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Entry
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- *600678 - MutS HOMOLOG 6; MSH6
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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">*600678</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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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="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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 role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600678">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>
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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=ENSG00000116062;t=ENST00000234420" 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=2956" 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=600678" 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=ENSG00000116062;t=ENST00000234420" 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_000179,NM_001281492,NM_001281493,NM_001281494,NM_001406795,NM_001406796,NM_001406797,NM_001406798,NM_001406799,NM_001406800,NM_001406801,NM_001406802,NM_001406803,NM_001406804,NM_001406805,NM_001406806,NM_001406807,NM_001406808,NM_001406809,NM_001406811,NM_001406812,NM_001406813,NM_001406814,NM_001406815,NM_001406816,NM_001406817,NM_001406818,NM_001406819,NM_001406820,NM_001406821,NM_001406822,NM_001406823,NM_001406824,NM_001406825,NM_001406826,NM_001406827,NM_001406828,NM_001406829,NM_001406830,NM_001406831,NM_001406832,NM_001407362,NR_176256,NR_176257,NR_176258,NR_176259,NR_176261" 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_000179" 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=600678" 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=07202&isoform_id=07202_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/MSH6" 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/1294813,1840467,2662381,2696085,2696086,4504191,6063479,13279008,13383965,19548099,34481396,68067672,74356430,119620613,119620614,194375916,194388224,528078296,528078300,528078302,2164862771,2164862773,2241236865,2241236870,2241236880,2241236892,2241236904,2241236914,2241236922,2241236939,2241236941,2241236945,2241236960,2241236964,2241236980,2241236982,2241236985,2241236987,2241236993,2241237019,2241237030,2241237035,2241237037,2241237039,2241237047,2241237051,2241237058,2245367892,2245367910,2245367931,2245367937,2245367951,2245367991,2245367993,2245367998,2245368003,2245368020,2245789801,2247445934,2250210845,2436992061,2577097970,2703623496,2703623498" 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/P52701" 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=2956" 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=ENSG00000116062;t=ENST00000234420" 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=MSH6" 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=MSH6" 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+2956" 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/MSH6" 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:2956" 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/2956" 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=chr2&hgg_gene=ENST00000234420.11&hgg_start=47783145&hgg_end=47810101&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:7329" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:7329" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/msh6" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600678[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=600678[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/MSH6/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000116062" 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=MSH6" 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=MSH6" 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=MSH6" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://databases.lovd.nl/genomed/home.php?select_db=MSH6" title="Zhejiang University-Adinovo Center MSH6 Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Zhejiang University-Adinov…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/MSH6" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">MSH6 database at LOVD</a></div><div style="margin-left: 0.5em;"><a href="http://www.insight-group.org/" title="Hereditary Non-Polyposis Colorectal Cancer, HNPCC" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Hereditary Non-Polyposis C…</a></div><div style="margin-left: 0.5em;"><a href="http://www.med.mun.ca/mmrvariants/" title="Mismatch Repair Genes Variant Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Mismatch Repair Genes Vari…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MSH6&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/PA184" 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:7329" 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/FBgn0036486.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:1343961" 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/MSH6#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:1343961" 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/2956/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://omia.org/OMIA002160/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2956" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00003422;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-020905-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2956" 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=MSH6&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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600678
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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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MutS HOMOLOG 6; MSH6
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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MutS, E. COLI, HOMOLOG OF, 6<br />
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G/T MISMATCH-BINDING PROTEIN; GTBP
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MSH6" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MSH6</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/2/245?start=-3&limit=10&highlight=245">2p16.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:47783145-47810101&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'})">2:47,783,145-47,810,101</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=608089,614350,619097" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
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View Clinical Synopses
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</a>
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</span>
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Inheritance
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<span class="mim-font">
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<a href="/geneMap/2/245?start=-3&limit=10&highlight=245">
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2p16.3
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{Endometrial cancer, familial}
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<span class="mim-font">
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<a href="/entry/608089"> 608089 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Lynch syndrome 5
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<span class="mim-font">
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<a href="/entry/614350"> 614350 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Mismatch repair cancer syndrome 3
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<span class="mim-font">
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<a href="/entry/619097"> 619097 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/600678" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/600678" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p><a href="#7" class="mim-tip-reference" title="Drummond, J. T., Li, G.-M., Longley, M. J., Modrich, P. <strong>Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells.</strong> Science 268: 1909-1912, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604264</a>] [<a href="https://doi.org/10.1126/science.7604264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7604264">Drummond et al. (1995)</a> and <a href="#22" class="mim-tip-reference" title="Palombo, F., Gallinari, P., Iaccarino, I., Lettieri, T., Hughes, M., D'Arrigo, A., Truong, O., Hsuan, J. J., Jiricny, J. <strong>GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells.</strong> Science 268: 1912-1914, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604265</a>] [<a href="https://doi.org/10.1126/science.7604265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7604265">Palombo et al. (1995)</a> showed that the mismatch-binding factor is a heterodimer of the 100-kD MSH2 (<a href="/entry/609309">609309</a>) and a 160-kD polypeptide called GTBP (for G/T binding protein). Sequence analysis identified GTBP as a new member of the MutS homolog family. Both proteins are required for mismatch-specific binding, a result consistent with the finding that tumor-derived cell lines devoid of either protein are also devoid of mismatch-binding activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7604264+7604265" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Nicolaides, N. C., Palombo, F., Kinzler, K. W., Vogelstein, B., Jiricny, J. <strong>Molecular cloning of the N-terminus of GTBP.</strong> Genomics 31: 395-397, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8838326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8838326</a>] [<a href="https://doi.org/10.1006/geno.1996.0067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8838326">Nicolaides et al. (1996)</a> described the 5-prime end of the GTBP gene, thus allowing definition of the entire coding region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8838326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>All homologs of the MutS proteins contain a highly conserved region of approximately 150 amino acids that encompasses a helix-turn-helix domain associated with an adenine nucleotide and magnesium binding motif, termed Walker-A motif. This part of the molecule has ATPase activity. <a href="#10" class="mim-tip-reference" title="Gradia, S., Acharya, S., Fishel, R. <strong>The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch.</strong> Cell 91: 995-1005, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9428522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9428522</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80490-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9428522">Gradia et al. (1997)</a> found that this ATPase activity and the associated adenine nucleotide-binding domain functions to regulate mismatch binding as a molecular switch. The MSH2-MSH6 complex is 'on' (binds mismatched nucleotides) in the ADP-bound form and 'off' in the ATP-bound form. Hydrolysis of ATP results in the recovery of mismatch binding, while ADP-to-ATP exchange results in mismatch dissociation. These results suggested to <a href="#10" class="mim-tip-reference" title="Gradia, S., Acharya, S., Fishel, R. <strong>The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch.</strong> Cell 91: 995-1005, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9428522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9428522</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80490-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9428522">Gradia et al. (1997)</a> a new model for the function of MutS proteins during mismatch repair in which the switch determines the timing of downstream events. <a href="#11" class="mim-tip-reference" title="Gradia, S., Subramanian, D., Wilson, T., Acharya, S., Makhov, A., Griffith, J., Fishel, R. <strong>hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA.</strong> Molec. Cell 3: 255-261, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10078208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10078208</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80316-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10078208">Gradia et al. (1999)</a> showed that ATP-induced release of MSH2-MSH6 from mismatched DNA is prevented if the ends are blocked or if the DNA is circular. The authors demonstrated that mismatched DNA provokes ADP-to-ATP exchange, resulting in a conformational transition that converts MSH2-MSH6 into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. These results suggested to <a href="#11" class="mim-tip-reference" title="Gradia, S., Subramanian, D., Wilson, T., Acharya, S., Makhov, A., Griffith, J., Fishel, R. <strong>hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA.</strong> Molec. Cell 3: 255-261, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10078208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10078208</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80316-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10078208">Gradia et al. (1999)</a> a model for bidirectional mismatch repair in which stochastic loading of multiple ATP-bound MSH2-MSH6 sliding clamps onto mismatch-containing DNA leads to activation of the repair machinery and/or other signaling effectors similar to G protein switches. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9428522+10078208" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., Qin, J. <strong>BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.</strong> Genes Dev. 14: 927-939, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10783165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10783165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10783165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10783165">Wang et al. (2000)</a> used immunoprecipitation and mass spectrometry analyses to identify BRCA1 (<a href="/entry/113705">113705</a>)-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (<a href="/entry/607585">607585</a>), BLM (<a href="/entry/604610">604610</a>), MSH2, MSH6, MLH1, the RAD50 (<a href="/entry/604040">604040</a>)-MRE11 (<a href="/entry/600814">600814</a>)-NBS1 (<a href="/entry/602667">602667</a>) complex, and the RFC1 (<a href="/entry/102579">102579</a>)-RFC2 (<a href="/entry/600404">600404</a>)-RFC4 (<a href="/entry/102577">102577</a>) complex. <a href="#30" class="mim-tip-reference" title="Wang, Y., Cortez, D., Yazdi, P., Neff, N., Elledge, S. J., Qin, J. <strong>BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.</strong> Genes Dev. 14: 927-939, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10783165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10783165</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10783165[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>]" pmid="10783165">Wang et al. (2000)</a> suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10783165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Hombauer, H., Srivatsan, A., Putnam, C. D., Kolodner, R. D. <strong>Mismatch repair, but not heteroduplex rejection, is temporally coupled to DNA replication.</strong> Science 334: 1713-1716, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22194578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22194578</a>] [<a href="https://doi.org/10.1126/science.1210770" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22194578">Hombauer et al. (2011)</a> fused S. cerevisiae Msh6 with cyclins to restrict the availability of the Msh2-Msh6 mismatch recognition complex to either S phase or G2/M phase of the cell cycle. The Msh6-S cyclin fusion was proficient for suppressing mutations at 3 loci that replicate at mid-S phase, whereas the Msh6-G2/M cyclin fusion was defective. However, the Msh6-G2/M cyclin fusion was functional for mismatch repair at a very late-replicating region of the genome. In contrast, the heteroduplex rejection function of mismatch repair during recombination was partially functional during both S phase and G2/M phase. <a href="#14" class="mim-tip-reference" title="Hombauer, H., Srivatsan, A., Putnam, C. D., Kolodner, R. D. <strong>Mismatch repair, but not heteroduplex rejection, is temporally coupled to DNA replication.</strong> Science 334: 1713-1716, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22194578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22194578</a>] [<a href="https://doi.org/10.1126/science.1210770" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22194578">Hombauer et al. (2011)</a> concluded that their results indicate a temporal coupling of mismatch repair, but not heteroduplex rejection, to DNA replication. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22194578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Mapping</strong>
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<p><a href="#23" class="mim-tip-reference" title="Papadopoulos, N., Nicolaides, N. C., Liu, B., Parsons, R., Lengauer, C., Palombo, F., D'Arrigo, A., Markowitz, S., Willson, J. K. V., Kinzler, K. W., Jiricny, J., Vogelstein, B. <strong>Mutations of GTBP in genetically unstable cells.</strong> Science 268: 1915-1917, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604266</a>] [<a href="https://doi.org/10.1126/science.7604266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7604266">Papadopoulos et al. (1995)</a> localized the GTBP gene to 2p16 by PCR evaluation of a panel of somatic cell hybrids containing segments of chromosome 2. They found that GTBP resides in the same YAC as MSH2; on the basis of the size of this YAC, GTBP was inferred to reside within 1 Mb of MSH2. The localization was confirmed by fluorescence in situ hybridization. From the colocalization of fluorescent signals, the maximum distance separating GTBP and MSH2 was estimated at 0.5 Mb. Thus, MSH2 and GTBP may have been produced by duplication of a primordial mutS repair gene. Adjacency of duplicated genes is not uncommon in the mammalian genome. Although MSH2 and GTBP exist in the cell as a heterodimer, the functions of these 2 proteins seem distinguishable. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7604266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Lynch Syndrome 5</em></strong></p><p>
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<a href="#23" class="mim-tip-reference" title="Papadopoulos, N., Nicolaides, N. C., Liu, B., Parsons, R., Lengauer, C., Palombo, F., D'Arrigo, A., Markowitz, S., Willson, J. K. V., Kinzler, K. W., Jiricny, J., Vogelstein, B. <strong>Mutations of GTBP in genetically unstable cells.</strong> Science 268: 1915-1917, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604266</a>] [<a href="https://doi.org/10.1126/science.7604266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7604266">Papadopoulos et al. (1995)</a> stated that whereas germline mutations of MSH2 account for about 50% of all cases of hereditary nonpolyposis colon cancer (Lynch syndrome; see <a href="/entry/120435">120435</a>), germline GTBP mutations in HNPCC, if they occur at all, are rare. They hypothesized that GTBP mutations may not cause sufficient genetic instability to result in predisposition to tumor formation. Alternatively, GTBP may participate in processes other than mismatch repair, and the haploinsufficiency that would be associated with its germline mutation might be incompatible with normal embryogenesis or development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7604266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Papadopoulos, N., Nicolaides, N. C., Liu, B., Parsons, R., Lengauer, C., Palombo, F., D'Arrigo, A., Markowitz, S., Willson, J. K. V., Kinzler, K. W., Jiricny, J., Vogelstein, B. <strong>Mutations of GTBP in genetically unstable cells.</strong> Science 268: 1915-1917, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604266</a>] [<a href="https://doi.org/10.1126/science.7604266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7604266">Papadopoulos et al. (1995)</a> found the GTBP gene to be inactivated in 3 hypermutable cell lines. Unlike cells defective in other mismatch repair genes, which display widespread alterations in mononucleotide, dinucleotide, and other simple repeated sequences, the GTBP-deficient cells showed alterations primarily in mononucleotide tracts. One of the cell lines found to carry a GTBP mutation was the HCT-15 colorectal tumor cell line, which is selectively defective in the repair of base-base and single-nucleotide insertion-deletion mismatches (<a href="#7" class="mim-tip-reference" title="Drummond, J. T., Li, G.-M., Longley, M. J., Modrich, P. <strong>Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells.</strong> Science 268: 1909-1912, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604264</a>] [<a href="https://doi.org/10.1126/science.7604264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7604264">Drummond et al., 1995</a>). Such defects had been shown to be corrected by GTBP by <a href="#7" class="mim-tip-reference" title="Drummond, J. T., Li, G.-M., Longley, M. J., Modrich, P. <strong>Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells.</strong> Science 268: 1909-1912, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604264</a>] [<a href="https://doi.org/10.1126/science.7604264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7604264">Drummond et al. (1995)</a>. <a href="#23" class="mim-tip-reference" title="Papadopoulos, N., Nicolaides, N. C., Liu, B., Parsons, R., Lengauer, C., Palombo, F., D'Arrigo, A., Markowitz, S., Willson, J. K. V., Kinzler, K. W., Jiricny, J., Vogelstein, B. <strong>Mutations of GTBP in genetically unstable cells.</strong> Science 268: 1915-1917, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604266</a>] [<a href="https://doi.org/10.1126/science.7604266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7604266">Papadopoulos et al. (1995)</a> observed what appeared to be truncation of both alleles due to frameshift mutations: they detected a 1-bp deletion at codon 222 which changed a leucine to a termination codon and a 5-bp deletion/substitution at codon 1103 that created a new termination codon 9-bp downstream. MT1, an alkylation-resistant lymphoblastoid cell line with a biochemical deficiency similar to that of HCT-15, was shown to have 2 mutations in GTBP: an A-to-T transversion at codon 1145, resulting in the substitution of valine for aspartic acid in the highly conserved domain of GTBP, and a G-to-A transition at codon 1192, resulting in the substitution of isoleucine for valine. Cloning of the RT-PCR products revealed that the 2 mutations were on separate alleles. Neither of these mutations were present in the mismatch repair-proficient and alkylation-sensitive cells from which the MT1 cells were derived. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7604266+7604264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Nicolaides, N. C., Palombo, F., Kinzler, K. W., Vogelstein, B., Jiricny, J. <strong>Molecular cloning of the N-terminus of GTBP.</strong> Genomics 31: 395-397, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8838326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8838326</a>] [<a href="https://doi.org/10.1006/geno.1996.0067" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8838326">Nicolaides et al. (1996)</a> identified several polymorphisms within the 5-prime end of the GTBP gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8838326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Risinger, J. I., Umar, A., Boyd, J., Berchuck, A., Kunkel, T. A., Barrett, J. C. <strong>Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair.</strong> Nature Genet. 14: 102-109, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782829</a>] [<a href="https://doi.org/10.1038/ng0996-102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782829">Risinger et al. (1996)</a> demonstrated a missense mutation in the MSH6 gene in an endometrial carcinoma cell line that also contained a mutation in the MSH3 gene (<a href="/entry/600887">600887</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="Miyaki, M., Konishi, M., Tanaka, K., Kikuchi-Yanoshita, R., Muraoka, M., Yasuno, M., Igari, T., Koike, M., Chiba, M., Mori, T. <strong>Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. (Letter)</strong> Nature Genet. 17: 271-272, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9354786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9354786</a>] [<a href="https://doi.org/10.1038/ng1197-271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9354786">Miyaki et al. (1997)</a> stated that the following germline mutations of DNA mismatch repair genes had been identified in HNPCC families: more than 50 in MSH2 (<a href="/entry/609309">609309</a>), nearly 60 in MLH1 (<a href="/entry/120436">120436</a>), 1 in PMS1 (<a href="/entry/600258">600258</a>), and 2 in PMS2 (<a href="/entry/600259">600259</a>). They had identified 8 germline mutations of MSH2 and MLH1 in Japanese HNPCC families, but mutation of these genes could not be found in 5 other HNPCC families. Even in cases of HNPCC in which germline mutations had not yet been identified, tumors showed a replication error, RER(+) phenotype, suggesting that these cases have germline mutations in other mismatch repair genes. They studied 5 Japanese HNPCC families in which germline mutations of MSH2 or MLH1 could not be detected and found that 1 had a germline mutation in GTBP (<a href="#0004">600678.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9354786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Wijnen, J., de Leeuw, W., Vasen, H., van der Klift, H., Moller, P., Stormorken, A., Meijers-Heijboer, H., Lindhout, D., Menko, F., Vossen, S., Moslein, G., Tops, C., Brocker-Vriends, A., Wu, Y., Hofstra, R., Sijmons, R., Cornelisse, C., Morreau, H., Fodde, R. <strong>Familial endometrial cancer in female carriers of MSH6 germline mutations. (Letter)</strong> Nature Genet. 23: 142-144, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508506</a>] [<a href="https://doi.org/10.1038/13773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508506">Wijnen et al. (1999)</a> found that 7 of 10 germline mutations in MSH6 had been identified in atypical HNPCC families not fulfilling the Amsterdam criteria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Germline mutations in mismatch repair (MMR) genes are rarely found in families with HNPCC or suspected HNPCC that do not show microsatellite instability (MSI), i.e., the MSI-low phenotype. Therefore, an MSI-high phenotype is often used as an inclusion criterion for mutation testing of MMR genes. Correction of base-base mismatches is a major function of MSH6. Since mismatches present with an MSI-low phenotype, <a href="#32" class="mim-tip-reference" title="Wu, Y., Berends, M. J. W., Mensink, R. G. J., Kempinga, C., Sijmons, R. H., van der Zee, A. G. J., Hollema, H., Kleibeuker, J. H., Buys, C. H. C. M., Hofstra, R. M. W. <strong>Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations.</strong> Am. J. Hum. Genet. 65: 1291-1298, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10521294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10521294</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10521294[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10521294">Wu et al. (1999)</a> assumed that the phenotype in patients with HNPCC-related tumors might be associated with MSH6 germline mutations. They detected presumably causative mutations in the MSH6 gene in 4 of 18 patients (22%) who had suspected HNPCC and MSI-low tumors. In a group of 18 patients who had suspected HNPCC and MSI-high tumors, 1 MSH6 missense mutation was found, but the same patient also had an MLH1 mutation, which may explain the MSI-high phenotype. The results suggested that MSH6 may be involved in a substantial proportion of patients with HNPCC or suspected HNPCC and MSI-low tumors. Furthermore, the data emphasized that an MSI-low phenotype cannot be considered an exclusion criterion for mutation testing of MMR genes in general. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10521294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Verma, L., Kane, M. F., Brassett, C., Schmeits, J., Evans, D. G. R., Kolodner, R. D., Maher, E. R. <strong>Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer.</strong> J. Med. Genet. 36: 678-682, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10507723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10507723</a>]" pmid="10507723">Verma et al. (1999)</a> identified a subset of individuals with early-onset (before age 50 years) colorectal cancer whose tumors showed microsatellite instability for mono- but not dinucleotide repeat markers. Six of 7 of these tumors were left-sided. Sequence analysis of DNA from the blood of 5 of the individuals with this subgroup of tumors identified a germline nonsense mutation in MSH6 in an isolated case of early-onset (43 years) colorectal cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10507723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Wagner, A., Hendriks, Y., Meijers-Heijboer, E. J., de Leeuw, W. J. F., Morreau, H., Hofstra, R., Tops, C., Bik, E., Brocker-Vriends, A. H. J. T., van der Meer, C., Lindhout, D., Vasen, H. F. A., Breuning, M. H., Cornelisse, C. J., van Krimpen, C., Niermeijer, M. F., Zwinderman, A. H., Wijnen, J., Fodde, R. <strong>Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree.</strong> J. Med. Genet. 38: 318-322, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11333868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11333868</a>] [<a href="https://doi.org/10.1136/jmg.38.5.318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11333868">Wagner et al. (2001)</a> reported a large Dutch family with atypical HNPCC not meeting Amsterdam criteria in which they found a frameshift mutation in MSH6 (<a href="#0005">600678.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11333868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Huang, J., Kuismanen, S. A., Liu, T., Chadwick, R. B., Johnson, C. K., Stevens, M. W., Richards, S. K., Meek, J. E., Gao, X., Wright, F. A., Mecklin, J.-P., Jarvinen, H. J., Gronberg, H., Bisgaard, M. L., Lindblom, A., Peltomaki, P. <strong>MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer.</strong> Cancer Res. 61: 1619-1623, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11245474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11245474</a>]" pmid="11245474">Huang et al. (2001)</a> screened for mutations in the MSH6 and MSH3 genes in 90 HNPCC families in which germline mutations of MSH2 and MLH1 had been excluded. Although MSH3 was not involved in any family, a large family that fulfilled Amsterdam I criteria and had late-onset HNPCC showed a novel germline mutation in MSH6 (3052_3053delCT; <a href="#0008">600678.0008</a>). <a href="#15" class="mim-tip-reference" title="Huang, J., Kuismanen, S. A., Liu, T., Chadwick, R. B., Johnson, C. K., Stevens, M. W., Richards, S. K., Meek, J. E., Gao, X., Wright, F. A., Mecklin, J.-P., Jarvinen, H. J., Gronberg, H., Bisgaard, M. L., Lindblom, A., Peltomaki, P. <strong>MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer.</strong> Cancer Res. 61: 1619-1623, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11245474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11245474</a>]" pmid="11245474">Huang et al. (2001)</a> also sequenced the entire MSH6 gene exon by exon in families with frameshift mutations in the (C)8 tract in tumors, previously suggested as a predictor of MSH6 germline mutations; no mutations were found. They concluded that MSH6 and MSH3 are rarely involved in genetic predisposition to HNPCC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11245474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Berends, M. J. W., Wu, Y., Sijmons, R. H., Mensink, R. G. J., van der Sluis, T., Hordijk-Hos, J. M., de Vries, E. G. E., Hollema, H., Karrenbeld, A., Buys, C. H. C. M., van der Zee, A. G. J., Hofstra, R. M. W., Kleibeuker, J. H. <strong>Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant.</strong> Am. J. Hum. Genet. 70: 26-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11709755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11709755</a>] [<a href="https://doi.org/10.1086/337944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11709755">Berends et al. (2002)</a> searched for MSH6 germline mutations in 316 individuals who were known or suspected to have HNPCC. They described the molecular and clinical features of 25 index patients and 8 relatives with MSH6 variants. Five truncating MSH6 mutations, one of which was found 7 times, were detected in 12 index patients, and 10 MSH6 variants with unknown pathogenicity were found in 13 index patients. Based on these and other findings, <a href="#3" class="mim-tip-reference" title="Berends, M. J. W., Wu, Y., Sijmons, R. H., Mensink, R. G. J., van der Sluis, T., Hordijk-Hos, J. M., de Vries, E. G. E., Hollema, H., Karrenbeld, A., Buys, C. H. C. M., van der Zee, A. G. J., Hofstra, R. M. W., Kleibeuker, J. H. <strong>Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant.</strong> Am. J. Hum. Genet. 70: 26-37, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11709755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11709755</a>] [<a href="https://doi.org/10.1086/337944" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11709755">Berends et al. (2002)</a> concluded that MSH6 mutation analysis should be considered in all patients suspected to have HNPCC. Neither microsatellite instability nor immunohistochemistry should be a definitive selection criterion for MSH6 mutation analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11709755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine whether and how MSH6 mutations cause susceptibility to HNPCC, <a href="#16" class="mim-tip-reference" title="Kariola, R., Raevaara, T. E., Lonnqvist, K. E., Nystrom-Lahti, M. <strong>Functional analysis of MSH6 mutations linked to kindreds with putative hereditary non-polyposis colorectal cancer syndrome.</strong> Hum. Molec. Genet. 11: 1303-1310, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12019211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12019211</a>] [<a href="https://doi.org/10.1093/hmg/11.11.1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12019211">Kariola et al. (2002)</a> studied heterodimerization of 4 MSH6 variants with MSH2 and the functionality of these MutS complexes in an in vitro MMR assay. All mutations occurred in putative HNPCC patients lacking known MSH2 or MLH1 mutations, and were not found among more than 185 healthy controls. Irrespective of the type or the site of the amino acid substitutions, all the variants repaired GT mismatches to AT comparable to wildtype MSH6 protein. However, the MSH6 protein carrying a mutation in the MSH2/MSH6 interaction region was poorly expressed, suggesting problems in its stability. The authors recommended caution in interpretation of mutation data in those putative HNPCC families that do not fulfill the Amsterdam criteria, and suggested that the pathogenicity of mutations in putative HNPCC families may be linked to other biochemical events. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12019211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Endometrial cancer is the most common gynecologic malignancy in the United States and the most frequent extracolonic tumor in hereditary nonpolyposis colorectal cancer. Sporadic endometrial cancers exhibit microsatellite instability (MSI), usually associated with methylation of the MLH1 promoter. Germline MSH6 mutations, which are rare in HNPCC, have been reported in several families with multiple members affected with endometrial carcinoma (see, e.g., <a href="#0005">600678.0005</a>). <a href="#9" class="mim-tip-reference" title="Goodfellow, P. J., Buttin, B. M., Herzog, T. J., Rader, J. S., Gibb, R. K., Swisher, E., Look, K., Walls, K. C., Fan, M.-Y., Mutch, D. G. <strong>Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers.</strong> Proc. Nat. Acad. Sci. 100: 5908-5913, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12732731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12732731</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12732731[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1030231100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12732731">Goodfellow et al. (2003)</a> reasoned that MSH6 mutation might account for loss of MMR in MSI-positive endometrial cancers in which the cause of MSI was unknown. They therefore investigated MSI and MLH1 promoter methylation in 441 endometrial cancer patients unselected for age or personal and family history of cancers. Evaluation for MSH6 defects was performed in 100 cases (23% of the entire series). Inactivating germline MSH6 mutations were identified in 7 women with MSI-positive, MLH1 promoter unmethylated cancers. Most of the MSI in these cases was seen with mononucleotide repeat markers. MSH6 mutation carriers were significantly younger than the rest of the population (mean age 54.8 vs 64.6, P = 0.04). Somatic mutations were seen in 17 tumors, all of which had MSI. The minimum estimate of the prevalence of inherited MSH6 mutation in endometrial cancer was placed at 1.6% (7 of 441), comparable with the predicted prevalence for patients with colorectal cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12732731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 substantial fraction of germline mutations in the mismatch repair genes MLH1 and MSH2 represent genomic rearrangements. See, for example, the Alu-mediated deletions of the former (<a href="/entry/120436#0004">120436.0004</a>) and the latter (<a href="/entry/609309#0017">609309.0017</a>). In 2 patients with HNPCC who developed tumors with loss of MSH6 expression, <a href="#24" class="mim-tip-reference" title="Plaschke, J., Ruschoff, J., Schackert, H. K. <strong>Genomic rearrangements of hMSH6 contribute to the genetic predisposition in suspected hereditary non-polyposis colorectal cancer syndrome.</strong> J. Med. Genet. 40: 597-600, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920072</a>] [<a href="https://doi.org/10.1136/jmg.40.8.597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920072">Plaschke et al. (2003)</a> identified an Alu-mediated deletion (<a href="#0010">600678.0010</a>) in 1 and a 4.9-kb duplication (<a href="#0011">600678.0011</a>) in the other. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Without preselection and regardless of family history, <a href="#2" class="mim-tip-reference" title="Barnetson, R. A., Tenesa, A., Farrington, S. M., Nicholl, I. D., Cetnarskyj, R., Porteous, M. E., Campbell, H., Dunlop, M. G. <strong>Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.</strong> New Eng. J. Med. 354: 2751-2763, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16807412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16807412</a>] [<a href="https://doi.org/10.1056/NEJMoa053493" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16807412">Barnetson et al. (2006)</a> recruited 870 patients under the age of 55 years soon after they received the diagnosis of colorectal cancer. They studied these patients for germline mutations in DNA mismatch-repair genes MLH1, MSH2, and MSH6 and developed a 2-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes. Stage 1 of the model incorporated only clinical variables; stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability. The model was validated in an independent population of patients. Furthermore, they analyzed 2,938 patient-years of follow-up to determine whether genotype influenced survival. Among the 870 participants, 38 mutations were found: 15 in MLH1, 16 in MSH2, and 7 in MSH6. Carrier frequencies in men (6%) and women (3%) differed significantly (P less than 0.04). Survival among carriers was not significantly different from that among noncarriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16807412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="#5" class="mim-tip-reference" title="Cyr, J. L., Heinen, C. D. <strong>Hereditary cancer-associated missense mutations in hMSH6 uncouple ATP hydrolysis from DNA mismatch binding.</strong> J. Biol. Chem. 283: 31641-31648, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18790734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18790734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18790734[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/10.1074/jbc.M806018200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18790734">Cyr and Heinen (2008)</a> showed that 5 HNPCC-associated MSH6 missense mutations, including the V878A mutation (<a href="#0006">600678.0006</a>), disrupted DNA mismatch-stimulated ATP hydrolysis activity, providing functional evidence that these mutations contribute to disease. The R976H and H1248D mutations affected mismatch recognition. The V878A, G566R, and D803G mutations uncoupled mismatch binding and ATP hydrolysis activities of the MSH2/MSH6 heterodimer and altered ATP-dependent conformation changes of the MSH2/MSH6 heterodimer. None of the mutations affected heterodimer formation with MSH2, and most showed normal binding to mismatched DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18790734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate the association of MMR genes with breast cancer, <a href="#26" class="mim-tip-reference" title="Roberts, M. E., Jackson, S. A., Susswein, L. R., Zeinomar, N., Ma, X., Marshall, M. L., Stettner, A. R., Milewski, B., Xu, Z., Solomon, B. D., Terry, M. B., Hruska, K. S., Klein, R. T., Chung, W. K. <strong>MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer.</strong> Genet. Med. 20: 1167-1174, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29345684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29345684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29345684[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/gim.2017.254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29345684">Roberts et al. (2018)</a> conducted a retrospective review of personal and family cancer history in 423 women with pathogenic or likely pathogenic germline variants in MMR genes identified via clinical multigene hereditary cancer testing: 65 in MLH1 (<a href="/entry/120436">120436</a>), 94 in MSH2 (<a href="/entry/609309">609309</a>), 140 in MSH6, and 124 in PMS2 (<a href="/entry/600259">600259</a>). Standard incidence ratios (SIRs) of breast cancer were calculated by comparing breast cancer frequencies in the study population with those in the general population. When evaluating by gene, the age-standardized breast cancer risks for MSH6 (SIR = 2.11; 95% CI, 1.56-2.86) and PMS2 (SIR = 2.92; 95% CI, 2.17-3.92) were associated with a statistically significant risk for breast cancer, whereas MLH1 and MSH2 were not. <a href="#26" class="mim-tip-reference" title="Roberts, M. E., Jackson, S. A., Susswein, L. R., Zeinomar, N., Ma, X., Marshall, M. L., Stettner, A. R., Milewski, B., Xu, Z., Solomon, B. D., Terry, M. B., Hruska, K. S., Klein, R. T., Chung, W. K. <strong>MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer.</strong> Genet. Med. 20: 1167-1174, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29345684/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29345684</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29345684[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/gim.2017.254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29345684">Roberts et al. (2018)</a> concluded that the MMR genes MSH6 and PMS2, mutations in which cause HNPCC5 and HNPCC4 (<a href="/entry/614334">614334</a>), respectively, should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29345684" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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>Mismatch Repair Cancer Syndrome 3</em></strong></p><p>
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In 2 sibs with mismatch repair cancer syndrome-3 (MMRCS3; <a href="/entry/619097">619097</a>), also known as brain tumor-polyposis syndrome-1 or Turcot syndrome, <a href="#21" class="mim-tip-reference" title="Ostergaard, J. R., Sunde, L., Okkels, H. <strong>Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6.</strong> Am. J. Med. Genet. 139A: 96-105, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16283678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16283678</a>] [<a href="https://doi.org/10.1002/ajmg.a.30998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16283678">Ostergaard et al. (2005)</a> identified compound heterozygosity for 2 mutations in the MSH6 gene (<a href="#0012">600678.0012</a>, <a href="#0013">600678.0013</a>). One sib developed an anaplastic astrocytoma at age 9.4 years and later developed a T-cell lymphoma. His sister had a glioblastoma of the spinal cord at age 2 years. Both children had multiple cafe-au-lait spots without other features of neurofibromatosis I (NF1; <a href="/entry/162200">162200</a>). Three additional heterozygous family members had colon and/or endometrial cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16283678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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 patients with childhood onset of colonic adenocarcinoma, lymphoma, and brain tumors, <a href="#17" class="mim-tip-reference" title="Menko, F. H., Kaspers, G. L., Meijer, G. A., Claes, K., van Hagen, J. M., Gille, J. J. P. <strong>A homozygous MSH6 mutation in a child with cafe-au-lait spots, oligodendroglioma and rectal cancer.</strong> Fam. Cancer 3: 123-127, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15340263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15340263</a>] [<a href="https://doi.org/10.1023/B:FAME.0000039893.19289.18" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15340263">Menko et al. (2004)</a> and <a href="#13" class="mim-tip-reference" title="Hegde, M. R., Chong, B., Blazo, M. E., Chin, L. H. E., Ward, P. A., Chintagumpala, M. M., Kim, J. Y., Plon, S. E., Richards, C. S. <strong>A homozygous mutation in MSH6 causes Turcot syndrome.</strong> Clin. Cancer Res. 11: 4689-4693, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16000562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16000562</a>] [<a href="https://doi.org/10.1158/1078-0432.CCR-04-2025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16000562">Hegde et al. (2005)</a> identified homozygous mutations in the MSH6 gene (<a href="#0014">600678.0014</a> and <a href="#0015">600678.0015</a>, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15340263+16000562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#8" class="mim-tip-reference" title="Edelmann, W., Yang, K., Umar, A., Heyer, J., Lau, K., Fan, K., Liedtke, W., Cohen, P. E., Kane, M. F., Lipford, J. R., Yu, N., Crouse, G. F., Pollard, J. W., Kunkel, T., Lipkin, M., Kolodner, R., Kucherlapati, R. <strong>Mutation in the mismatch repair gene Msh6 causes cancer susceptibility.