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Entry
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- *600375 - X-RAY REPAIR CROSS COMPLEMENTING 2; XRCC2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600375</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600375">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000196584;t=ENST00000359321" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=7516" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=600375" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000196584;t=ENST00000359321" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_005431" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_005431" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=600375" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02656&isoform_id=02656_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/XRCC2" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/2921392,2961445,3273086,3288461,4885657,20140429,21489902,27503147,51476244,119574352,119574353,189069340,308219382" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/O43543" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=7516" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000196584;t=ENST00000359321" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=XRCC2" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=XRCC2" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+7516" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/XRCC2" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:7516" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/7516" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr7&hgg_gene=ENST00000359321.2&hgg_start=152644776&hgg_end=152676141&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:12829" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600375[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600375[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000196584" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=XRCC2" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=XRCC2" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=XRCC2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=XRCC2&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA37421" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:12829" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0030931.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1927345" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/XRCC2#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1927345" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/7516/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7516" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-121029-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7516" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=XRCC2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
600375
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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X-RAY REPAIR CROSS COMPLEMENTING 2; XRCC2
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</span>
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
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<span class="mim-font">
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|
<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
X-RAY REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 2
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=XRCC2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">XRCC2</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/7/844?start=-3&limit=10&highlight=844">7q36.1</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:152644776-152676141&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">7:152,644,776-152,676,141</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=617247,619146,619145" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/7/844?start=-3&limit=10&highlight=844">
|
|
7q36.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Fanconi anemia, complementation group U
|
|
|
|
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/617247"> 617247 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
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|
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|
|
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</tr>
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
?Premature ovarian failure 17
|
|
|
|
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619146"> 619146 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spermatogenic failure 50
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619145"> 619145 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
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|
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</tbody>
|
|
</table>
|
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</div>
|
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</div>
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<div>
|
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<p>The XRCC2 gene is a member of the RAD51 gene family (see, e.g., <a href="/entry/179617">179617</a>), which encode proteins involved in homologous recombination repair of DNA damage (summary by <a href="#18" class="mim-tip-reference" title="Tambini, C. E., George, A. M., Rommens, J. M., Tsui, L.-C., Scherer, S. W., Thacker, J. <strong>The XRCC2 DNA repair gene: identification of a positional candidate.</strong> Genomics 41: 84-92, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126486</a>] [<a href="https://doi.org/10.1006/geno.1997.4636" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126486">Tambini et al., 1997</a>). The XRCC2 gene acts late in the Fanconi anemia (FA)-BRCA (see, e.g., BRCA1; <a href="/entry/113705">113705</a>) pathway of DNA repair (summary by <a href="#14" class="mim-tip-reference" title="Park, J.-Y., Virts, E. L., Jankowska, A., Wiek, C., Othman, M., Chakraborty, S. C., Vance, G. H., Alkuraya, F. S., Hanenberg, H., Andreassen, P. R. <strong>Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene.</strong> J. Med. Genet. 53: 672-680, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27208205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27208205</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27208205">Park et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9126486+27208205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#19" class="mim-tip-reference" title="Thacker, J., Tambini, C. E., Simpson, P. J., Tsui, L.-C., Scherer, S. W. <strong>Localization to chromosome 7q36.1 of the human XRCC2 gene, determining sensitivity to DNA-damaging agents.</strong> Hum. Molec. Genet. 4: 113-120, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7711722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7711722</a>] [<a href="https://doi.org/10.1093/hmg/4.1.113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7711722">Thacker et al. (1995)</a> fused the V79 hamster cell line irs1, which is a repair-deficient mutant that shows hypersensitivity to a number of different DNA-damaging agents (<a href="#5" class="mim-tip-reference" title="Jones, N. J., Cox, R., Thacker, J. <strong>Isolation and cross-sensitivity of x-ray-sensitive mutants of V79-4 hamster cells.</strong> Mutat. Res. 183: 279-286, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3106801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3106801</a>] [<a href="https://doi.org/10.1016/0167-8817(87)90011-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3106801">Jones et al., 1987</a>), to normal human cells, resulting in complementation of the defect. The resultant hybrids were analyzed by Alu-PCR, chromosome painting, and DNA markers to map the complementing gene, designated XRCC2, to a specific chromosome region. The hybrid cells showed correction of sensitivity to both x-rays and mitomycin C and contained human chromosome 7, often as their only human component. Hybrids showing unstable retention of human chromosomes were subcloned to show that loss of chromosome 7 and loss of resistance to mitomycin C occurred concordantly. Two separate hybrids were found to have a smaller piece of chromosome 7, and specific DNA probes and microsatellite markers defined this as a contiguous region at 7q35-q36. Hybrid irradiation-fusion methods were used to reduce further the size of the complementing genomic region and to localize the gene to an approximately 3- to 5-Mb region at 7q36.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7711722+3106801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Jones, N. J., Zhao, Y., Siciliano, M. J., Thompson, L. H. <strong>Assignment of the XRCC2 human DNA repair gene to chromosome 7q36 by complementation analysis.</strong> Genomics 26: 619-622, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7607692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7607692</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80187-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7607692">Jones et al. (1995)</a> mapped the XRCC2 gene to 7q36 by studying complementation of the defect in the irs1 hamster cell line described by <a href="#5" class="mim-tip-reference" title="Jones, N. J., Cox, R., Thacker, J. <strong>Isolation and cross-sensitivity of x-ray-sensitive mutants of V79-4 hamster cells.</strong> Mutat. Res. 183: 279-286, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3106801/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3106801</a>] [<a href="https://doi.org/10.1016/0167-8817(87)90011-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3106801">Jones et al. (1987)</a>. <a href="#6" class="mim-tip-reference" title="Jones, N. J., Zhao, Y., Siciliano, M. J., Thompson, L. H. <strong>Assignment of the XRCC2 human DNA repair gene to chromosome 7q36 by complementation analysis.</strong> Genomics 26: 619-622, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7607692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7607692</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80187-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7607692">Jones et al. (1995)</a> formed somatic cell hybrids by fusing irs1 cells with human lymphocytes and selecting for complementation in medium containing concentrations of mitomycin C that are toxic to irs1 cells but not their human fusion partners. Retention of chromosome 7 or of the region 7q36 resulted in cells that were resistant to mitomycin C. