3936 lines
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Entry
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- #612555 - BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2; BROVCA2
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- OMIM
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<p>
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<span class="h4">#612555</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/612555"><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="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<div style="display: table-cell;">Clinical Resources</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>
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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/7866" 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://medlineplus.gov/genetics/condition/breast-cancer" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=612555[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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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>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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612555
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</span>
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</span>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2; BROVCA2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<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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HBOC2
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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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<div>
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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, 2, 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, 2, 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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</tr>
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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/13/83?start=-3&limit=10&highlight=83">
|
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13q13.1
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Breast-ovarian cancer, familial, 2}
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/612555"> 612555 </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>
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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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</td>
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<td>
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<span class="mim-font">
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BRCA2
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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/600185"> 600185 </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/612555" 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/612555" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/612555" 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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</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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|
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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 60 to 85%<br /> -
|
|
Lifetime risk of ovarian cancer in mutation carriers is 10 to 20%<br /> -
|
|
Lifetime risk of breast cancer in male mutation carriers in 6%<br /> -
|
|
Increased risk of bilateral breast cancer<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
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|
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|
|
<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 2 gene (BRCA2, <a href="/entry/600185#0001">600185.0001</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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|
|
<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">
|
|
<a href="/entry/613399"> {Breast-ovarian cancer, familial, susceptibility to, 3} </a>
|
|
</span>
|
|
</td>
|
|
<td>
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<p>A number sign (#) is used with this entry because susceptibility to familial breast-ovarian cancer-2 (BROVCA2) results from heterozygous germline mutations in the BRCA2 gene (<a href="/entry/600185">600185</a>) on chromosome 13q13.</p><p>For a discussion of genetic heterogeneity of breast-ovarian cancer susceptibility, see BROVCA1 (<a href="/entry/604370">604370</a>).</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><a href="#39" class="mim-tip-reference" title="Wooster, R., Neuhausen, S. L., Mangion, J., Quirk, Y., Ford, D., Collins, N., Nguyen, K., Seal, S., Tran, T., Averill, D., Fields, P., Marshall, G., and 19 others. <strong>Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13.</strong> Science 265: 2088-2090, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8091231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8091231</a>] [<a href="https://doi.org/10.1126/science.8091231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8091231">Wooster et al. (1994)</a> reported a large family from Utah segregating early-onset breast cancer, ovarian cancer, and male breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8091231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Thorlacius, S., Tryggvadottir, L., Olafsdottir, G. H., Jonasson, J. G., Ogmundsdottir, H. M., Tulinius, H., Eyfjord, J. E. <strong>Linkage to BRCA2 region in hereditary male breast cancer.</strong> Lancet 346: 544-545, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7658781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7658781</a>] [<a href="https://doi.org/10.1016/s0140-6736(95)91383-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7658781">Thorlacius et al. (1995)</a> described a family with multiple cases of male breast cancer but no increase in female breast cancer. Seven males in 3 generations had breast cancer. Other members of the family had other forms of cancer. Linkage of breast cancer to the BRCA2 region on chromosome 13q was demonstrated and all the affected men shared the same haplotype for BRCA2 markers and loss of the other alleles in their tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7658781" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Early age at first full-term pregnancy and increasing parity are associated with a reduced risk of breast cancer. However, <a href="#15" class="mim-tip-reference" title="Jernstrom, H., Lerman, C., Ghadirian, P., Lynch, H. T., Weber, B., Garber, J., Daly, M., Olopade, O. I., Foulkes, W. D., Warner, E., Brunet, J.-S., Narod, S. A. <strong>Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2.</strong> Lancet 354: 1846-1850, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10584720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10584720</a>] [<a href="https://doi.org/10.1016/s0140-6736(99)04336-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10584720">Jernstrom et al. (1999)</a> found that carriers of the BRCA1 and BRCA2 mutations who have children are significantly more likely to develop breast cancer by age 40 than carriers who are nulliparous. Each pregnancy is associated with an increased cancer risk. The authors found that early first pregnancy does not confer protection for carriers of BRCA1 or BRCA2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10584720" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#3" class="mim-tip-reference" title="Boyd, J., Sonoda, Y., Federici, M. G., Bogomolniy, F., Rhei, E., Maresco, D. L., Saigo, P. E., Almadrones, L. A., Barakat, R. R., Brown, C. L., Chi, D. S., Curtin, J. P., Poynor, E. A., Hoskins, W. J. <strong>Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.