</strong> Cell 91: 467-477, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9390556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9390556</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80433-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9390556">Edelmann et al. (1997)</a> used gene targeting to generate mice carrying a null mutation in the murine mismatch repair gene Msh6. The PGKneo expression cassette was inserted into the fourth exon of the gene. Cells that were homozygous for the mutation did not produce any detectable MSH6 protein, and extracts prepared from these cells were defective for repair of single nucleotide mismatches. Repair of 1-, 2-, and 4-nucleotide insertion/deletion mismatches was unaffected. Mice that were homozygous for the mutation had a reduced life span. The mice developed a spectrum of tumors, predominantly gastrointestinal tumors and B- and T-cell lymphomas. The tumors did not show any microsatellite instability. <a href="#8" class="mim-tip-reference" title="Edelmann, W., Yang, K., Umar, A., Heyer, J., Lau, K., Fan, K., Liedtke, W., Cohen, P. E., Kane, M. F., Lipford, J. R., Yu, N., Crouse, G. F., Pollard, J. W., Kunkel, T., Lipkin, M., Kolodner, R., Kucherlapati, R. <strong>Mutation in the mismatch repair gene Msh6 causes cancer susceptibility.</strong> Cell 91: 467-477, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9390556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9390556</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80433-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9390556">Edelmann et al. (1997)</a> concluded that MSH6 mutations, like those in some other members of the family of mismatch repair genes, lead to cancer susceptibility, and that germline mutations in this gene may be associated with a cancer predisposition syndrome that does not show microsatellite instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9390556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-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="de Wind, N., Dekker, M., Claij, N., Jansen, L., van Klink, Y., Radman, M., Riggins, G., van der Valk, M., van't Wout, K., te Riele, H. <strong>HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions.</strong> Nature Genet. 23: 359-362, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10545954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10545954</a>] [<a href="https://doi.org/10.1038/15544" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10545954">De Wind et al. (1999)</a> inactivated the mouse Msh3 and Msh6 genes by targeted disruption. Msh6-deficient mice were prone to cancer. Most animals developed lymphomas or epithelial tumors originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in a Msh6-deficient background, loss of Msh3 accelerated intestinal tumorigenesis. The frequency of lymphomas was not affected. Furthermore, mismatch-directed antirecombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of mismatch repair functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10545954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Oxidation of G in DNA yields 8-oxo-G (GO), a mutagenic lesion that leads to misincorporation of A opposite GO. In S. cerevisiae, <a href="#19" class="mim-tip-reference" title="Ni, T. T., Marsischky, G. T., Kolodner, R. D. <strong>MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S. cerevisiae.</strong> Molec. Cell 4: 439-444, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10518225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10518225</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80346-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10518225">Ni et al. (1999)</a> found that mutations in the MSH2 or MSH6 genes caused a synergistic increase in mutation rate when in combination with mutations in the OGG1 gene (<a href="/entry/601982">601982</a>), resulting in a 140- to 218-fold increase in the G:C-to-T:A transversion rate. Consistent with this, MSH2-MSH6 complex bound with high affinity and specificity to GO:A mispairs and GO:C basepairs. These data indicated that in S. cerevisiae, MSH2-MSH6-dependent mismatch repair is the major mechanism by which misincorporation of A opposite GO is corrected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10518225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009484" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009484" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009484</a>
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<p><a href="#23" class="mim-tip-reference" title="Papadopoulos, N., Nicolaides, N. C., Liu, B., Parsons, R., Lengauer, C., Palombo, F., D'Arrigo, A., Markowitz, S., Willson, J. K. V., Kinzler, K. W., Jiricny, J., Vogelstein, B. <strong>Mutations of GTBP in genetically unstable cells.</strong> Science 268: 1915-1917, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7604266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7604266</a>] [<a href="https://doi.org/10.1126/science.7604266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7604266">Papadopoulos et al. (1995)</a> found a 1-bp deletion mutation of the MSH6 gene in the HCT-15 colorectal cancer cell line (LYNCH5; <a href="/entry/614350">614350</a>) at codon 222, which changed a leucine to a termination codon. They also found a 5-bp deletion/substitution at codon 1103 (TTGATAGAGT to TTTGT), which created a new termination codon 9-bp downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7604266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs63751234 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63751234;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/rs63751234?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=rs63751234" 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=rs63751234" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#18" class="mim-tip-reference" title="Miyaki, M., Konishi, M., Tanaka, K., Kikuchi-Yanoshita, R., Muraoka, M., Yasuno, M., Igari, T., Koike, M., Chiba, M., Mori, T. <strong>Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. (Letter)</strong> Nature Genet. 17: 271-272, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9354786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9354786</a>] [<a href="https://doi.org/10.1038/ng1197-271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9354786">Miyaki et al. (1997)</a> demonstrated an MHS6 germline mutation in an HNPCC family (LYNCH5; <a href="/entry/614350">614350</a>) in which no mutation could be identified in the MSH2 (<a href="/entry/609309">609309</a>) or MLH1 (<a href="/entry/120436">120436</a>) genes. Carcinoma of the transverse colon in a 52-year-old member of the family showed alterations in 5 of 7 dinucleotide repeat loci and all 4 mononucleotide repeat loci analyzed. Mutations were also identified in TGFBR2 (<a href="/entry/190182">190182</a>), BAX (<a href="/entry/600040">600040</a>), and APC (<a href="/entry/611731">611731</a>), but did not exhibit loss of heterozygosity at 5q, 8p, 17p, and 18q, or mutations of the TP53 (<a href="/entry/191170">191170</a>) and KRAS2 (<a href="/entry/190070">190070</a>) genes. At age 53 this patient also had an endometrial carcinoma, which exhibited RER(+) at 3 of 4 dinucleotide repeats and 3 of 4 mononucleotide repeats. PCR-SSCP analysis of DNA from the colon and endometrial carcinoma and normal tissues detected a mutant band for MSH6. Direct sequencing of the mutant band revealed a C deletion at codon 534 of the MSH6 gene, predicting premature stop at codon 570 and truncation of the MSH6 protein. The same germline mutation was also detected in the patient's sister, who presented with endometrial carcinoma at the age of 53 years. Other sisters who had had endometrial or ovarian carcinoma were assumed to have the same germline mutation, as it was detected in their offspring. In addition to the germline mutation, somatic mutations of MSH6 were detected in carcinomas from the proband in this family, including a T deletion at codon 128 in the colon carcinoma and a C deletion at codon 1085 in the endometrial carcinoma, both of which led to stop codons. These somatic mutations were presumably in the alleles without the germline mutation, suggesting that inactivation of both alleles of MSH6 was the cause of the RER(+) phenotype and the stimulus for neoplasia. Although this family did not fulfill the Amsterdam criteria, patients in the family had colonic, endometrial, ovarian, and pancreatic carcinomas. <a href="#18" class="mim-tip-reference" title="Miyaki, M., Konishi, M., Tanaka, K., Kikuchi-Yanoshita, R., Muraoka, M., Yasuno, M., Igari, T., Koike, M., Chiba, M., Mori, T. <strong>Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. (Letter)</strong> Nature Genet. 17: 271-272, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9354786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9354786</a>] [<a href="https://doi.org/10.1038/ng1197-271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9354786">Miyaki et al. (1997)</a> considered it noteworthy that endometrial and ovarian carcinomas were predominant in this family, in contrast to the predominance of colorectal carcinomas in families with MSH2 or MLH1 germline mutations. The mean age for carcinoma formation in this family was 58 years, which is somewhat later than the mean age of 41 years for the first appearance of cancer in the usual HNPCC families with germline mutation of MSH2 or MLH1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9354786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009485" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009485" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009485</a>
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<p>In 10 families with atypical HNPCC in which endometrial cancer was the leading feature (LYNCH5; <a href="/entry/614350">614350</a>), <a href="#31" class="mim-tip-reference" title="Wijnen, J., de Leeuw, W., Vasen, H., van der Klift, H., Moller, P., Stormorken, A., Meijers-Heijboer, H., Lindhout, D., Menko, F., Vossen, S., Moslein, G., Tops, C., Brocker-Vriends, A., Wu, Y., Hofstra, R., Sijmons, R., Cornelisse, C., Morreau, H., Fodde, R. <strong>Familial endometrial cancer in female carriers of MSH6 germline mutations. (Letter)</strong> Nature Genet. 23: 142-144, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508506</a>] [<a href="https://doi.org/10.1038/13773" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508506">Wijnen et al. (1999)</a> identified germline mutations of the MSH6 gene; one of the families had deletion of a T at nucleotide 594, resulting in frameshift and stop at codon 609. Ovarian, endometrial, and urothelial tumors were found in this family, but only one instance of rectal tumor and one instance of colonic tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Wagner, A., Hendriks, Y., Meijers-Heijboer, E. J., de Leeuw, W. J. F., Morreau, H., Hofstra, R., Tops, C., Bik, E., Brocker-Vriends, A. H. J. T., van der Meer, C., Lindhout, D., Vasen, H. F. A., Breuning, M. H., Cornelisse, C. J., van Krimpen, C., Niermeijer, M. F., Zwinderman, A. H., Wijnen, J., Fodde, R. <strong>Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree.</strong> J. Med. Genet. 38: 318-322, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11333868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11333868</a>] [<a href="https://doi.org/10.1136/jmg.38.5.318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11333868">Wagner et al. (2001)</a> reported this mutation in a Dutch family with atypical HNPCC. Colorectal tumors were uncommon, while endometrial tumors and urinary tract tumours were more prevalent; the age of onset was delayed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11333868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs2020912 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2020912;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/rs2020912?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=rs2020912" 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=rs2020912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009486 OR RCV000030264 OR RCV000034495 OR RCV000121581 OR RCV000148644 OR RCV000157763 OR RCV001080582 OR RCV001269491 OR RCV001353988 OR RCV001797998 OR RCV002490347" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009486, RCV000030264, RCV000034495, RCV000121581, RCV000148644, RCV000157763, RCV001080582, RCV001269491, RCV001353988, RCV001797998, RCV002490347" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009486...</a>