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7607692+3106801" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Tambini, C. E., George, A. M., Rommens, J. M., Tsui, L.-C., Scherer, S. W., Thacker, J. <strong>The XRCC2 DNA repair gene: identification of a positional candidate.</strong> Genomics 41: 84-92, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126486</a>] [<a href="https://doi.org/10.1006/geno.1997.4636" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126486">Tambini et al. (1997)</a> took the radiation reduction of human/hamster hybrids further to locate the XRCC2 gene to a small genomic region defined by a single microsatellite marker D7S483. Yeast artificial chromosomes (YACs) carrying that marker were then fused to the irs1 hamster cell line and a YAC that carried the complementing gene was identified. This YAC was used for direct cDNA selection experiments to identify the XRCC2 gene. The gene was found to share homology with the yeast RAD51 gene and its human homolog (<a href="/entry/179617">179617</a>), which are involved in the recombinational repair of DNA damage. Strong support for the candidacy of this gene as XRCC2 was obtained from its refined map position and by the full complementation of irs1 sensitivity with a 40-kb cosmid carrying the gene. <a href="#18" class="mim-tip-reference" title="Tambini, C. E., George, A. M., Rommens, J. M., Tsui, L.-C., Scherer, S. W., Thacker, J. <strong>The XRCC2 DNA repair gene: identification of a positional candidate.</strong> Genomics 41: 84-92, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126486</a>] [<a href="https://doi.org/10.1006/geno.1997.4636" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9126486">Tambini et al. (1997)</a> noted that, although the XRCC2 candidate gene on chromosome 7 showed homology to yeast RAD51, it must be distinct from the human RAD51 homolog, which is located on chromosome 15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9126486" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#19" class="mim-tip-reference" title="Thacker, J., Tambini, C. E., Simpson, P. J., Tsui, L.-C., Scherer, S. W. <strong>Localization to chromosome 7q36.1 of the human XRCC2 gene, determining sensitivity to DNA-damaging agents.</strong> Hum. Molec. Genet. 4: 113-120, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7711722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7711722</a>] [<a href="https://doi.org/10.1093/hmg/4.1.113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7711722">Thacker et al. (1995)</a> and <a href="#6" class="mim-tip-reference" title="Jones, N. J., Zhao, Y., Siciliano, M. J., Thompson, L. H. <strong>Assignment of the XRCC2 human DNA repair gene to chromosome 7q36 by complementation analysis.</strong> Genomics 26: 619-622, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7607692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7607692</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80187-q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7607692">Jones et al. (1995)</a> mapped the XRCC2 gene to chromosome 7q36.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7711722+7607692" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#4" class="mim-tip-reference" title="Johnson, R. D., Liu, N., Jasin, M. <strong>Mammalian XRCC2 promotes the repair of DNA double-strand breaks by homologous recombination.</strong> Nature 401: 397-399, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10517641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10517641</a>] [<a href="https://doi.org/10.1038/43932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10517641">Johnson et al. (1999)</a> demonstrated that XRCC2 is essential for the efficient repair of DNA double-strand breaks by homologous recombination between sister chromatids. Hamster cells deficient in XRCC2 showed a more than 100-fold decrease in homologous recombination induced by double-strand breaks compared with the parental cell line. This defect was corrected to almost wildtype levels by transient transfection with a plasmid expressing XRCC2. The repair defect in XRCC2 mutant cells appeared to be restricted to recombinational repair because nonhomologous end joining was normal. <a href="#4" class="mim-tip-reference" title="Johnson, R. D., Liu, N., Jasin, M. <strong>Mammalian XRCC2 promotes the repair of DNA double-strand breaks by homologous recombination.</strong> Nature 401: 397-399, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10517641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10517641</a>] [<a href="https://doi.org/10.1038/43932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10517641">Johnson et al. (1999)</a> concluded that XRCC2 is involved in the repair of DNA double-strand breaks by homologous recombination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10517641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a yeast 2-hybrid assay, <a href="#2" class="mim-tip-reference" title="Braybrooke, J. P., Spink, K. G., Thacker, J., Hickson, I. D. <strong>The RAD51 family member, RAD51L3, is a DNA-stimulated ATPase that forms a complex with XRCC2.</strong> J. Biol. Chem. 275: 29100-29106, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10871607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10871607</a>] [<a href="https://doi.org/10.1074/jbc.M002075200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10871607">Braybrooke et al. (2000)</a> identified a direct interaction between XRCC2 and RAD51L3 (<a href="/entry/602954">602954</a>), and they confirmed the interaction by pull-down assays between recombinant XRCC2 and endogenous RAD51L3 in HeLa cell extracts. Size-exclusion chromatography followed by Western blot analysis suggested that the 2 proteins exist as a heterodimer of about 70 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10871607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Masson, J.-Y., Tarsounas, M. C., Stasiak, A. Z., Stasiak, A., Shah, R., McIlwraith, M. J., Benson, F. E., West, S. C. <strong>Identification and purification of two distinct complexes containing the five RAD51 paralogs.</strong> Genes Dev. 15: 3296-3307, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11751635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11751635</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11751635[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.947001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11751635">Masson et al. (2001)</a> found that antibody directed against RAD51L3 immunoprecipitated a complex from HeLa cell lysates that included XRCC2, RAD51B (RAD51L1; <a href="/entry/602948">602948</a>), and RAD51C (<a href="/entry/602774">602774</a>), along with RAD51L3. Interactions between these proteins were confirmed in pull-down assays using recombinant proteins expressed in sf9 insect cells. Gel filtration of the complexes indicated an apparent molecular mass of about 180 kD, suggesting a 1:1:1:1 stoichiometry of the 4 subunits. Binding assays, confirmed by electron microscopy, indicated that the purified complex bound single-stranded or nicked DNA. This binding was dependent on Mg(2+) but independent of ATP. The DNA-stimulated ATPase activity of the complex was extremely low. <a href="#10" class="mim-tip-reference" title="Masson, J.-Y., Tarsounas, M. C., Stasiak, A. Z., Stasiak, A., Shah, R., McIlwraith, M. J., Benson, F. E., West, S. C. <strong>Identification and purification of two distinct complexes containing the five RAD51 paralogs.</strong> Genes Dev. 15: 3296-3307, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11751635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11751635</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11751635[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.947001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11751635">Masson et al. (2001)</a> also identified a second, heterodimeric protein complex between RAD51C and XRCC3 (<a href="/entry/600675">600675</a>). Using coprecipitation and multiple pull-down assays, <a href="#9" class="mim-tip-reference" title="Liu, N., Schild, D., Thelen, M. P., Thompson, L. H. <strong>Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs in human cells.</strong> Nucleic Acids Res. 30: 1009-1015, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11842113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11842113</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11842113[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/nar/30.4.1009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11842113">Liu et al. (2002)</a> confirmed interaction between the same RAD51 paralogs in the same 2 distinct protein complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11751635+11842113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a yeast 2-hybrid screen of a human brain cDNA library using XRCC2 as bait, <a href="#7" class="mim-tip-reference" title="Kurumizaka, H., Ikawa, S., Nakada, M., Enomoto, R., Kagawa, W., Kinebuchi, T., Yamazoe, M., Yokoyama, S., Shibata, T. <strong>Homologous pairing and ring and filament structure formation activities of the human Xrcc2-Rad51D complex.</strong> J. Biol. Chem. 277: 14315-14320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11834724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11834724</a>] [<a href="https://doi.org/10.1074/jbc.M105719200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11834724">Kurumizaka et al. (2002)</a> also found that RAD51L3 interacts directly with XRCC2. Using a D-loop formation assay, they found that RAD51L3 and XRCC2, coexpressed and purified from bacterial cultures, catalyze homologous pairing between a single-stranded oligonucleotide and a superhelical double-stranded DNA. Significant single- and double-stranded DNA were bound by the complex in the absence of ATP, but homologous pairing was dependent on ATP and Mg(2+). By electron microscopy, they found that RAD51L3 and XRCC2 form a multimeric ring structure in the absence of DNA, and they form filamentous structures in the presence of single-stranded DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11834724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Adelman, C. A., Lolo, R. L., Birkbak, N. J., Murina, O., Matsuzaki, K., Horejsi, Z., Parmar, K., Borel, V., Skehel, J. M., Stamp, G., D'Andrea, A., Sartori, A. A., Swanton, C., Boulton, S. J. <strong>HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis.</strong> Nature 502: 381-384, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24005329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24005329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24005329[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/nature12565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24005329">Adelman et al. (2013)</a> reported that Helq (<a href="/entry/606769">606769</a>) helicase-deficient mice exhibit subfertility, germ cell attrition, interstrand crosslink (ICL) sensitivity, and tumor predisposition, with Helq heterozygous mice exhibiting a similar, albeit less severe, phenotype than the null, indicative of haploinsufficiency. <a href="#1" class="mim-tip-reference" title="Adelman, C. A., Lolo, R. L., Birkbak, N. J., Murina, O., Matsuzaki, K., Horejsi, Z., Parmar, K., Borel, V., Skehel, J. M., Stamp, G., D'Andrea, A., Sartori, A. A., Swanton, C., Boulton, S. J. <strong>HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis.</strong> Nature 502: 381-384, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24005329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24005329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24005329[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/nature12565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24005329">Adelman et al. (2013)</a> established that HELQ interacts directly with the RAD51 paralog complex BCDX2 (RAD51B, RAD51C, RAD51D, and XRCC2) and functions in parallel to the Fanconi anemia pathway to promote efficient homologous recombination at damaged replication forks. <a href="#1" class="mim-tip-reference" title="Adelman, C. A., Lolo, R. L., Birkbak, N. J., Murina, O., Matsuzaki, K., Horejsi, Z., Parmar, K., Borel, V., Skehel, J. M., Stamp, G., D'Andrea, A., Sartori, A. A., Swanton, C., Boulton, S. J. <strong>HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis.</strong> Nature 502: 381-384, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24005329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24005329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24005329[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/nature12565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24005329">Adelman et al. (2013)</a> concluded that their results revealed a critical role for HELQ in replication-coupled DNA repair, germ cell maintenance, and tumor suppression in mammals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24005329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Fanconi Anemia, Complementation Group U</em></strong></p><p>
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In a boy, born of consanguineous Saudi Arabian parents, with an atypical form of Fanconi anemia, complementation group U (FANCU; <a href="/entry/617247">617247</a>), <a href="#17" class="mim-tip-reference" title="Shamseldin, H. E., Elfaki, M., Alkuraya, F. S. <strong>Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation.</strong> J. Med. Genet. 49: 184-186, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22232082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22232082</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22232082">Shamseldin et al. (2012)</a> identified a homozygous truncating mutation in the XRCC2 gene (R215X; <a href="#0001">600375.0001</a>). The mutation was found by whole-exome sequencing followed by autozygome filtering. Chromosome testing in patient fibroblasts showed a marked increase in the frequency of dsDNA breaks in response to damage, indicating a defect in homologous recombination repair. Complementation studies were not performed. <a href="#17" class="mim-tip-reference" title="Shamseldin, H. E., Elfaki, M., Alkuraya, F. S. <strong>Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation.</strong> J. Med. Genet. 49: 184-186, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22232082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22232082</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22232082">Shamseldin et al. (2012)</a> noted the phenotypic similarities to Xrcc2-null mice (<a href="#3" class="mim-tip-reference" title="Deans, B., Griffin, C. S., Maconochie, M., Thacker, J. <strong>Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice.</strong> EMBO J. 19: 6675-6685, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11118202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11118202</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11118202[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/19.24.6675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11118202">Deans et al., 2000</a>). <a href="#14" class="mim-tip-reference" title="Park, J.-Y., Virts, E. L., Jankowska, A., Wiek, C., Othman, M., Chakraborty, S. C., Vance, G. H., Alkuraya, F. S., Hanenberg, H., Andreassen, P. R. <strong>Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene.</strong> J. Med. Genet. 53: 672-680, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27208205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27208205</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27208205">Park et al. (2016)</a> found that expression of wildtype XRCC2 in cells derived from the patient reported by <a href="#17" class="mim-tip-reference" title="Shamseldin, H. E., Elfaki, M., Alkuraya, F. S. <strong>Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation.</strong> J. Med. Genet. 49: 184-186, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22232082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22232082</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22232082">Shamseldin et al. (2012)</a> corrected all 3 abnormal cellular phenotypes that were apparent in patient cells: cellular sensitivity to DNA interstrand crosslinking agents, chromosome instability, and accumulation of cells at the G2/M stage of the cell cycle. Patient cells showed normal levels of monoubiquitinated FANCD2 (<a href="/entry/613984">613984</a>), a central step in the FA pathway, and decreased assembly of RAD51 (<a href="/entry/179617">179617</a>) foci, suggesting that XRCC2 acts downstream of this event. Patient cells showed defective assembly of the components of the BCDX2 complex, particularly RAD51C (<a href="/entry/602774">602774</a>). Patient cells also showed increased sensitivity to ionizing radiation, consistent with a defect in proteins that act downstream in the FA pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22232082+11118202+27208205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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>Spermatogenic Failure 50 and Premature Ovarian Failure 17</em></strong></p><p>
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In a consanguineous Chinese family in which 2 infertile brothers had azoospermia due to meiotic arrest (SPGF50; <a href="/entry/619145">619145</a>), <a href="#20" class="mim-tip-reference" title="Yang, Y., Guo, J., Dai, L., Zhu, Y., Hu, H., Tan, L., Chen, W., Liang, D., He, J., Tu, M., Wang, K., Wu, L. <strong>XRCC2 mutation causes meiotic arrest, azoospermia and infertility.</strong> J. Med. Genet. 55: 628-636, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30042186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30042186</a>] [<a href="https://doi.org/10.1136/jmedgenet-2017-105145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30042186">Yang et al. (2018)</a> identified homozygosity for a missense mutation in the XRCC2 gene (L14P; <a href="#0002">600375.0002</a>) that segregated with disease. The authors noted that there was no evidence of cancer in the family, and that examination of the affected brothers by a neurologist, hematologist, and orthopedist did not detect any additional signs of disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30042186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Chinese woman with premature ovarian failure (POF17; <a href="/entry/619146">619146</a>) and her brother, who was infertile due to azoospermia, <a href="#21" class="mim-tip-reference" title="Zhang, Y.-X., Li, H.-Y., He, W.-B., Tu, C., Du, J., Li, W., Lu, G.-X., Lin, G., Yang, Y., Tan, Y.-Q. <strong>XRCC2 mutation causes premature ovarian insufficiency as well as non-obstructive azoospermia in humans.</strong> Clin. Genet. 95: 442-443, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30489636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30489636</a>] [<a href="https://doi.org/10.1111/cge.13475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30489636">Zhang et al. (2019)</a> identified homozygosity for the L14P mutation in XRCC2. Their first-cousin parent were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30489636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Role In Malignancy</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Kuschel, B., Auranen, A., McBride, S., Novik, K. L., Antoniou, A., Lipscombe, J. M., Day, N. E., Easton, D. F., Ponder, B. A. J., Pharoah, P. D. P., Dunning, A. <strong>Variants in DNA double-strand break repair genes and breast cancer susceptibility.</strong> Hum. Molec. Genet. 11: 1399-1407, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12023982/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12023982</a>] [<a href="https://doi.org/10.1093/hmg/11.12.1399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12023982">Kuschel et al. (2002)</a> performed genetic association studies in a population-based breast cancer case-control study analyzing polymorphisms in 7 genes involved in DNA repair. The association of a rare variant in XRCC2 (R188H) was marginally significant. In a comparable English cohort, <a href="#16" class="mim-tip-reference" title="Rafii, S., O'Regan, P., Xinarianos, G., Azmy, I., Stephenson, T., Reed, M., Meuth, M., Thacker, J., Cox, A. <strong>A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer.</strong> Hum. Molec. Genet. 11: 1433-1438, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12023985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12023985</a>] [<a href="https://doi.org/10.1093/hmg/11.12.1433" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12023985">Rafii et al. (2002)</a> found that carriage of R188H was associated with breast cancer overall, and this association was enhanced when younger-onset cases with a positive family history were compared with older controls with no family history. Using site-directed mutagenesis of XRCC2, <a href="#16" class="mim-tip-reference" title="Rafii, S., O'Regan, P., Xinarianos, G., Azmy, I., Stephenson, T., Reed, M., Meuth, M., Thacker, J., Cox, A. <strong>A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer.</strong> Hum. Molec. Genet. 11: 1433-1438, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12023985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12023985</a>] [<a href="https://doi.org/10.1093/hmg/11.12.1433" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12023985">Rafii et al. (2002)</a> further showed that nonconservative substitution or deletion of amino acid 188 of XRCC2 could significantly affect cellular sensitivity to DNA damage. The authors hypothesized that subtle variation in DNA repair capacity may influence cancer susceptibility in the population. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12023985+12023982" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Loss of mismatch repair (MMR) leads to a complex mutator phenotype that appears to drive the development of a subset of colon cancers (see <a href="#15" class="mim-tip-reference" title="Peltomaki, P. <strong>Deficient DNA mismatch repair: a common etiologic factor for colon cancer.</strong> Hum. Molec. Genet. 10: 735-740, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11257106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11257106</a>] [<a href="https://doi.org/10.1093/hmg/10.7.735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11257106">Peltomaki, 2001</a>). <a href="#12" class="mim-tip-reference" title="Mohindra, A., Hays, L. E., Phillips, E. N., Preston, B. D., Helleday, T., Meuth, M. <strong>Defects in homologous recombination repair in mismatch-repair-deficient tumour cell lines.</strong> Hum. Molec. Genet. 11: 2189-2200, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189171</a>] [<a href="https://doi.org/10.1093/hmg/11.18.2189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12189171">Mohindra et al. (2002)</a> showed that MMR-defective tumor cell lines were defective in homologous recombination repair (HRR) induced by DNA double-strand breaks (DSBs). A frameshift mutation (342delT) in XRCC2 found in the MMR-deficient uterine tumor cell line, SKUT-1, conferred thymidine sensitivity when introduced into an MMR-proficient line. Like other cells with defective XRCC2, SKUT-1 cells were sensitive to mitomycin C, and MMR-proficient cells expressing the mutant XRCC2 allele also became more sensitive to this agent. The authors suggested that the thymidine sensitivity of MMR-deficient tumor cell lines may be a consequence of defects in the homologous recombination repair pathway. <a href="#11" class="mim-tip-reference" title="Mohindra, A., Bolderson, E., Stone, J., Wells, M., Helleday, T., Meuth, M. <strong>A tumour-derived mutant allele of XRCC2 preferentially suppresses homologous recombination at DNA replication forks.</strong> Hum. Molec. Genet. 13: 203-212, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14645207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14645207</a>] [<a href="https://doi.org/10.1093/hmg/ddh022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14645207">Mohindra et al. (2004)</a> introduced 342delT into HRR-proficient cells containing a recombination reporter substrate. In 1 set of transfectants, expression of 342delT conferred sensitivity to thymidine and mitomycin C and suppressed HRR induced at the recombination reporter by thymidine, but not by DSBs. In a second set of transfectants, expression of 342delT was accompanied by a decreased level of full-length XRCC2, and these cells were defective in induction of HRR by either thymidine or DSBs. <a href="#11" class="mim-tip-reference" title="Mohindra, A., Bolderson, E., Stone, J., Wells, M., Helleday, T., Meuth, M. <strong>A tumour-derived mutant allele of XRCC2 preferentially suppresses homologous recombination at DNA replication forks.</strong> Hum. Molec. Genet. 13: 203-212, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14645207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14645207</a>] [<a href="https://doi.org/10.1093/hmg/ddh022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14645207">Mohindra et al. (2004)</a> concluded that 342delT suppresses recombination induced by thymidine in a dominant-negative manner, while recombination induced by DSBs appears to depend upon the level of XRCC2, as well as expression of the mutant XRCC2 allele. The authors suggested that HRR pathways responding to stalled replication forks or DSBs are genetically distinguishable and that XRCC2 has a critical role in HRR at replication forks, possibly in the loading of RAD51 onto gapped DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12189171+11257106+14645207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Park, D. J., Lesueur, F., Nguyen-Dumont, T., Pertesi, M., Odefrey, F., Hammet, F., Neuhausen, S. L., John, E. M., Andrulis, I. L., Terry, M. B., Daly, M., Buys, S., and 17 others. <strong>Rare mutations in XRCC2 increase the risk of breast cancer.</strong> Am. J. Hum. Genet. 90: 734-739, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22464251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22464251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22464251[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.2012.02.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22464251">Park et al. (2012)</a> performed an exome-sequencing study of families with multiple breast cancer-affected individuals and identified 2 families with mutations, 1 with a protein-truncating mutation and 1 with a probable deleterious missense mutation in the XRCC2 gene. <a href="#13" class="mim-tip-reference" title="Park, D. J., Lesueur, F., Nguyen-Dumont, T., Pertesi, M., Odefrey, F., Hammet, F., Neuhausen, S. L., John, E. M., Andrulis, I. L., Terry, M. B., Daly, M., Buys, S., and 17 others. <strong>Rare mutations in XRCC2 increase the risk of breast cancer.</strong> Am. J. Hum. Genet. 90: 734-739, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22464251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22464251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22464251[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.2012.02.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22464251">Park et al. (2012)</a> then performed a population-based case-control mutation screening study that identified 6 probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p less than 0.02). They then performed additional mutation screening in 689 multiple-case families and identified 10 breast cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22464251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Deans, B., Griffin, C. S., Maconochie, M., Thacker, J. <strong>Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice.</strong> EMBO J. 19: 6675-6685, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11118202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11118202</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11118202[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/19.24.6675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11118202">Deans et al. (2000)</a> found that most homozygous Xrcc2-null mice die midgestation. The few mice that survived to later stages showed developmental abnormalities and died at birth. Neonatal lethality, apparently due to respiratory failure, was associated with a high frequency of apoptotic death of postmitotic neurons in the developing brain, leading to abnormal cortical structure. Embryonic cells showed genetic instability, revealed by a high level of chromosomal aberrations, and were sensitive to gamma-rays. The findings demonstrated that homologous recombination has an important role in endogenous damage repair in the developing embryo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11118202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Yang, Y., Guo, J., Dai, L., Zhu, Y., Hu, H., Tan, L., Chen, W., Liang, D., He, J., Tu, M., Wang, K., Wu, L. <strong>XRCC2 mutation causes meiotic arrest, azoospermia and infertility.</strong> J. Med. Genet. 55: 628-636, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30042186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30042186</a>] [<a href="https://doi.org/10.1136/jmedgenet-2017-105145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30042186">Yang et al. (2018)</a> generated mice homozygous for an L14P mutation (<a href="#0002">600375.0002</a>) in the Xrcc2 gene. The homozygous males were infertile and had smaller testes than wildtype mice. Histologic examination of the infertile males' testes showed that nearly all of the seminiferous tubules were depleted, with no mature sperm present in any of the tubules after 7 days postpartum (dpp), consistent with complete meiotic arrest. The tubules contained multiple layers of spermatocytes arrested at the zygotene and pachytene states of meiotic prophase I. In addition, half of female homozygotes were infertile, and the other half had significantly reduced litter sizes. Infertile females had bilateral small, atrophic, and fibrotic ovaries without identifiable follicles, whereas homozygotes with reduced fertility had unilateral atrophic ovaries. Analysis of L14P homozygous ovaries from 7 dpp to 180 dpp showed gradual reduction in the percentage of ovaries with follicles, from 100% to 20%, consistent with premature ovarian failure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30042186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs143153871 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs143153871;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs143153871?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs143153871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs143153871" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 2.5-year-old boy, born of consanguineous Saudi Arabian parents, with an atypical form of Fanconi anemia, complementation group U (FANCU; <a href="/entry/617247">617247</a>), <a href="#17" class="mim-tip-reference" title="Shamseldin, H. E., Elfaki, M., Alkuraya, F. S. <strong>Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation.</strong> J. Med. Genet. 49: 184-186, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22232082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22232082</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22232082">Shamseldin et al. (2012)</a> identified a homozygous c.643C-T transition (c.643C-T, NM_005431) in the XRCC2 gene, resulting in an arg215-to-ter (R215X) substitution predicted to remove the C terminus and abolish XRCC2 activity. The mutation was found by whole-exome sequencing followed by autozygome filtering. Chromosome testing in patient fibroblasts showed a marked increase in the frequency of dsDNA breaks in response to damage, indicating a defect in homologous recombination repair. Complementation studies were not performed. <a href="#17" class="mim-tip-reference" title="Shamseldin, H. E., Elfaki, M., Alkuraya, F. S. <strong>Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation.</strong> J. Med. Genet. 49: 184-186, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22232082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22232082</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22232082">Shamseldin et al. (2012)</a> noted the phenotypic similarities to Xrcc2-null mice (<a href="#3" class="mim-tip-reference" title="Deans, B., Griffin, C. S., Maconochie, M., Thacker, J. <strong>Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice.</strong> EMBO J. 19: 6675-6685, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11118202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11118202</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11118202[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/19.24.6675" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11118202">Deans et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22232082+11118202" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Park, J.-Y., Virts, E. L., Jankowska, A., Wiek, C., Othman, M., Chakraborty, S. C., Vance, G. H., Alkuraya, F. S., Hanenberg, H., Andreassen, P. R. <strong>Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene.</strong> J. Med. Genet. 53: 672-680, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27208205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27208205</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27208205">Park et al. (2016)</a> performed detailed studies on cells derived from the patient reported by <a href="#17" class="mim-tip-reference" title="Shamseldin, H. E., Elfaki, M., Alkuraya, F. S. <strong>Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation.</strong> J. Med. Genet. 49: 184-186, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22232082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22232082</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100585" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22232082">Shamseldin et al. (2012)</a>. The mutant protein was not found by Western blot analysis, indicating that it is unstable, but likely not subject to nonsense-mediated mRNA decay since the mutation occurs in the last exon. Expression of wildtype XRCC2 corrected all 3 abnormal cellular phenotypes that were apparent in patient cells: cellular sensitivity to DNA interstrand crosslinking agents, chromosome instability, and accumulation of cells at the G2/M stage of the cell cycle. Patient cells showed normal levels of monoubiquitinated FANCD2 (<a href="/entry/613984">613984</a>), a central step in the FA pathway, and decreased assembly of RAD51 (<a href="/entry/179617">179617</a>) foci, suggesting that XRCC2 acts downstream of this event. Patient cells showed defective assembly of the components of the BCDX2 complex, particularly RAD51C (<a href="/entry/602774">602774</a>). Patient cells also showed increased sensitivity to ionizing radiation, consistent with a defect in proteins that act downstream in the FA pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22232082+27208205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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In 2 infertile brothers from a consanguineous Chinese family with azoospermia due to meiotic arrest (SPGF50; <a href="/entry/619145">619145</a>), <a href="#20" class="mim-tip-reference" title="Yang, Y., Guo, J., Dai, L., Zhu, Y., Hu, H., Tan, L., Chen, W., Liang, D., He, J., Tu, M., Wang, K., Wu, L. <strong>XRCC2 mutation causes meiotic arrest, azoospermia and infertility.</strong> J. Med. Genet. 55: 628-636, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30042186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30042186</a>] [<a href="https://doi.org/10.1136/jmedgenet-2017-105145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30042186">Yang et al. (2018)</a> identified homozygosity for a c.41T-C transition (c.41T-C, NM_005431) in the XRCC2 gene, resulting in a leu14-to-pro (L14P) substitution at a highly conserved residue near the splicing site of exon 2. The mutation segregated fully with disease in the family. Immunohistochemical analysis of seminiferous tubules from 1 of the affected brothers showed that XRCC2 protein was present, and RNA and protein assay on peripheral blood lymphocytes from the brothers confirmed the presence of the full XRCC2 transcript and the full XRCC2 protein. Quantification of chromosomal breaks induced by 2 chromosomal crosslinking agents, MMC or DPP, showed a similar frequency of chromosomal breaks in patient cells compared to control cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30042186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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>Premature Ovarian Failure 17</em></strong></p><p>
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In a Chinese woman with premature ovarian failure (POF17; <a href="/entry/619146">619146</a>) and her infertile brother, who had azoospermia due to meiotic arrest, <a href="#21" class="mim-tip-reference" title="Zhang, Y.-X., Li, H.-Y., He, W.-B., Tu, C., Du, J., Li, W., Lu, G.-X., Lin, G., Yang, Y., Tan, Y.-Q. <strong>XRCC2 mutation causes premature ovarian insufficiency as well as non-obstructive azoospermia in humans.</strong> Clin. Genet. 95: 442-443, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30489636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30489636</a>] [<a href="https://doi.org/10.1111/cge.13475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30489636">Zhang et al. (2019)</a> identified homozygosity for the L14P mutation in XRCC2. Their first-cousin parent were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30489636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Kuschel, B., Auranen, A., McBride, S., Novik, K. L., Antoniou, A., Lipscombe, J. M., Day, N. E., Easton, D. F., Ponder, B. A. J., Pharoah, P. D. P., Dunning, A.
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[<a href="https://doi.org/10.1093/nar/30.4.1009" target="_blank">Full Text</a>]
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Masson, J.-Y., Tarsounas, M. C., Stasiak, A. Z., Stasiak, A., Shah, R., McIlwraith, M. J., Benson, F. E., West, S. C.
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[<a href="https://doi.org/10.1101/gad.947001" target="_blank">Full Text</a>]
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Mohindra, A., Bolderson, E., Stone, J., Wells, M., Helleday, T., Meuth, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14645207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14645207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14645207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh022" target="_blank">Full Text</a>]
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Mohindra, A., Hays, L. E., Phillips, E. N., Preston, B. D., Helleday, T., Meuth, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12189171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12189171</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12189171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.18.2189" target="_blank">Full Text</a>]
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Park, D. J., Lesueur, F., Nguyen-Dumont, T., Pertesi, M., Odefrey, F., Hammet, F., Neuhausen, S. L., John, E. M., Andrulis, I. L., Terry, M. B., Daly, M., Buys, S., and 17 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22464251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22464251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22464251[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=22464251" 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.2012.02.027" target="_blank">Full Text</a>]
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<a id="Park2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Park, J.-Y., Virts, E. L., Jankowska, A., Wiek, C., Othman, M., Chakraborty, S. C., Vance, G. H., Alkuraya, F. S., Hanenberg, H., Andreassen, P. R.
|
|
<strong>Complementation of hypersensitivity to DNA interstrand crosslinking agents demonstrates that XRCC2 is a Fanconi anaemia gene.</strong>
|
|
J. Med. Genet. 53: 672-680, 2016.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27208205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27208205</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27208205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2016-103847" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Peltomaki2001" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
|
|
Peltomaki, P.
|
|
<strong>Deficient DNA mismatch repair: a common etiologic factor for colon cancer.</strong>
|
|
Hum. Molec. Genet. 10: 735-740, 2001.
|
|
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11257106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11257106</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11257106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/10.7.735" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Rafii2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rafii, S., O'Regan, P., Xinarianos, G., Azmy, I., Stephenson, T., Reed, M., Meuth, M., Thacker, J., Cox, A.
|
|
<strong>A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer.</strong>
|
|
Hum. Molec. Genet. 11: 1433-1438, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12023985/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12023985</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12023985" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.12.1433" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Shamseldin2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shamseldin, H. E., Elfaki, M., Alkuraya, F. S.
|
|
<strong>Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation.</strong>
|
|
J. Med. Genet. 49: 184-186, 2012.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22232082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22232082</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22232082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2011-100585" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Tambini1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tambini, C. E., George, A. M., Rommens, J. M., Tsui, L.-C., Scherer, S. W., Thacker, J.