</strong> JAMA 283: 2260-2265, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10807385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10807385</a>] [<a href="https://doi.org/10.1001/jama.283.17.2260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10807385">Boyd et al. (2000)</a> performed a retrospective cohort study of a consecutive series of 933 ovarian cancers diagnosed and treated at the Sloan-Kettering Cancer Center. This study was restricted to patients of Jewish origin because of the ease of BRCA1 and BRCA2 genotyping in this ethnic group. Of the 189 patients who identified themselves as Jewish, 88 hereditary cases were identified with the presence of a germline founder mutation in BRCA1 or BRCA2. The remaining 101 cases from the same series not associated with a BRCA mutation and 2 additional groups with ovarian cancer from clinical trials were included for comparison. Hereditary cancers were rarely diagnosed before age 40 years and were common after age 60 years, with mean age at diagnosis being significantly younger for BRCA1 versus BRCA2-linked patients (54 vs 62 years). Histology, grade, stage, and success of cytoreductive surgery were similar for hereditary and sporadic cases. The hereditary group had a longer disease-free interval following primary chemotherapy in comparison with the nonhereditary group, with a median time to recurrence of 14 months and 7 months, respectively (P less than 0.001). Those with hereditary cancers had improved survival compared with the nonhereditary group. <a href="#3" class="mim-tip-reference" title="Boyd, J., Sonoda, Y., Federici, M. G., Bogomolniy, F., Rhei, E., Maresco, D. L., Saigo, P. E., Almadrones, L. A., Barakat, R. R., Brown, C. L., Chi, D. S., Curtin, J. P., Poynor, E. A., Hoskins, W. J. <strong>Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.</strong> JAMA 283: 2260-2265, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10807385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10807385</a>] [<a href="https://doi.org/10.1001/jama.283.17.2260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10807385">Boyd et al. (2000)</a> concluded that although BRCA-associated hereditary ovarian cancers in this population have surgical and pathologic characteristics similar to those of sporadic cancers, advanced-stage hereditary cancer patients may survive longer than nonhereditary cancer patients. Age penetrance was greater for BRCA1-linked than for BRCA2-linked cancers in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10807385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 large, systematically ascertained families in which breast cancer showed linkage to 13q12-q13, <a href="#9" class="mim-tip-reference" title="Easton, D. F., Steele, L., Fields, P., Ormiston, W., Averill, D., Daly, P. A., McManus, R., Neuhausen, S. L., Ford, D., Wooster, R., Cannon-Albright, L. A., Stratton, M. R., Goldgar, D. E. <strong>Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13.</strong> Am. J. Hum. Genet. 61: 120-128, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9245992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9245992</a>] [<a href="https://doi.org/10.1086/513891" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9245992">Easton et al. (1997)</a> determined the penetrance of the BRCA2 gene by use of a maximum-likelihood method to incorporate both cancer-incidence data and 13q marker typings. The cumulative risk of breast cancer in female gene carriers was estimated to be 59.8% by age 50 years (95% confidence interval (CI) 25.9 to 78.5%) and 79.5% by age 70 years (95% CI 28.9 to 97.5%). Cumulative risk of breast cancer in male carriers was estimated to be 6.3% (95% CI 1.4 to 25.6%) by age 70 years. The results indicated that the lifetime breast cancer risk in BRCA2 carriers, for at least a subset of mutations, is comparable to that for BRCA1, in which <a href="#7" class="mim-tip-reference" title="Easton, D. F., Ford, D., Bishop, D. T., Breast Cancer Linkage Consortium. <strong>Breast and ovarian cancer incidence in BRCA1-mutation carriers.</strong> Am. J. Hum. Genet. 56: 265-271, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7825587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7825587</a>]" pmid="7825587">Easton et al. (1995)</a> estimated the risk of breast cancer to be 51% by age 50 years. The corresponding estimates by age 60 years were 54% for BRCA1-mutation carriers, compared with 71% for BRCA2. A significant excess of ovarian cancer in BRCA2 gene carriers was observed (relative risk 17.69, based on 3 cases), but the absolute risk of ovarian cancer was less than that reported for BRCA1. Significant excesses of laryngeal cancer (relative risk 7.67, based on 2 possible carriers) and prostate cancer (relative risk 2.89, based on 5 possible carriers) were also observed. One case of ocular melanoma, as well as a second eye cancer of unspecified histology, occurred in obligate gene carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9245992+7825587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Risch, H. A., McLaughlin, J. R., Cole, D. E. C., Rosen, B., Bradley, L., Kwan, E., Jack, E., Vesprini, D. J., Kuperstein, G., Abrahamson, J. L. A., Fan, I., Wong, B., Narod, S. A. <strong>Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.</strong> Am. J. Hum. Genet. 68: 700-710, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11179017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11179017</a>] [<a href="https://doi.org/10.1086/318787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11179017">Risch et al. (2001)</a> found that ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer cluster region of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. The results suggested that BRCA2 mutations may prove to be a greater cause of cancer in male carriers than had previously been thought. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11179017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#39" class="mim-tip-reference" title="Wooster, R., Neuhausen, S. L., Mangion, J., Quirk, Y., Ford, D., Collins, N., Nguyen, K., Seal, S., Tran, T., Averill, D., Fields, P., Marshall, G., and 19 others. <strong>Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13.</strong> Science 265: 2088-2090, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8091231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8091231</a>] [<a href="https://doi.org/10.1126/science.8091231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8091231">Wooster et al. (1994)</a> performed a genomic linkage search in 15 high-risk breast cancer families that were unlinked to the BRCA1 locus on 17q21. This analysis uncovered a second breast cancer susceptibility locus, BRCA2, located in a 6-cM interval on chromosome 13q12-q13. The authors noted that BRCA2, while conferring a high risk of breast cancer, did not appear to confer as strong an elevated risk of ovarian cancer as observed with BRCA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8091231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Stratton, M. R., Ford, D., Neuhasen, S., Seal, S., Wooster, R., Friedman, L. S., King, M.-C., Egilsson, V., Devilee, P., McManus, R., Daly, P. A., Smyth, E., Ponder, B. A. J., Peto, J., Cannon-Albright, L., Easton, D. F., Goldgar, D. E. <strong>Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q.</strong> Nature Genet. 7: 103-107, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8075631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8075631</a>] [<a href="https://doi.org/10.1038/ng0594-103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8075631">Stratton et al. (1994)</a> examined 22 families with at least 1 case of male breast cancer for linkage to the BRCA1 locus on 17q. They found strong evidence against linkage to BRCA1 (lod score, -16.63) and the best estimate of the proportion of linked families was 0% (95% confidence interval, 0-18%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8075631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>According to the conclusions of the <a href="#4" 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 authors suggested that breast cancer due to BRCA1 has a different natural history than that in 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>