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<p>This variant, formerly designated COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 5, DIGENIC, has been reclassified based on a review of ClinVar on December 7, 2016 by <a href="#12" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. December 7, 2016."None>Hamosh (2016)</a>.</p><p>In a patient with hereditary nonpolyposis colorectal cancer (see LYNCH5, <a href="/entry/614350">614350</a>) who had a mutation in the MLH3 gene (E1451K; <a href="/entry/604395#0005">604395.0005</a>), <a href="#33" class="mim-tip-reference" title="Wu, Y., Berends, M. J. W., Sijmons, R. H., Mensink, R. G. J., Verlind, E., Kooi, K. A., van der Sluis, T., Kempinga, C., van der Zee, A. G. J., Hollema, H., Buys, C. H. C. M., Kleibeuker, J. H., Hofstra, R. M. W. <strong>A role for MLH3 in hereditary nonpolyposis colorectal cancer.</strong> Nature Genet. 29: 137-138, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586295</a>] [<a href="https://doi.org/10.1038/ng1001-137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586295">Wu et al. (2001)</a> also found a heterozygous val878-to-ala (V878A) mutation in the MSH6 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11586295" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#33" class="mim-tip-reference" title="Wu, Y., Berends, M. J. W., Sijmons, R. H., Mensink, R. G. J., Verlind, E., Kooi, K. A., van der Sluis, T., Kempinga, C., van der Zee, A. G. J., Hollema, H., Buys, C. H. C. M., Kleibeuker, J. H., Hofstra, R. M. W. <strong>A role for MLH3 in hereditary nonpolyposis colorectal cancer.</strong> Nature Genet. 29: 137-138, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586295</a>] [<a href="https://doi.org/10.1038/ng1001-137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11586295">Wu et al. (2001)</a> identified a 1-bp insertion in the MSH6 gene (650insT) in a patient with hereditary nonpolyposis colorectal cancer (see LYNCH5, <a href="/entry/614350">614350</a>). This patient also had a mutation in the MLH3 gene (E1451K; <a href="/entry/604395#0005">604395.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11586295" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 LYNCH SYNDROME 5</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs63751407 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63751407;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs63751407" 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=rs63751407" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009489 OR RCV000074799 OR RCV001018330 OR RCV002514331 OR RCV003460675" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009489, RCV000074799, RCV001018330, RCV002514331, RCV003460675" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009489...</a>
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<p><a href="#15" class="mim-tip-reference" title="Huang, J., Kuismanen, S. A., Liu, T., Chadwick, R. B., Johnson, C. K., Stevens, M. W., Richards, S. K., Meek, J. E., Gao, X., Wright, F. A., Mecklin, J.-P., Jarvinen, H. J., Gronberg, H., Bisgaard, M. L., Lindblom, A., Peltomaki, P. <strong>MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer.</strong> Cancer Res. 61: 1619-1623, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11245474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11245474</a>]" pmid="11245474">Huang et al. (2001)</a> described a 2-bp deletion (CT) at nucleotide 3052 in exon 4 of the MSH6 gene in a large family that met Amsterdam I criteria and had late-onset HNPCC (LYNCH5, <a href="/entry/614350">614350</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11245474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0009 LYNCH SYNDROME 5</strong>
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MSH6, 2-BP DEL, 3311TT
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608092 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608092;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608092" 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=rs267608092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009490 OR RCV000074837 OR RCV000202034 OR RCV000223509 OR RCV000630139 OR RCV003460681" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009490, RCV000074837, RCV000202034, RCV000223509, RCV000630139, RCV003460681" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009490...</a>
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<p>In a Polish family, <a href="#27" class="mim-tip-reference" title="Suchy, J., Kurzawski, G., Jakubowska, A., Lubinski, J. <strong>Ovarian cancer of endometrioid type as part of the MSH6 gene mutation phenotype.</strong> J. Hum. Genet. 47: 529-531, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12376742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12376742</a>] [<a href="https://doi.org/10.1007/s100380200079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12376742">Suchy et al. (2002)</a> described a woman in whom bilateral ovarian cancer of the endometrioid type was diagnosed at the age of 49 years and who had a positive family history for both colon cancer (<a href="/entry/614350">614350</a>) and endometrial cancer (<a href="/entry/608089">608089</a>). The 3311_3312delTT mutation created a termination codon at 1106 and removed a C-terminal MSH2 (<a href="/entry/609309">609309</a>) interaction region and a nucleotide-binding region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12376742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 LYNCH SYNDROME 5</strong>
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MSH6, 13-KB DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009491" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009491" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009491</a>
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<p>In a patient with hereditary nonpolyposis colon cancer (LYNCH5; <a href="/entry/614350">614350</a>) with loss of MSH6 expression in tumors and no germline mutations, <a href="#24" class="mim-tip-reference" title="Plaschke, J., Ruschoff, J., Schackert, H. K. <strong>Genomic rearrangements of hMSH6 contribute to the genetic predisposition in suspected hereditary non-polyposis colorectal cancer syndrome.</strong> J. Med. Genet. 40: 597-600, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920072</a>] [<a href="https://doi.org/10.1136/jmg.40.8.597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920072">Plaschke et al. (2003)</a> identified an Alu repeat-mediated deletion of 13 kb affecting the promoter region, exon 1, and exon 2 of the MSH6 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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MSH6, 4.9-KB DUP
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009492" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009492" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009492</a>
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<p>In a patient with hereditary nonpolyposis colorectal cancer (LYNCH5; <a href="/entry/614350">614350</a>) with loss of MSH6 expression in tumors and no germline mutations, <a href="#24" class="mim-tip-reference" title="Plaschke, J., Ruschoff, J., Schackert, H. K. <strong>Genomic rearrangements of hMSH6 contribute to the genetic predisposition in suspected hereditary non-polyposis colorectal cancer syndrome.</strong> J. Med. Genet. 40: 597-600, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12920072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12920072</a>] [<a href="https://doi.org/10.1136/jmg.40.8.597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12920072">Plaschke et al. (2003)</a> identified a duplication of 4.9 kb of the MSH6 gene containing 1.6 kb of the 3-prime end of exon 4 and exon 5, integrated into intron 5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12920072" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0012 MISMATCH REPAIR CANCER SYNDROME 3</strong>
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LYNCH SYNDROME 5, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587779252 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587779252;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587779252" 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=rs587779252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009493 OR RCV000074796 OR RCV000202503 OR RCV002433574 OR RCV004696679" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009493, RCV000074796, RCV000202503, RCV002433574, RCV004696679" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009493...</a>
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<p>In 2 sibs with mismatch repair cancer syndrome (MMRCS3; <a href="/entry/619097">619097</a>), <a href="#21" class="mim-tip-reference" title="Ostergaard, J. R., Sunde, L., Okkels, H. <strong>Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6.</strong> Am. J. Med. Genet. 139A: 96-105, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16283678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16283678</a>] [<a href="https://doi.org/10.1002/ajmg.a.30998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16283678">Ostergaard et al. (2005)</a> identified compound heterozygosity for 2 mutations in the MSH6 gene: a c.3073G-A transition resulting in a trp1024-to-ter (W1024X) substitution, and a 4-bp deletion (c.3609_3612del; <a href="#0013">600678.0013</a>). One sib developed an anaplastic astrocytoma at age 9.4 years and later developed a T-cell lymphoma. His sister had a glioblastoma of the spinal cord at age 2 years. Both children had multiple cafe-au-lait spots without other features of neurofibromatosis I (<a href="/entry/162200">162200</a>). Three additional heterozygous family members had colon and/or endometrial cancer (LYNCH5; <a href="/entry/614350">614350</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16283678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 MISMATCH REPAIR CANCER SYNDROME 3</strong>
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MSH6, 4-BP DEL, NT3609
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587779274 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587779274;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587779274" 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=rs587779274" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000074893 OR RCV002267831 OR RCV002514332 OR RCV003450975 OR RCV004537279 OR RCV004576919" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074893, RCV002267831, RCV002514332, RCV003450975, RCV004537279, RCV004576919" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074893...</a>