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|
<strong>The XRCC2 DNA repair gene: identification of a positional candidate.</strong>
|
|
Genomics 41: 84-92, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9126486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9126486</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9126486" 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/10.1006/geno.1997.4636" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Thacker1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thacker, J., Tambini, C. E., Simpson, P. J., Tsui, L.-C., Scherer, S. W.
|
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<strong>Localization to chromosome 7q36.1 of the human XRCC2 gene, determining sensitivity to DNA-damaging agents.</strong>
|
|
Hum. Molec. Genet. 4: 113-120, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7711722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7711722</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7711722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/4.1.113" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Yang2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yang, Y., Guo, J., Dai, L., Zhu, Y., Hu, H., Tan, L., Chen, W., Liang, D., He, J., Tu, M., Wang, K., Wu, L.
|
|
<strong>XRCC2 mutation causes meiotic arrest, azoospermia and infertility.</strong>
|
|
J. Med. Genet. 55: 628-636, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30042186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30042186</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30042186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2017-105145" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Zhang2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, Y.-X., Li, H.-Y., He, W.-B., Tu, C., Du, J., Li, W., Lu, G.-X., Lin, G., Yang, Y., Tan, Y.-Q.
|
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<strong>XRCC2 mutation causes premature ovarian insufficiency as well as non-obstructive azoospermia in humans.</strong>
|
|
Clin. Genet. 95: 442-443, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30489636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30489636</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30489636" 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/10.1111/cge.13475" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 12/30/2020
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 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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Cassandra L. Kniffin - updated : 12/08/2016<br>Ada Hamosh - updated : 12/4/2013<br>Ada Hamosh - updated : 7/24/2012<br>Cassandra L. Kniffin - updated : 4/9/2012<br>George E. Tiller - updated : 2/17/2006<br>George E. Tiller - updated : 9/24/2003<br>George E. Tiller - updated : 2/25/2003<br>Patricia A. Hartz - updated : 8/21/2002<br>Ada Hamosh - updated : 2/3/2000<br>Victor A. McKusick - updated : 5/8/1997
|
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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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<a id="creationDate" class="mim-anchor"></a>
|
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
|
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</span>
|
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
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Victor A. McKusick : 2/6/1995
|
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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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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
|
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
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carol : 03/05/2021
|
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</span>
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</div>
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
|
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
alopez : 12/30/2020<br>alopez : 12/30/2020<br>carol : 12/09/2016<br>ckniffin : 12/08/2016<br>carol : 06/24/2015<br>joanna : 6/19/2015<br>alopez : 12/4/2013<br>carol : 10/29/2013<br>alopez : 8/2/2012<br>terry : 7/24/2012<br>carol : 6/5/2012<br>alopez : 4/11/2012<br>alopez : 4/11/2012<br>terry : 4/10/2012<br>ckniffin : 4/9/2012<br>wwang : 3/9/2006<br>terry : 2/17/2006<br>cwells : 9/24/2003<br>cwells : 2/25/2003<br>mgross : 8/21/2002<br>alopez : 2/9/2000<br>terry : 2/3/2000<br>carol : 8/10/1998<br>mark : 5/8/1997<br>terry : 5/6/1997<br>mark : 5/16/1995<br>carol : 2/6/1995
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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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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
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<strong>*</strong> 600375
|
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</span>
|
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</h3>
|
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</div>
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<div>
|
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<h3>
|
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<span class="mim-font">
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|
|
X-RAY REPAIR CROSS COMPLEMENTING 2; XRCC2
|
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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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<div >
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
X-RAY REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 2
|
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</span>
|
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: XRCC2</em></strong>
|
|
</span>
|
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</p>
|
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 7q36.1
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 7:152,644,776-152,676,141 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
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</p>
|
|
</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
7q36.1
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Fanconi anemia, complementation group U
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
617247
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
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|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
?Premature ovarian failure 17
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
619146
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spermatogenic failure 50
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
619145
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The XRCC2 gene is a member of the RAD51 gene family (see, e.g., 179617), which encode proteins involved in homologous recombination repair of DNA damage (summary by Tambini et al., 1997). The XRCC2 gene acts late in the Fanconi anemia (FA)-BRCA (see, e.g., BRCA1; 113705) pathway of DNA repair (summary by Park et al., 2016). </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>Thacker et al. (1995) fused the V79 hamster cell line irs1, which is a repair-deficient mutant that shows hypersensitivity to a number of different DNA-damaging agents (Jones et al., 1987), to normal human cells, resulting in complementation of the defect. The resultant hybrids were analyzed by Alu-PCR, chromosome painting, and DNA markers to map the complementing gene, designated XRCC2, to a specific chromosome region. The hybrid cells showed correction of sensitivity to both x-rays and mitomycin C and contained human chromosome 7, often as their only human component. Hybrids showing unstable retention of human chromosomes were subcloned to show that loss of chromosome 7 and loss of resistance to mitomycin C occurred concordantly. Two separate hybrids were found to have a smaller piece of chromosome 7, and specific DNA probes and microsatellite markers defined this as a contiguous region at 7q35-q36. Hybrid irradiation-fusion methods were used to reduce further the size of the complementing genomic region and to localize the gene to an approximately 3- to 5-Mb region at 7q36.1. </p><p>Jones et al. (1995) mapped the XRCC2 gene to 7q36 by studying complementation of the defect in the irs1 hamster cell line described by Jones et al. (1987). Jones et al. (1995) formed somatic cell hybrids by fusing irs1 cells with human lymphocytes and selecting for complementation in medium containing concentrations of mitomycin C that are toxic to irs1 cells but not their human fusion partners. Retention of chromosome 7 or of the region 7q36 resulted in cells that were resistant to mitomycin C. </p><p>Tambini et al. (1997) took the radiation reduction of human/hamster hybrids further to locate the XRCC2 gene to a small genomic region defined by a single microsatellite marker D7S483. Yeast artificial chromosomes (YACs) carrying that marker were then fused to the irs1 hamster cell line and a YAC that carried the complementing gene was identified. This YAC was used for direct cDNA selection experiments to identify the XRCC2 gene. The gene was found to share homology with the yeast RAD51 gene and its human homolog (179617), which are involved in the recombinational repair of DNA damage. Strong support for the candidacy of this gene as XRCC2 was obtained from its refined map position and by the full complementation of irs1 sensitivity with a 40-kb cosmid carrying the gene. Tambini et al. (1997) noted that, although the XRCC2 candidate gene on chromosome 7 showed homology to yeast RAD51, it must be distinct from the human RAD51 homolog, which is located on chromosome 15. </p>
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<h4>
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<strong>Mapping</strong>