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<p><a href="#17" 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="#23" 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="#17" 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="#23" 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><a href="#25" class="mim-tip-reference" title="Sakai, W., Swisher, E. M., Karlan, B. Y., Agarwal, M. K., Higgins, J., Friedman, C., Villegas, E., Jacquemont, C., Farrugia, D. J., Couch, F. J., Urban, N., Taniguchi, T. <strong>Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers.</strong> Nature 451: 1116-1120, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18264087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18264087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18264087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature06633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18264087">Sakai et al. (2008)</a> showed that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wildtype BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, CAPAN1, led to 5 different secondary mutations that restored the wildtype BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP; <a href="/entry/173870">173870</a>) inhibitor (AG14361). Finally, <a href="#25" class="mim-tip-reference" title="Sakai, W., Swisher, E. M., Karlan, B. Y., Agarwal, M. K., Higgins, J., Friedman, C., Villegas, E., Jacquemont, C., Farrugia, D. J., Couch, F. J., Urban, N., Taniguchi, T. <strong>Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers.</strong> Nature 451: 1116-1120, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18264087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18264087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18264087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature06633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18264087">Sakai et al. (2008)</a> evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumor that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. <a href="#25" class="mim-tip-reference" title="Sakai, W., Swisher, E. M., Karlan, B. Y., Agarwal, M. K., Higgins, J., Friedman, C., Villegas, E., Jacquemont, C., Farrugia, D. J., Couch, F. J., Urban, N., Taniguchi, T. <strong>Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers.</strong> Nature 451: 1116-1120, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18264087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18264087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18264087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature06633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18264087">Sakai et al. (2008)</a> concluded that secondary mutations that restore the wildtype BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18264087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#10" 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="#10" 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="#10" 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="#21" 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://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>In families with breast cancer linked to chromosome 13q12, <a href="#38" class="mim-tip-reference" title="Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C., Micklem, G., Barfoot, R., Hamoudi, R., and 29 others. <strong>Identification of the breast cancer susceptibility gene BRCA2.</strong> Nature 378: 789-792, 1995. Note: Erratum: Nature: 379: 749 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8524414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8524414</a>] [<a href="https://doi.org/10.1038/378789a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8524414">Wooster et al. (1995)</a> identified 6 different germline mutations in the BRCA2 gene (see, e.g., <a href="/entry/600185#0001">600185.0001</a>), each causing serious disruption to the open reading frame of the transcriptional unit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8524414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 9 of 18 kindreds with familial breast cancer selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer, <a href="#31" class="mim-tip-reference" title="Tavtigian, S. V., Simard, J., Rommens, J., Couch, F., Shattuck-Eidens, D., Neuhausen, S., Merajver, S., Thorlacius, S., Offit, K., Stoppa-Lyonnet, D., Belanger, C., Bell, R., and 37 others. <strong>The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.</strong> Nature Genet. 12: 333-337, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8589730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8589730</a>] [<a href="https://doi.org/10.1038/ng0396-333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8589730">Tavtigian et al. (1996)</a> identified potentially deleterious sequence alterations in the BRCA2 gene (see, e.g., <a href="/entry/600185#0007">600185.0007</a>). All except 1, a deletion of 3 nucleotides, involved nucleotide deletions that altered the reading frame, leading to truncation of the BRCA2 protein. No missense or nonsense mutations were found. The authors noted that the mutation profile of BRCA2 differs from that of BRCA1: microinsertions and point mutations are about as common in BRCA1 as microdeletions, which predominate in BRCA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8589730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Friedman, L. S., Gayther, S. A., Kurosaki, T., Gordon, D., Noble, B., Casey, G., Ponder, B. A. J., Anton-Culver, H. <strong>Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population.</strong> Am. J. Hum. Genet. 60: 313-319, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9012404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9012404</a>]" pmid="9012404">Friedman et al. (1997)</a> analyzed a population-based series of 54 male breast cancer cases from southern California for germline mutations in the BRCA1 and BRCA2 genes. A family history of breast and/or ovarian cancer in at least one first-degree relative was found in 9 patients (17%). A further 7 (13%) reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. The 54 patients showed no germline BRCA1 mutations. On the other hand, 2 of the male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only 1 of the 2 had a family history of cancer, with 1 case of ovarian cancer in a first-degree relative. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9012404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Casilli, F., Tournier, I., Sinilnikova, O. M., Coulet, F., Soubrier, F., Houdayer, C., Hardouin, A., Berthet, P., Sobol, H., Bourdon, V., Muller, D., Fricker, J. P., and 23 others. <strong>The contribution of germline rearrangements to the spectrum of BRCA2 mutations.</strong> J. Med. Genet. 43: e49, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16950820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16950820</a>] [<a href="https://doi.org/10.1136/jmg.2005.040212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16950820">Casilli et al. (2006)</a> used quantitative multiplex PCR of short fluorescent fragments (QMPSF) to screen for BRCA2 germline rearrangements in 120 families with familial breast cancer who were negative for BRCA1 and BRCA2 mutations. Three novel and distinct BRCA2 deletions were identified in 3 families: deletion of exons 14 through 18, exons 15 and 16, and exons 12 and 13, respectively. Combined with data from the larger cohort of 194 families selected for the study in which 36 BRCA2 mutations were identified, <a href="#6" class="mim-tip-reference" title="Casilli, F., Tournier, I., Sinilnikova, O. M., Coulet, F., Soubrier, F., Houdayer, C., Hardouin, A., Berthet, P., Sobol, H., Bourdon, V., Muller, D., Fricker, J. P., and 23 others. <strong>The contribution of germline rearrangements to the spectrum of BRCA2 mutations.</strong> J. Med. Genet. 43: e49, 2006. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16950820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16950820</a>] [<a href="https://doi.org/10.1136/jmg.2005.040212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16950820">Casilli et al. (2006)</a> estimated that approximately 7.7% of germline BRCA2 mutations are rearrangements, which is similar to the contribution of rearrangements to the mutation spectrum of BRCA1 (approximately 15%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16950820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifier Genes</em></strong></p><p>