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<p>For discussion of the 4-bp deletion (c.3609_3612del) in the MSH6 gene that was found in compound heterozygous state in 2 sibs with mismatch repair cancer syndrome (MMRCS3; <a href="/entry/619097">619097</a>) by <a href="#21" class="mim-tip-reference" title="Ostergaard, J. R., Sunde, L., Okkels, H. <strong>Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6.</strong> Am. J. Med. Genet. 139A: 96-105, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16283678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16283678</a>] [<a href="https://doi.org/10.1002/ajmg.a.30998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16283678">Ostergaard et al. (2005)</a>, see <a href="#0012">600678.0012</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16283678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs587776705 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776705;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776705" 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=rs587776705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009496" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009496" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009496</a>
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<p>In a boy with mismatch repair cancer syndrome (MMRCS3; <a href="/entry/619097">619097</a>), who was born of healthy consanguineous parents, <a href="#17" class="mim-tip-reference" title="Menko, F. H., Kaspers, G. L., Meijer, G. A., Claes, K., van Hagen, J. M., Gille, J. J. P. <strong>A homozygous MSH6 mutation in a child with cafe-au-lait spots, oligodendroglioma and rectal cancer.</strong> Fam. Cancer 3: 123-127, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15340263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15340263</a>] [<a href="https://doi.org/10.1023/B:FAME.0000039893.19289.18" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15340263">Menko et al. (2004)</a> identified a homozygous 3-bp deletion (c.3386_3388delGTG) in exon 5 of the MSH6 gene, resulting in a frameshift. The boy developed a malignant oligodendroglioma at age 10 years and a colonic adenocarcinoma at age 12 years. Tissue from the rectal cancer showed absence of MSH6 staining and high microsatellite instability, whereas tissue from the brain tumor showed MSH6-positive cells and microsatellite stability, suggesting different pathways of carcinogenesis. Although physical examination of the patient showed multiple cafe-au-lait spots, germline mutations in the NF1 gene (<a href="/entry/613113">613113</a>) were not identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15340263" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs587776706 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776706;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776706" 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=rs587776706" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009497 OR RCV000507938 OR RCV000774609 OR RCV001069945 OR RCV001355519 OR RCV003450623 OR RCV003996081" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009497, RCV000507938, RCV000774609, RCV001069945, RCV001355519, RCV003450623, RCV003996081" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009497...</a>
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<p>In a Pakistani girl with mismatch repair cancer syndrome (MMRCS3; <a href="/entry/619097">619097</a>) manifest as childhood onset of glioblastoma multiforme and early death, <a href="#13" class="mim-tip-reference" title="Hegde, M. R., Chong, B., Blazo, M. E., Chin, L. H. E., Ward, P. A., Chintagumpala, M. M., Kim, J. Y., Plon, S. E., Richards, C. S. <strong>A homozygous mutation in MSH6 causes Turcot syndrome.</strong> Clin. Cancer Res. 11: 4689-4693, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16000562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16000562</a>] [<a href="https://doi.org/10.1158/1078-0432.CCR-04-2025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16000562">Hegde et al. (2005)</a> identified a homozygous 1-bp insertion (c.3634insT, NM_000179) in exon 7 of the MSH6 gene, resulting in a truncated protein missing the last 179 amino acids. Her brother, who died at age 9 years, had colonic adenocarcinoma and lymphoma. Both children had cafe-au-lait spots and axillary freckling. Tumor tissue from the girl showed increased microsatellite instability. The unaffected parents were heterozygous for the mutation and denied consanguinity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16000562" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 MISMATCH REPAIR CANCER SYNDROME 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587779217 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587779217;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587779217" 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=rs587779217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009498 OR RCV000074668" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009498, RCV000074668" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009498...</a>
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<p>In a girl with multiple colonic polyps and cafe-au-lait spots (MMRCS3; <a href="/entry/619097">619097</a>), <a href="#1" class="mim-tip-reference" title="Auclair, J., Leroux, D., Desseigne, F., Lasset, C., Saurin, J. C., Joly, M. O., Pinson, S., Xu, X. L., Montmain, G., Ruano, E., Navarro, C., Puisieux, A., Wang, Q. <strong>Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation.</strong> Hum. Mutat. 28: 1084-1090, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17557300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17557300</a>] [<a href="https://doi.org/10.1002/humu.20569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17557300">Auclair et al. (2007)</a> identified compound heterozygosity for 2 mutations in the MSH6 gene: a 1-bp duplication (c.1596_1597dupT, NM_000179.1) in exon 4 and a 1-bp deletion (3261delC; <a href="#0017">600678.0017</a>) in exon 5. Both mutations resulted in frameshift and premature termination of the protein (Glu533fs and Pro1087fs, respectively). A sister had died of glioblastoma at age 7 years; she also had cafe-au-lait spots. Each unaffected parent was heterozygous for 1 of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17557300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0017 MISMATCH REPAIR CANCER SYNDROME 3</strong>
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MSH6, 1-BP DEL, 3261C
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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> rs267608078 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608078;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/rs267608078?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=rs267608078" 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=rs267608078" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009499 OR RCV000074830 OR RCV000115411 OR RCV000202045 OR RCV000524165 OR RCV001249957 OR RCV001353984 OR RCV001762178 OR RCV001824596 OR RCV002498358 OR RCV003162476" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009499, RCV000074830, RCV000115411, RCV000202045, RCV000524165, RCV001249957, RCV001353984, RCV001762178, RCV001824596, RCV002498358, RCV003162476" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009499...</a>
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<p>For discussion of the 1-bp deletion in the MSH6 gene (c.3261delC, NM_000179.1) that was found in compound heterozygous state in a patient with mismatch repair cancer syndrome (MMRCS3; <a href="/entry/619097">619097</a>) by <a href="#1" class="mim-tip-reference" title="Auclair, J., Leroux, D., Desseigne, F., Lasset, C., Saurin, J. C., Joly, M. O., Pinson, S., Xu, X. L., Montmain, G., Ruano, E., Navarro, C., Puisieux, A., Wang, Q. <strong>Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation.</strong> Hum. Mutat. 28: 1084-1090, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17557300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17557300</a>] [<a href="https://doi.org/10.1002/humu.20569" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17557300">Auclair et al. (2007)</a>, see <a href="#0016">600678.0016</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17557300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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MSH6, GLN4TER
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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> rs786201042 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786201042;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/rs786201042?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=rs786201042" 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=rs786201042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000162425 OR RCV000199142 OR RCV000202232 OR RCV000202528 OR RCV000524100 OR RCV001254934 OR RCV001353573 OR RCV001798562 OR RCV002478495 OR RCV003462113 OR RCV004528905" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000162425, RCV000199142, RCV000202232, RCV000202528, RCV000524100, RCV001254934, RCV001353573, RCV001798562, RCV002478495, RCV003462113, RCV004528905" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000162425...</a>
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<p>In 11 probands of French Canadian descent in the Province of Quebec with hereditary nonpolyposis colorectal cancer type 5 (LYNCH5; <a href="/entry/614350">614350</a>), <a href="#4" class="mim-tip-reference" title="Castellsague, E., Liu, J., Volenik, A., Giroux, S., Gagne, R., Maranda, B., Roussel-Jobin, A., Latreille, J., Laframboise, R., Palma, L., Kasprzak, L., Marcus, V. A., and 14 others. <strong>Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population.</strong> Clin. Genet. 87: 536-542, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25318681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25318681</a>] [<a href="https://doi.org/10.1111/cge.12526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25318681">Castellsague et al. (2015)</a> identified a heterozygous c.10C-T transition in the MSH6 gene, resulting in a gln4-to-ter (Q4X) substitution. Analysis of 27 additional family members indicated that the mutation cosegregated with cancer in 15 of 23 carriers, consistent with incomplete penetrance. Heterozygous carriers had an average age of cancer diagnosis at 44.2 years; 1 homozygous carrier had onset at age 10 years. Haplotype analysis indicated a founder effect in this population, and the mutation was estimated to have occurred about 513 years ago. The carrier rate in this population was estimated at about 1 in 400. All evaluable tumors showed loss of MSH6 protein and microsatellite instability (MSI); no loss of heterozygosity (LOH) was identified in any of the evaluated tumors, but the authors suggested that the gene was likely inactivated by point mutations or deletions. Among all families, 8 (73%) of 11 affected carrier females had endometrial cancer, suggesting that this is a typical presenting MSH6-related cancer in women. Analysis of this mutation among a larger population-based cohort of French Canadians showed that only 1 of 187 patients with colorectal cancer had the mutation, whereas 7 of 381 patients with endometrial cancer carried the mutation, yielding an odds ratio (OR) of 7.5 (p less than 0.0001). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25318681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11709755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11709755</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11709755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Castellsague, E., Liu, J., Volenik, A., Giroux, S., Gagne, R., Maranda, B., Roussel-Jobin, A., Latreille, J., Laframboise, R., Palma, L., Kasprzak, L., Marcus, V. A., and 14 others.