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<p>Thacker et al. (1995) and Jones et al. (1995) mapped the XRCC2 gene to chromosome 7q36.1. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<p>Johnson et al. (1999) demonstrated that XRCC2 is essential for the efficient repair of DNA double-strand breaks by homologous recombination between sister chromatids. Hamster cells deficient in XRCC2 showed a more than 100-fold decrease in homologous recombination induced by double-strand breaks compared with the parental cell line. This defect was corrected to almost wildtype levels by transient transfection with a plasmid expressing XRCC2. The repair defect in XRCC2 mutant cells appeared to be restricted to recombinational repair because nonhomologous end joining was normal. Johnson et al. (1999) concluded that XRCC2 is involved in the repair of DNA double-strand breaks by homologous recombination. </p><p>Using a yeast 2-hybrid assay, Braybrooke et al. (2000) identified a direct interaction between XRCC2 and RAD51L3 (602954), and they confirmed the interaction by pull-down assays between recombinant XRCC2 and endogenous RAD51L3 in HeLa cell extracts. Size-exclusion chromatography followed by Western blot analysis suggested that the 2 proteins exist as a heterodimer of about 70 kD. </p><p>Masson et al. (2001) found that antibody directed against RAD51L3 immunoprecipitated a complex from HeLa cell lysates that included XRCC2, RAD51B (RAD51L1; 602948), and RAD51C (602774), along with RAD51L3. Interactions between these proteins were confirmed in pull-down assays using recombinant proteins expressed in sf9 insect cells. Gel filtration of the complexes indicated an apparent molecular mass of about 180 kD, suggesting a 1:1:1:1 stoichiometry of the 4 subunits. Binding assays, confirmed by electron microscopy, indicated that the purified complex bound single-stranded or nicked DNA. This binding was dependent on Mg(2+) but independent of ATP. The DNA-stimulated ATPase activity of the complex was extremely low. Masson et al. (2001) also identified a second, heterodimeric protein complex between RAD51C and XRCC3 (600675). Using coprecipitation and multiple pull-down assays, Liu et al. (2002) confirmed interaction between the same RAD51 paralogs in the same 2 distinct protein complexes. </p><p>In a yeast 2-hybrid screen of a human brain cDNA library using XRCC2 as bait, Kurumizaka et al. (2002) also found that RAD51L3 interacts directly with XRCC2. Using a D-loop formation assay, they found that RAD51L3 and XRCC2, coexpressed and purified from bacterial cultures, catalyze homologous pairing between a single-stranded oligonucleotide and a superhelical double-stranded DNA. Significant single- and double-stranded DNA were bound by the complex in the absence of ATP, but homologous pairing was dependent on ATP and Mg(2+). By electron microscopy, they found that RAD51L3 and XRCC2 form a multimeric ring structure in the absence of DNA, and they form filamentous structures in the presence of single-stranded DNA. </p><p>Adelman et al. (2013) reported that Helq (606769) helicase-deficient mice exhibit subfertility, germ cell attrition, interstrand crosslink (ICL) sensitivity, and tumor predisposition, with Helq heterozygous mice exhibiting a similar, albeit less severe, phenotype than the null, indicative of haploinsufficiency. Adelman et al. (2013) established that HELQ interacts directly with the RAD51 paralog complex BCDX2 (RAD51B, RAD51C, RAD51D, and XRCC2) and functions in parallel to the Fanconi anemia pathway to promote efficient homologous recombination at damaged replication forks. Adelman et al. (2013) concluded that their results revealed a critical role for HELQ in replication-coupled DNA repair, germ cell maintenance, and tumor suppression in mammals. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Fanconi Anemia, Complementation Group U</em></strong></p><p>
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In a boy, born of consanguineous Saudi Arabian parents, with an atypical form of Fanconi anemia, complementation group U (FANCU; 617247), Shamseldin et al. (2012) identified a homozygous truncating mutation in the XRCC2 gene (R215X; 600375.0001). The mutation was found by whole-exome sequencing followed by autozygome filtering. Chromosome testing in patient fibroblasts showed a marked increase in the frequency of dsDNA breaks in response to damage, indicating a defect in homologous recombination repair. Complementation studies were not performed. Shamseldin et al. (2012) noted the phenotypic similarities to Xrcc2-null mice (Deans et al., 2000). Park et al. (2016) found that expression of wildtype XRCC2 in cells derived from the patient reported by Shamseldin et al. (2012) corrected all 3 abnormal cellular phenotypes that were apparent in patient cells: cellular sensitivity to DNA interstrand crosslinking agents, chromosome instability, and accumulation of cells at the G2/M stage of the cell cycle. Patient cells showed normal levels of monoubiquitinated FANCD2 (613984), a central step in the FA pathway, and decreased assembly of RAD51 (179617) foci, suggesting that XRCC2 acts downstream of this event. Patient cells showed defective assembly of the components of the BCDX2 complex, particularly RAD51C (602774). Patient cells also showed increased sensitivity to ionizing radiation, consistent with a defect in proteins that act downstream in the FA pathway. </p><p><strong><em>Spermatogenic Failure 50 and Premature Ovarian Failure 17</em></strong></p><p>
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In a consanguineous Chinese family in which 2 infertile brothers had azoospermia due to meiotic arrest (SPGF50; 619145), Yang et al. (2018) identified homozygosity for a missense mutation in the XRCC2 gene (L14P; 600375.0002) that segregated with disease. The authors noted that there was no evidence of cancer in the family, and that examination of the affected brothers by a neurologist, hematologist, and orthopedist did not detect any additional signs of disease. </p><p>In a Chinese woman with premature ovarian failure (POF17; 619146) and her brother, who was infertile due to azoospermia, Zhang et al. (2019) identified homozygosity for the L14P mutation in XRCC2. Their first-cousin parent were heterozygous for the mutation. </p><p><strong><em>Role In Malignancy</em></strong></p><p>
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Kuschel et al. (2002) performed genetic association studies in a population-based breast cancer case-control study analyzing polymorphisms in 7 genes involved in DNA repair. The association of a rare variant in XRCC2 (R188H) was marginally significant. In a comparable English cohort, Rafii et al. (2002) found that carriage of R188H was associated with breast cancer overall, and this association was enhanced when younger-onset cases with a positive family history were compared with older controls with no family history. Using site-directed mutagenesis of XRCC2, Rafii et al. (2002) further showed that nonconservative substitution or deletion of amino acid 188 of XRCC2 could significantly affect cellular sensitivity to DNA damage. The authors hypothesized that subtle variation in DNA repair capacity may influence cancer susceptibility in the population. </p><p>Loss of mismatch repair (MMR) leads to a complex mutator phenotype that appears to drive the development of a subset of colon cancers (see Peltomaki, 2001). Mohindra et al. (2002) showed that MMR-defective tumor cell lines were defective in homologous recombination repair (HRR) induced by DNA double-strand breaks (DSBs). A frameshift mutation (342delT) in XRCC2 found in the MMR-deficient uterine tumor cell line, SKUT-1, conferred thymidine sensitivity when introduced into an MMR-proficient line. Like other cells with defective XRCC2, SKUT-1 cells were sensitive to mitomycin C, and MMR-proficient cells expressing the mutant XRCC2 allele also became more sensitive to this agent. The authors suggested that the thymidine sensitivity of MMR-deficient tumor cell lines may be a consequence of defects in the homologous recombination repair pathway. Mohindra et al. (2004) introduced 342delT into HRR-proficient cells containing a recombination reporter substrate. In 1 set of transfectants, expression of 342delT conferred sensitivity to thymidine and mitomycin C and suppressed HRR induced at the recombination reporter by thymidine, but not by DSBs. In a second set of transfectants, expression of 342delT was accompanied by a decreased level of full-length XRCC2, and these cells were defective in induction of HRR by either thymidine or DSBs. Mohindra et al. (2004) concluded that 342delT suppresses recombination induced by thymidine in a dominant-negative manner, while recombination induced by DSBs appears to depend upon the level of XRCC2, as well as expression of the mutant XRCC2 allele. The authors suggested that HRR pathways responding to stalled replication forks or DSBs are genetically distinguishable and that XRCC2 has a critical role in HRR at replication forks, possibly in the loading of RAD51 onto gapped DNA. </p><p>Park et al. (2012) performed an exome-sequencing study of families with multiple breast cancer-affected individuals and identified 2 families with mutations, 1 with a protein-truncating mutation and 1 with a probable deleterious missense mutation in the XRCC2 gene. Park et al. (2012) then performed a population-based case-control mutation screening study that identified 6 probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p less than 0.02). They then performed additional mutation screening in 689 multiple-case families and identified 10 breast cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Deans et al. (2000) found that most homozygous Xrcc2-null mice die midgestation. The few mice that survived to later stages showed