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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 associations between breast cancer and 2 different SNPs in the FGFR2 (<a href="/entry/176943">176943</a>) and MAP3K1 (<a href="/entry/600982">600982</a>) genes in BRCA2 carriers, but not in BRCA1 carriers. A SNP in the TNRC9 gene (TOX3; <a href="/entry/611416">611416</a>) showed increased risk in both BRCA2 and BRCA1 carriers. The authors postulated a multiplicative effect for the SNPs 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>Among 7 large Icelandic breast cancer families, <a href="#12" class="mim-tip-reference" title="Gudmundsson, J., Johannesdottir, G., Arason, A., Bergthorsson, J. T., Ingvarsson, S., Egilsson, V., Barkardottir, R. B. <strong>Frequent occurrence of BRCA2 linkage in Icelandic breast cancer families and segregation of a common BRCA2 haplotype.</strong> Am. J. Hum. Genet. 58: 749-756, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644738</a>]" pmid="8644738">Gudmundsson et al. (1996)</a> found that 5 showed strong evidence of linkage to the BRCA2 region. The maximum 2-point lod scores in the 5 families ranged from 1.06 to 3.19. Furthermore, haplotype analyses revealed a region with identical allele sizes in the families, suggesting to the authors that they inherited the mutation from a common ancestor. Cancer types other than breast cancer occurred in both males and females segregating the affected haplotype in these families. <a href="#32" class="mim-tip-reference" title="Thorlacius, S., Olafsdottir, G., Tryggvadottir, L., Neuhausen, S., Jonasson, J. G., Tavtigian, S. V., Tulinius, H., Ogmundsdottir, H. M., Eyfjord, J. E. <strong>A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes.</strong> Nature Genet. 13: 117-122, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8673089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8673089</a>] [<a href="https://doi.org/10.1038/ng0596-117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8673089">Thorlacius et al. (1996)</a> studied 21 Icelandic families selected on the basis of a high frequency of breast cancer in females or the occurrence of one or more cases of male breast cancer. Strong evidence for linkage to the BRCA2 region was found in 16 families; these families shared a common haplotype in the BRCA2 region, suggesting a founder effect. In all 16 families there was evidence for a 5-bp deletion in exon 9 (999del5; <a href="/entry/600185#0010">600185.0010</a>). The authors noted that in the Icelandic population, the 999del5 mutation has been found in individuals with different tumor types including cancer of the prostate, pancreas, ovary, colon, stomach, thyroid, cervix, and endometrium. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8673089+8644738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Barkardottir, R. B., Sarantaus, L., Arason, A., Vehmanen, P., Bendahl, P.-O., Kainu, T., Syrjakoski, K., Krahe, R., Huusko, P., Pyrhonen, S., Holli, K., Kallioniemi, O.-P., Egilsson, V., Kere, J., Nevanlinna, H. <strong>Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.</strong> Europ. J. Hum. Genet. 9: 773-779, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781689</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11781689">Barkardottir et al. (2001)</a> constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in 18 Icelandic and 10 Finnish breast and breast-ovarian cancer families with the 999del5 mutation. All the Icelandic families shared a common haplotype covering approximately 0.85 Mb, or 1.7 cM. The common ancestors were estimated to trace back 320 to 1,000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country mainly by Vikings between the years 860 to 1060. Analysis of the Finnish families revealed 2 distinct haplotypes. A rarer haplotype was present in 3 families and shared a core haplotype with the Icelandic haplotype spanning about 200 kb, or 0.5 cM. A more common haplotype was present in 7 Finnish families and shared a region covering about 6 cM. These 7 families originated from 2 geographic regions in Finland: (1) from the same small region as the families segregating the rare haplotype (early settlement region in the southwest of Finland), and (2) from the 'new' settlement region in the most eastern part of the country. The 2 distinct haplotypes in the Finnish families may represent different mutational events. The authors, however, suggested that another possible explanation is a gene conversion (in agreement with the population historical records), and the results may indicate a common ancient origin of the 999del5 mutation in Iceland and Finland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11781689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#28" 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 (<a href="/entry/113705#0003">113705.0003</a>) 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="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=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><a href="#29" 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="#30" class="mim-tip-reference" title="Taillon-Miller, P., Bauer-Sardina, I., Zakeri, H., Hillier, L., Mutch, D. G., Kwok, P.-Y. <strong>The homozygous complete hydatidiform mole: a unique resource for genome studies.</strong> Genomics 46: 307-310, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9417922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9417922</a>] [<a href="https://doi.org/10.1006/geno.1997.5042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9417922">Taillon-Miller et al. (1997)</a> pointed out that complete 46,XX homozygote hydatidiform moles can serve as homozygous controls in the development of single-nucleotide polymorphism (SNP) markers and provide a way to obtain long-range haplotypes and estimate allele frequencies that are useful in population studies. They used 11 diallelic markers in the BRCA2 region of 13q12-q13 to compare polymorphism allele frequencies of Caucasian, Hispanic, and African American populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9417922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 investigate both mutation origin and mutation-specific phenotypes due to BRCA2 mutations, <a href="#22" class="mim-tip-reference" title="Neuhausen, S. L., Godwin, A. K., Gershoni-Baruch, R., Schubert, E., Garbert, J., Stoppa-Lyonnet, D., Olah, E., Csokay, B., Serova, O., Lalloo, F., Osorio, A., Stratton, M., and 18 others. <strong>Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: Results of an international study.</strong> Am. J. Hum. Genet. 