 6.3% for each gene). The most common recurrent mutations per group were 5385insC (also known as 5382insC; 113705.0018) in BRCA1, accounting for 5.2% of all mutations among Western Europeans and 14.9% of all mutations among Central Europeans; 943ins10 (113705.0029) in BRCA1, accounting for 10% of all mutations among Africans; and 187delAG (also known as 185delAG; 113705.0003) in BRCA1, accounting for 6.7% of all mutations among Native Americans, 12.2% of all mutations among Latin Americans, and 15.2% of all mutations among Middle Eastern women. </p>
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<strong>History</strong>
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<p><strong><em>Exclusion Studies</em></strong></p><p>
|
|
Simard et al. (1993) were able to exclude the RARA gene (180240) as a candidate disease gene by genetic recombination. Although BRCA1 and the gene for estradiol 17-beta-hydroxysteroid dehydrogenase II (HSD17B2; 109685) map to a 6-cM interval and no recombination was observed between the 2 genes, direct sequencing of overlapping PCR products containing the entire EDH17B2 gene in 4 unrelated affected woman did not uncover any pathogenic sequence variations, thus excluding the EDH17B2 gene. </p><p>Kelsell et al. (1993) did not identify pathogenic variations in the EDH17B1 or EDH17B2 gene in 4 affected members of a family with breast cancer. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Arason et al. (1993); Donnai and Warrell (1983); Narod et al. (1991);
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Struewing et al. (1995)
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</span>
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<div>
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<br />
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Dear OMIM User,
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<p>
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To ensure long-term funding for the OMIM project, we have diversified
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our revenue stream. We are determined to keep this website freely
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accessible. Unfortunately, it is not free to produce. Expert curators
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review the literature and organize it to facilitate your work. Over 90%
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of the OMIM's operating expenses go to salary support for MD and PhD
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science writers and biocurators. Please join your colleagues by making a
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donation now and again in the future. Donations are an important
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component of our efforts to ensure long-term funding to provide you the
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information that you need at your fingertips.
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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<button type="button" id="mimDonationPopupDonate" class="btn btn-success btn-block" data-dismiss="modal"> Donate To OMIM! </button>
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