developmental abnormalities and died at birth. Neonatal lethality, apparently due to respiratory failure, was associated with a high frequency of apoptotic death of postmitotic neurons in the developing brain, leading to abnormal cortical structure. Embryonic cells showed genetic instability, revealed by a high level of chromosomal aberrations, and were sensitive to gamma-rays. The findings demonstrated that homologous recombination has an important role in endogenous damage repair in the developing embryo. </p><p>Yang et al. (2018) generated mice homozygous for an L14P mutation (600375.0002) in the Xrcc2 gene. The homozygous males were infertile and had smaller testes than wildtype mice. Histologic examination of the infertile males' testes showed that nearly all of the seminiferous tubules were depleted, with no mature sperm present in any of the tubules after 7 days postpartum (dpp), consistent with complete meiotic arrest. The tubules contained multiple layers of spermatocytes arrested at the zygotene and pachytene states of meiotic prophase I. In addition, half of female homozygotes were infertile, and the other half had significantly reduced litter sizes. Infertile females had bilateral small, atrophic, and fibrotic ovaries without identifiable follicles, whereas homozygotes with reduced fertility had unilateral atrophic ovaries. Analysis of L14P homozygous ovaries from 7 dpp to 180 dpp showed gradual reduction in the percentage of ovaries with follicles, from 100% to 20%, consistent with premature ovarian failure. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>2 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 FANCONI ANEMIA, COMPLEMENTATION GROUP U (1 patient)</strong>
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</span>
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</h4>
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<div>
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<span class="mim-text-font">
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XRCC2, ARG215TER
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<br />
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SNP: rs143153871,
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gnomAD: rs143153871,
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ClinVar: RCV000022966, RCV000210083, RCV000236424, RCV001261591
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a 2.5-year-old boy, born of consanguineous Saudi Arabian parents, with an atypical form of Fanconi anemia, complementation group U (FANCU; 617247), Shamseldin et al. (2012) identified a homozygous c.643C-T transition (c.643C-T, NM_005431) in the XRCC2 gene, resulting in an arg215-to-ter (R215X) substitution predicted to remove the C terminus and abolish XRCC2 activity. The mutation was found by whole-exome sequencing followed by autozygome filtering. Chromosome testing in patient fibroblasts showed a marked increase in the frequency of dsDNA breaks in response to damage, indicating a defect in homologous recombination repair. Complementation studies were not performed. Shamseldin et al. (2012) noted the phenotypic similarities to Xrcc2-null mice (Deans et al., 2000). </p><p>Park et al. (2016) performed detailed studies on cells derived from the patient reported by Shamseldin et al. (2012). The mutant protein was not found by Western blot analysis, indicating that it is unstable, but likely not subject to nonsense-mediated mRNA decay since the mutation occurs in the last exon. Expression of wildtype XRCC2 corrected all 3 abnormal cellular phenotypes that were apparent in patient cells: cellular sensitivity to DNA interstrand crosslinking agents, chromosome instability, and accumulation of cells at the G2/M stage of the cell cycle. Patient cells showed normal levels of monoubiquitinated FANCD2 (613984), a central step in the FA pathway, and decreased assembly of RAD51 (179617) foci, suggesting that XRCC2 acts downstream of this event. Patient cells showed defective assembly of the components of the BCDX2 complex, particularly RAD51C (602774). Patient cells also showed increased sensitivity to ionizing radiation, consistent with a defect in proteins that act downstream in the FA pathway. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 SPERMATOGENIC FAILURE 50</strong>
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</span>
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</h4>
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<div>
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<span class="mim-text-font">
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PREMATURE OVARIAN FAILURE 17, INCLUDED (1 patient)
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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XRCC2, LEU14PRO
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<br />
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SNP: rs757140620,
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gnomAD: rs757140620,
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ClinVar: RCV001280534, RCV001280535, RCV002327617, RCV003738037
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</span>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Spermatogenic Failure 50</em></strong></p><p>
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In 2 infertile brothers from a consanguineous Chinese family with azoospermia due to meiotic arrest (SPGF50; 619145), Yang et al. (2018) identified homozygosity for a c.41T-C transition (c.41T-C, NM_005431) in the XRCC2 gene, resulting in a leu14-to-pro (L14P) substitution at a highly conserved residue near the splicing site of exon 2. The mutation segregated fully with disease in the family. Immunohistochemical analysis of seminiferous tubules from 1 of the affected brothers showed that XRCC2 protein was present, and RNA and protein assay on peripheral blood lymphocytes from the brothers confirmed the presence of the full XRCC2 transcript and the full XRCC2 protein. Quantification of chromosomal breaks induced by 2 chromosomal crosslinking agents, MMC or DPP, showed a similar frequency of chromosomal breaks in patient cells compared to control cells. </p><p><strong><em>Premature Ovarian Failure 17</em></strong></p><p>
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In a Chinese woman with premature ovarian failure (POF17; 619146) and her infertile brother, who had azoospermia due to meiotic arrest, Zhang et al. (2019) identified homozygosity for the L14P mutation in XRCC2. Their first-cousin parent were heterozygous for the mutation. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Adelman, C. A., Lolo, R. L., Birkbak, N. J., Murina, O., Matsuzaki, K., Horejsi, Z., Parmar, K., Borel, V., Skehel, J. M., Stamp, G., D'Andrea, A., Sartori, A. A., Swanton, C., Boulton, S. J.
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<strong>HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis.</strong>
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Nature 502: 381-384, 2013.
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[PubMed: 24005329]
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[Full Text: https://doi.org/10.1038/nature12565]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Braybrooke, J. P., Spink, K. G., Thacker, J., Hickson, I. D.
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<strong>The RAD51 family member, RAD51L3, is a DNA-stimulated ATPase that forms a complex with XRCC2.</strong>
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J. Biol. Chem. 275: 29100-29106, 2000.
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[PubMed: 10871607]
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[Full Text: https://doi.org/10.1074/jbc.M002075200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Deans, B., Griffin, C. S., Maconochie, M., Thacker, J.
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<strong>Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice.</strong>
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EMBO J. 19: 6675-6685, 2000.
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[PubMed: 11118202]
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[Full Text: https://doi.org/10.1093/emboj/19.24.6675]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Johnson, R. D., Liu, N., Jasin, M.
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<strong>Mammalian XRCC2 promotes the repair of DNA double-strand breaks by homologous recombination.</strong>
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Nature 401: 397-399, 1999.
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[PubMed: 10517641]
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[Full Text: https://doi.org/10.1038/43932]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Jones, N. J., Cox, R., Thacker, J.
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<strong>Isolation and cross-sensitivity of x-ray-sensitive mutants of V79-4 hamster cells.</strong>
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Mutat. Res. 183: 279-286, 1987.
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[PubMed: 3106801]
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[Full Text: https://doi.org/10.1016/0167-8817(87)90011-3]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Jones, N. J., Zhao, Y., Siciliano, M. J., Thompson, L. H.
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<strong>Assignment of the XRCC2 human DNA repair gene to chromosome 7q36 by complementation analysis.</strong>
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Genomics 26: 619-622, 1995.
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[PubMed: 7607692]
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<strong>Deficient DNA mismatch repair: a common etiologic factor for colon cancer.</strong>
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