62: 1381-1388, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585613</a>] [<a href="https://doi.org/10.1086/301885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585613">Neuhausen et al. (1998)</a> constructed a haplotype of 10 polymorphic short tandem repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having 1 of 9 recurrent BRCA2 mutations. Six of the individual mutations were estimated to have arisen 400 to 2,000 years ago. In particular, the 6174delT mutation (<a href="/entry/600185#0009">600185.0009</a>), found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-lod support interval = 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG (<a href="/entry/113705#0003">113705.0003</a>) mutation, 46 generations, derived from an analogous study of BRCA1 mutations. In general, <a href="#22" class="mim-tip-reference" title="Neuhausen, S. L., Godwin, A. K., Gershoni-Baruch, R., Schubert, E., Garbert, J., Stoppa-Lyonnet, D., Olah, E., Csokay, B., Serova, O., Lalloo, F., Osorio, A., Stratton, M., and 18 others. <strong>Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: Results of an international study.</strong> Am. J. Hum. Genet. 62: 1381-1388, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9585613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9585613</a>] [<a href="https://doi.org/10.1086/301885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9585613">Neuhausen et al. (1998)</a> found no evidence of multiple origins of identical BRCA2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9585613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" 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 and 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 BRCA1 4446C-T mutation (<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="#37" class="mim-tip-reference" title="Wagner, T. M. U., Hirtenlehner, K., Shen, P., Moeslinger, R., Muhr, D., Fleischmann, E., Concin, H., Doeller, W., Haid, A., Lang, A. H., Mayer, P., Petru, E., and 9 others. <strong>Global sequence diversity of BRCA2: analysis of 71 breast cancer families and 95 control individuals of worldwide populations.</strong> Hum. Molec. Genet. 8: 413-423, 1999. Note: Erratum: Hum. Molec. Genet. 8: 717-719, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9971877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9971877</a>] [<a href="https://doi.org/10.1093/hmg/8.3.413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9971877">Wagner et al. (1999)</a> studied the sequence diversity of the BRCA2 gene in 71 breast cancer and breast/ovarian cancer families and 95 control individuals from a wide range of ethnicities. In the 10,257 bp of the coding sequence and the 2,799 bp of the noncoding sequence, 82 sequence variants were identified. Disease-associated mutations were identified in 6 families (8%). Of the 79 sequence variants not obviously associated with disease, 8 were detected only in breast cancer and breast/ovarian cancer families. The 71 remaining variants were identified in both breast cancer and breast/ovarian cancer families and controls. Sixty-three sequence variants (80%) were continent specific; 42% were detected exclusively in Africa, though only 13% of the chromosomes screened were of African origin. Based on the finding of 1 variant in 194 bp in the coding region and 1 variant in 108 bp in the noncoding region, <a href="#37" class="mim-tip-reference" title="Wagner, T. M. U., Hirtenlehner, K., Shen, P., Moeslinger, R., Muhr, D., Fleischmann, E., Concin, H., Doeller, W., Haid, A., Lang, A. H., Mayer, P., Petru, E., and 9 others. <strong>Global sequence diversity of BRCA2: analysis of 71 breast cancer families and 95 control individuals of worldwide populations.</strong> Hum. Molec. Genet. 8: 413-423, 1999. Note: Erratum: Hum. Molec. Genet. 8: 717-719, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9971877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9971877</a>] [<a href="https://doi.org/10.1093/hmg/8.3.413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9971877">Wagner et al. (1999)</a> concluded that simple sequence variation is a frequent occurrence in the BRCA2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9971877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="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> screened 233 unselected Finnish ovarian carcinoma patients 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 (including the 2 BRCA2 mutations). 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="#20" 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>Using the population-based Icelandic Cancer Registry database, <a href="#35" class="mim-tip-reference" title="Tulinius, H., Olafsdottir, G. H., Sigvaldason, H., Arason, A., Barkardottir, R. B., Egilsson, V., Ogmundsdottir, H. M., Tryggvadottir, L., Gudlaugsdottir, S., Eyfjord, J. E. <strong>The effect of a single BRCA2 mutation on cancer in Iceland.</strong> J. Med. Genet. 39: 457-462, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114473</a>] [<a href="https://doi.org/10.1136/jmg.39.7.457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12114473">Tulinius et al. (2002)</a> found that 90 of 887 families (10%) of breast cancer patients had the 999del5 mutation in the BRCA2 gene (<a href="/entry/600185#0010">600185.0010</a>). Relatives of probands with the mutation had significantly increased relative risk of breast cancer: 7.55, 3.18, and 2.58 for first-, second-, and third-degree relatives, respectively. First- and second-degree relatives of patients with the mutation also had an increased risk for prostate and ovarian cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12114473" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#18" 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 50 years of age 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="#8" 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="#36" 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="#18" 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="#19" 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=14576434+15622557+15622558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#16" 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><a href="#14" 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. The BRCA2 999del5 mutation was present in 2 families whose ancestry could be traced to a common geographic region in eastern Finland. Another family had the BRCA2 6503delTT mutation (<a href="/entry/600185#0002">600185.0002</a>). <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="#13" 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 mutation in the BRCA2 gene was 6174delT (<a href="/entry/600185#0009">600185.0009</a>), accounting for 4.5% of all mutations among Central Europeans. <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 id="Antoniou2008" class="mim-anchor"></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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Barkardottir, R. B., Sarantaus, L., Arason, A., Vehmanen, P., Bendahl, P.-O., Kainu, T., Syrjakoski, K., Krahe, R., Huusko, P., Pyrhonen, S., Holli, K., Kallioniemi, O.-P., Egilsson, V., Kere, J., Nevanlinna, H.
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<strong>Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.</strong>
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Europ. J. Hum. Genet. 9: 773-779, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11781689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11781689</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11781689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200717" target="_blank">Full Text</a>]
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Boyd, J., Sonoda, Y., Federici, M. G., Bogomolniy, F., Rhei, E., Maresco, D. L., Saigo, P. E., Almadrones, L. A., Barakat, R. R., Brown, C. L., Chi, D. S., Curtin, J. P., Poynor, E. A., Hoskins, W. J.
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<strong>Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.</strong>
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JAMA 283: 2260-2265, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10807385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10807385</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10807385" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/jama.283.17.2260" target="_blank">Full Text</a>]
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Breast Cancer Linkage Consortium.
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<strong>Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 and BRCA2 mutations and sporadic cases.</strong>
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Lancet 349: 1505-1510, 1997.
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[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>, <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'})">related citations</a>]
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Breast Cancer Linkage Consortium.
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<strong>Cancer risks in BRCA2 mutation carriers.</strong>
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J. Nat. Cancer Inst. 91: 1310-1316, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10433620/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10433620</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10433620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/jnci/91.15.1310" target="_blank">Full Text</a>]
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Casilli, F., Tournier, I., Sinilnikova, O. M., Coulet, F., Soubrier, F., Houdayer, C., Hardouin, A., Berthet, P., Sobol, H., Bourdon, V., Muller, D., Fricker, J. P., and 23 others.
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Easton, D. F., Ford, D., Bishop, D. T., Breast Cancer Linkage Consortium.
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<strong>Breast and ovarian cancer incidence in BRCA1-mutation carriers.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7825587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7825587</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7825587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Easton, D. F., Hopper, J. L., Thomas, D. C., Antoniou, A., Pharoah, P. D. P., Whittemore, A. S., Haile, R. W.
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<strong>Breast cancer risks for BRCA1/2 carriers. (Letter)</strong>
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Science 306: 2187-2188, 2004.
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[<a href="https://doi.org/10.1126/science.306.5705.2187c" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/513891" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa0900212" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/cncr.24200" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2007.00866.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa020119" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1088759" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/301885" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa012158" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/318787" target="_blank">Full Text</a>]
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<a id="Wooster1994" class="mim-anchor"></a>
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Wooster, R., Neuhausen, S. L., Mangion, J., Quirk, Y., Ford, D., Collins, N., Nguyen, K., Seal, S., Tran, T., Averill, D., Fields, P., Marshall, G., and 19 others.
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[<a href="https://doi.org/10.1126/science.8091231" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 10/16/2018
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/16/2009<br>Cassandra L. Kniffin - updated : 8/4/2009
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Creation Date:
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<span class="mim-text-font">
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Cassandra L. Kniffin : 1/27/2009
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carol : 11/04/2021
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alopez : 10/16/2018<br>carol : 04/30/2018<br>carol : 05/27/2016<br>carol : 2/19/2014<br>terry : 4/4/2013<br>terry : 9/4/2012<br>alopez : 5/12/2010<br>alopez : 5/12/2010<br>carol : 4/5/2010<br>terry : 1/21/2010<br>terry : 1/21/2010<br>wwang : 1/8/2010<br>ckniffin : 12/16/2009<br>wwang : 8/28/2009<br>ckniffin : 8/4/2009<br>carol : 2/6/2009<br>terry : 2/6/2009<br>ckniffin : 1/30/2009
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<span class="mim-font">
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<strong>#</strong> 612555
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<h3>
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BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2; BROVCA2
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<em>Alternative titles; symbols</em>
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HBOC2
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Other entities represented in this entry:
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<span class="h3 mim-font">
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BREAST CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2, INCLUDED
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OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2, 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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13q13.1
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{Breast-ovarian cancer, familial, 2}
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<span class="mim-font">
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612555
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Autosomal dominant
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<span class="mim-font">
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3
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BRCA2
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600185
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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-2 (BROVCA2) results from heterozygous germline mutations in the BRCA2 gene (600185) on chromosome 13q13.</p><p>For a discussion of genetic heterogeneity of breast-ovarian cancer susceptibility, see BROVCA1 (604370).</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>Wooster et al. (1994) reported a large family from Utah segregating early-onset breast cancer, ovarian cancer, and male breast cancer. </p><p>Thorlacius et al. (1995) described a family with multiple cases of male breast cancer but no increase in female breast cancer. Seven males in 3 generations had breast cancer. Other members of the family had other forms of cancer. Linkage of breast cancer to the BRCA2 region on chromosome 13q was demonstrated and all the affected men shared the same haplotype for BRCA2 markers and loss of the other alleles in their tumors. </p><p>Early age at first full-term pregnancy and increasing parity are associated with a reduced risk of breast cancer. However, Jernstrom et al. (1999) found that carriers of the BRCA1 and BRCA2 mutations who have children are significantly more likely to develop breast cancer by age 40 than carriers who are nulliparous. Each pregnancy is associated with an increased cancer risk. The authors found that early first pregnancy does not confer protection for carriers of BRCA1 or BRCA2 mutations. </p><p>Boyd et al. (2000) performed a retrospective cohort study of a consecutive series of 933 ovarian cancers diagnosed and treated at the Sloan-Kettering Cancer Center. This study was restricted to patients of Jewish origin because of the ease of BRCA1 and BRCA2 genotyping in this ethnic group. Of the 189 patients who identified themselves as Jewish, 88 hereditary cases were identified with the presence of a germline founder mutation in BRCA1 or BRCA2. The remaining 101 cases from the same series not associated with a BRCA mutation and 2 additional groups with ovarian cancer from clinical trials were included for comparison. Hereditary cancers were rarely diagnosed before age 40 years and were common after age 60 years, with mean age at diagnosis being significantly younger for BRCA1 versus BRCA2-linked patients (54 vs 62 years). Histology, grade, stage, and success of cytoreductive surgery were similar for hereditary and sporadic cases. The hereditary group had a longer disease-free interval following primary chemotherapy in comparison with the nonhereditary group, with a median time to recurrence of 14 months and 7 months, respectively (P less than 0.001). Those with hereditary cancers had improved survival compared with the nonhereditary group. Boyd et al. (2000) concluded that although BRCA-associated hereditary ovarian cancers in this population have surgical and pathologic characteristics similar to those of sporadic cancers, advanced-stage hereditary cancer patients may survive longer than nonhereditary cancer patients. Age penetrance was greater for BRCA1-linked than for BRCA2-linked cancers in this population. </p>
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<strong>Inheritance</strong>
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<p>In 2 large, systematically ascertained families in which breast cancer showed linkage to 13q12-q13, Easton et al. (1997) determined the penetrance of the BRCA2 gene by use of a maximum-likelihood method to incorporate both cancer-incidence data and 13q marker typings. The cumulative risk of breast cancer in female gene carriers was estimated to be 59.8% by age 50 years (95% confidence interval (CI) 25.9 to 78.5%) and 79.5% by age 70 years (95% CI 28.9 to 97.5%). Cumulative risk of breast cancer in male carriers was estimated to be 6.3% (95% CI 1.4 to 25.6%) by age 70 years. The results indicated that the lifetime breast cancer risk in BRCA2 carriers, for at least a subset of mutations, is comparable to that for BRCA1, in which Easton et al. (1995) estimated the risk of breast cancer to be 51% by age 50 years. The corresponding estimates by age 60 years were 54% for BRCA1-mutation carriers, compared with 71% for BRCA2. A significant excess of ovarian cancer in BRCA2 gene carriers was observed (relative risk 17.69, based on 3 cases), but the absolute risk of ovarian cancer was less than that reported for BRCA1. Significant excesses of laryngeal cancer (relative risk 7.67, based on 2 possible carriers) and prostate cancer (relative risk 2.89, based on 5 possible carriers) were also observed. One case of ocular melanoma, as well as a second eye cancer of unspecified histology, occurred in obligate gene carriers. </p><p>Risch et al. (2001) found that ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer cluster region of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. The results suggested that BRCA2 mutations may prove to be a greater cause of cancer in male carriers than had previously been thought. </p>
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<strong>Mapping</strong>
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<p>Wooster et al. (1994) performed a genomic linkage search in 15 high-risk breast cancer families that were unlinked to the BRCA1 locus on 17q21. This analysis uncovered a second breast cancer susceptibility locus, BRCA2, located in a 6-cM interval on chromosome 13q12-q13. The authors noted that BRCA2, while conferring a high risk of breast cancer, did not appear to confer as strong an elevated risk of ovarian cancer as observed with BRCA1. </p><p>Stratton et al. (1994) examined 22 families with at least 1 case of male breast cancer for linkage to the BRCA1 locus on 17q. They found strong evidence against linkage to BRCA1 (lod score, -16.63) and the best estimate of the proportion of linked families was 0% (95% confidence interval, 0-18%). </p>
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<strong>Pathogenesis</strong>
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<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 authors suggested that breast cancer due to BRCA1 has a different natural history than that in BRCA2 or apparently sporadic disease, which may have implications for screening and management. </p>
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<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>Sakai et al. (2008) showed that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wildtype BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, CAPAN1, led to 5 different secondary mutations that restored the wildtype BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP; 173870) inhibitor (AG14361). Finally, Sakai et al. (2008) evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumor that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Sakai et al. (2008) concluded that secondary mutations that restore the wildtype BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy. </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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<strong>Molecular Genetics</strong>
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<p>In families with breast cancer linked to chromosome 13q12, Wooster et al. (1995) identified 6 different germline mutations in the BRCA2 gene (see, e.g., 600185.0001), each causing serious disruption to the open reading frame of the transcriptional unit. </p><p>In 9 of 18 kindreds with familial breast cancer selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer, Tavtigian et al. (1996) identified potentially deleterious sequence alterations in the BRCA2 gene (see, e.g., 600185.0007). All except 1, a deletion of 3 nucleotides, involved nucleotide deletions that altered the reading frame, leading to truncation of the BRCA2 protein. No missense or nonsense mutations were found. The authors noted that the mutation profile of BRCA2 differs from that of BRCA1: microinsertions and point mutations are about as common in BRCA1 as microdeletions, which predominate in BRCA2. </p><p>Friedman et al. (1997) analyzed a population-based series of 54 male breast cancer cases from southern California for germline mutations in the BRCA1 and BRCA2 genes. A family history of breast and/or ovarian cancer in at least one first-degree relative was found in 9 patients (17%). A further 7 (13%) reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. The 54 patients showed no germline BRCA1 mutations. On the other hand, 2 of the male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only 1 of the 2 had a family history of cancer, with 1 case of ovarian cancer in a first-degree relative. </p><p>Casilli et al. (2006) used quantitative multiplex PCR of short fluorescent fragments (QMPSF) to screen for BRCA2 germline rearrangements in 120 families with familial breast cancer who were negative for BRCA1 and BRCA2 mutations. Three novel and distinct BRCA2 deletions were identified in 3 families: deletion of exons 14 through 18, exons 15 and 16, and exons 12 and 13, respectively. Combined with data from the larger cohort of 194 families selected for the study in which 36 BRCA2 mutations were identified, Casilli et al. (2006) estimated that approximately 7.7% of germline BRCA2 mutations are rearrangements, which is similar to the contribution of rearrangements to the mutation spectrum of BRCA1 (approximately 15%). </p><p><strong><em>Modifier Genes</em></strong></p><p>
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In a sample of 10,358 carriers of BRCA1 or BRCA2 gene mutations from 23 studies, Antoniou et al. (2008) observed associations between breast cancer and 2 different SNPs in the FGFR2 (176943) and MAP3K1 (600982) genes in BRCA2 carriers, but not in BRCA1 carriers. A SNP in the TNRC9 gene (TOX3; 611416) showed increased risk in both BRCA2 and BRCA1 carriers. The authors postulated a multiplicative effect for the SNPs on breast cancer risk. </p>
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<p>Among 7 large Icelandic breast cancer families, Gudmundsson et al. (1996) found that 5 showed strong evidence of linkage to the BRCA2 region. The maximum 2-point lod scores in the 5 families ranged from 1.06 to 3.19. Furthermore, haplotype analyses revealed a region with identical allele sizes in the families, suggesting to the authors that they inherited the mutation from a common ancestor. Cancer types other than breast cancer occurred in both males and females segregating the affected haplotype in these families. Thorlacius et al. (1996) studied 21 Icelandic families selected on the basis of a high frequency of breast cancer in females or the occurrence of one or more cases of male breast cancer. Strong evidence for linkage to the BRCA2 region was found in 16 families; these families shared a common haplotype in the BRCA2 region, suggesting a founder effect. In all 16 families there was evidence for a 5-bp deletion in exon 9 (999del5; 600185.0010). The authors noted that in the Icelandic population, the 999del5 mutation has been found in individuals with different tumor types including cancer of the prostate, pancreas, ovary, colon, stomach, thyroid, cervix, and endometrium. </p><p>Barkardottir et al. (2001) constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in 18 Icelandic and 10 Finnish breast and breast-ovarian cancer families with the 999del5 mutation. All the Icelandic families shared a common haplotype covering approximately 0.85 Mb, or 1.7 cM. The common ancestors were estimated to trace back 320 to 1,000 years, not excluding the possibility that the mutation was brought to Iceland during the settlement of the country mainly by Vikings between the years 860 to 1060. Analysis of the Finnish families revealed 2 distinct haplotypes. A rarer haplotype was present in 3 families and shared a core haplotype with the Icelandic haplotype spanning about 200 kb, or 0.5 cM. A more common haplotype was present in 7 Finnish families and shared a region covering about 6 cM. These 7 families originated from 2 geographic regions in Finland: (1) from the same small region as the families segregating the rare haplotype (early settlement region in the southwest of Finland), and (2) from the 'new' settlement region in the most eastern part of the country. The 2 distinct haplotypes in the Finnish families may represent different mutational events. The authors, however, suggested that another possible explanation is a gene conversion (in agreement with the population historical records), and the results may indicate a common ancient origin of the 999del5 mutation in Iceland and Finland. </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 (113705.0003) 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. </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>Taillon-Miller et al. (1997) pointed out that complete 46,XX homozygote hydatidiform moles can serve as homozygous controls in the development of single-nucleotide polymorphism (SNP) markers and provide a way to obtain long-range haplotypes and estimate allele frequencies that are useful in population studies. They used 11 diallelic markers in the BRCA2 region of 13q12-q13 to compare polymorphism allele frequencies of Caucasian, Hispanic, and African American populations. </p><p>To investigate both mutation origin and mutation-specific phenotypes due to BRCA2 mutations, Neuhausen et al. (1998) constructed a haplotype of 10 polymorphic short tandem repeat (STR) markers flanking the BRCA2 locus, in a set of 111 breast or breast/ovarian cancer families selected for having 1 of 9 recurrent BRCA2 mutations. Six of the individual mutations were estimated to have arisen 400 to 2,000 years ago. In particular, the 6174delT mutation (600185.0009), found in approximately 1% of individuals of Ashkenazi Jewish ancestry, was estimated to have arisen 29 generations ago (1-lod support interval = 22-38). This is substantially more recent than the estimated age of the BRCA1 185delAG (113705.0003) mutation, 46 generations, derived from an analogous study of BRCA1 mutations. In general, Neuhausen et al. (1998) found no evidence of multiple origins of identical BRCA2 mutations. </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 BRCA1 4446C-T mutation (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>Wagner et al. (1999) studied the sequence diversity of the BRCA2 gene in 71 breast cancer and breast/ovarian cancer families and 95 control individuals from a wide range of ethnicities. In the 10,257 bp of the coding sequence and the 2,799 bp of the noncoding sequence, 82 sequence variants were identified. Disease-associated mutations were identified in 6 families (8%). Of the 79 sequence variants not obviously associated with disease, 8 were detected only in breast cancer and breast/ovarian cancer families. The 71 remaining variants were identified in both breast cancer and breast/ovarian cancer families and controls. Sixty-three sequence variants (80%) were continent specific; 42% were detected exclusively in Africa, though only 13% of the chromosomes screened were of African origin. Based on the finding of 1 variant in 194 bp in the coding region and 1 variant in 108 bp in the noncoding region, Wagner et al. (1999) concluded that simple sequence variation is a frequent occurrence in the BRCA2 gene. </p><p>Sarantaus et al. (2001) screened 233 unselected Finnish ovarian carcinoma patients 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 (including the 2 BRCA2 mutations). 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>Using the population-based Icelandic Cancer Registry database, Tulinius et al. (2002) found that 90 of 887 families (10%) of breast cancer patients had the 999del5 mutation in the BRCA2 gene (600185.0010). Relatives of probands with the mutation had significantly increased relative risk of breast cancer: 7.55, 3.18, and 2.58 for first-, second-, and third-degree relatives, respectively. First- and second-degree relatives of patients with the mutation also had an increased risk for prostate and ovarian cancer. </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 50 years of age 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>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. The BRCA2 999del5 mutation was present in 2 families whose ancestry could be traced to a common geographic region in eastern Finland. Another family had the BRCA2 6503delTT mutation (600185.0002). </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 mutation in the BRCA2 gene was 6174delT (600185.0009), accounting for 4.5% of all mutations among Central Europeans. </p>
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<strong>See Also:</strong>
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<span class="mim-text-font">
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Breast Cancer Linkage Consortium (1999)
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<p>
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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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