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<strong>Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population.</strong>
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Clin. Genet. 87: 536-542, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25318681/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25318681</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25318681" 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.12526" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18790734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18790734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18790734[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=18790734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Edelmann, W., Yang, K., Umar, A., Heyer, J., Lau, K., Fan, K., Liedtke, W., Cohen, P. E., Kane, M. F., Lipford, J. R., Yu, N., Crouse, G. F., Pollard, J. W., Kunkel, T., Lipkin, M., Kolodner, R., Kucherlapati, R.
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<strong>The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9428522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9428522</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9428522" 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/s0092-8674(00)80490-0" target="_blank">Full Text</a>]
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<a id="Gradia1999" class="mim-anchor"></a>
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Gradia, S., Subramanian, D., Wilson, T., Acharya, S., Makhov, A., Griffith, J., Fishel, R.
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<strong>hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10078208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10078208</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10078208" 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/s1097-2765(00)80316-0" target="_blank">Full Text</a>]
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<a id="Hamosh2016" class="mim-anchor"></a>
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Hamosh, A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. December 7, 2016.
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<a id="Hegde2005" class="mim-anchor"></a>
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Hegde, M. R., Chong, B., Blazo, M. E., Chin, L. H. E., Ward, P. A., Chintagumpala, M. M., Kim, J. Y., Plon, S. E., Richards, C. S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16000562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16000562</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16000562" 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/10.1158/1078-0432.CCR-04-2025" target="_blank">Full Text</a>]
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<a id="Hombauer2011" class="mim-anchor"></a>
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Hombauer, H., Srivatsan, A., Putnam, C. D., Kolodner, R. D.
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<strong>Mismatch repair, but not heteroduplex rejection, is temporally coupled to DNA replication.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22194578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22194578</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22194578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1210770" target="_blank">Full Text</a>]
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<a id="Huang2001" class="mim-anchor"></a>
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Huang, J., Kuismanen, S. A., Liu, T., Chadwick, R. B., Johnson, C. K., Stevens, M. W., Richards, S. K., Meek, J. E., Gao, X., Wright, F. A., Mecklin, J.-P., Jarvinen, H. J., Gronberg, H., Bisgaard, M. L., Lindblom, A., Peltomaki, P.
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<strong>MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer.</strong>
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<a id="32" class="mim-anchor"></a>
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<a id="Wu1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, Y., Berends, M. J. W., Mensink, R. G. J., Kempinga, C., Sijmons, R. H., van der Zee, A. G. J., Hollema, H., Kleibeuker, J. H., Buys, C. H. C. M., Hofstra, R. M. W.
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<strong>Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations.</strong>
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Am. J. Hum. Genet. 65: 1291-1298, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10521294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10521294</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10521294[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=10521294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/302612" 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="33" class="mim-anchor"></a>
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<a id="Wu2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, Y., Berends, M. J. W., Sijmons, R. H., Mensink, R. G. J., Verlind, E., Kooi, K. A., van der Sluis, T., Kempinga, C., van der Zee, A. G. J., Hollema, H., Buys, C. H. C. M., Kleibeuker, J. H., Hofstra, R. M. W.
|
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<strong>A role for MLH3 in hereditary nonpolyposis colorectal cancer.</strong>
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Nature Genet. 29: 137-138, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11586295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11586295</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11586295" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1001-137" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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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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Ada Hamosh - updated : 05/27/2020
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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 : 12/7/2015<br>Ada Hamosh - updated : 2/7/2012<br>Cassandra L. Kniffin - updated : 7/28/2011<br>Cassandra L. Kniffin - updated : 12/22/2010<br>Cassandra L. Kniffin - updated : 3/23/2009<br>Cassandra L. Kniffin - updated : 1/7/2008<br>Victor A. McKusick - updated : 11/1/2006<br>Victor A. McKusick - updated : 5/21/2004<br>Victor A. McKusick - updated : 10/1/2003<br>Victor A. McKusick - updated : 6/19/2003<br>George E. Tiller - updated : 2/14/2003<br>Victor A. McKusick - updated : 1/7/2003<br>Victor A. McKusick - updated : 8/9/2002<br>Victor A. McKusick - updated : 1/22/2002<br>Michael J. Wright - updated : 6/5/2001<br>Paul J. Converse - updated : 11/16/2000<br>Michael J. Wright - updated : 12/16/1999<br>Victor A. McKusick - updated : 11/16/1999<br>Ada Hamosh - updated : 11/3/1999<br>Stylianos E. Antonarakis - updated : 10/7/1999<br>Victor A. McKusick - updated : 9/28/1999<br>Stylianos E. Antonarakis - updated : 3/22/1999<br>Stylianos E. Antonarakis - updated : 2/20/1998<br>Victor A. McKusick - updated : 10/27/1997
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</span>
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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 : 7/24/1995
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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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 : 11/15/2022
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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">
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alopez : 11/24/2020<br>alopez : 05/27/2020<br>carol : 08/23/2019<br>carol : 01/24/2018<br>carol : 09/13/2016<br>carol : 12/18/2015<br>alopez : 12/15/2015<br>ckniffin : 12/7/2015<br>carol : 8/14/2015<br>mcolton : 8/12/2015<br>carol : 7/22/2015<br>alopez : 2/9/2012<br>terry : 2/7/2012<br>alopez : 11/21/2011<br>wwang : 8/11/2011<br>ckniffin : 7/28/2011<br>wwang : 1/4/2011<br>ckniffin : 12/22/2010<br>carol : 11/23/2009<br>wwang : 4/7/2009<br>ckniffin : 3/23/2009<br>carol : 2/6/2009<br>carol : 12/8/2008<br>ckniffin : 2/5/2008<br>carol : 1/15/2008<br>ckniffin : 1/7/2008<br>alopez : 11/1/2006<br>wwang : 5/17/2006<br>mgross : 4/15/2005<br>mgross : 4/14/2005<br>mgross : 4/13/2005<br>alopez : 5/27/2004<br>terry : 5/21/2004<br>alopez : 3/17/2004<br>tkritzer : 10/3/2003<br>tkritzer : 10/1/2003<br>tkritzer : 9/15/2003<br>alopez : 6/24/2003<br>terry : 6/19/2003<br>ckniffin : 3/11/2003<br>terry : 2/26/2003<br>cwells : 2/14/2003<br>cwells : 1/8/2003<br>tkritzer : 1/7/2003<br>tkritzer : 8/16/2002<br>tkritzer : 8/15/2002<br>terry : 8/9/2002<br>carol : 2/4/2002<br>mcapotos : 1/30/2002<br>terry : 1/22/2002<br>carol : 1/3/2002<br>alopez : 10/8/2001<br>alopez : 6/5/2001<br>joanna : 1/17/2001<br>mgross : 11/16/2000<br>alopez : 12/16/1999<br>mgross : 11/24/1999<br>terry : 11/16/1999<br>alopez : 11/3/1999<br>alopez : 10/13/1999<br>mgross : 10/7/1999<br>carol : 10/7/1999<br>mgross : 10/6/1999<br>terry : 9/28/1999<br>mgross : 9/16/1999<br>mgross : 4/7/1999<br>mgross : 3/22/1999<br>carol : 3/18/1999<br>dholmes : 2/20/1998<br>dholmes : 2/20/1998<br>dholmes : 2/19/1998<br>dholmes : 2/19/1998<br>carol : 1/8/1998<br>jenny : 10/28/1997<br>terry : 10/27/1997<br>mark : 9/1/1997<br>mark : 9/4/1996<br>terry : 9/4/1996<br>terry : 9/3/1996<br>mark : 3/20/1996<br>terry : 3/11/1996<br>mark : 7/24/1995
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600678
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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MutS HOMOLOG 6; MSH6
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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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<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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<div>
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<h4>
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<span class="mim-font">
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MutS, E. COLI, HOMOLOG OF, 6<br />
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G/T MISMATCH-BINDING PROTEIN; GTBP
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MSH6</em></strong>
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</span>
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</p>
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<strong>
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<em>
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Cytogenetic location: 2p16.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:47,783,145-47,810,101 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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2p16.3
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</span>
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<td>
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<span class="mim-font">
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{Endometrial cancer, familial}
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</span>
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</td>
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<td>
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<span class="mim-font">
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608089
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Somatic mutation
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Lynch syndrome 5
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</span>
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</td>
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<td>
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<span class="mim-font">
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614350
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Mismatch repair cancer syndrome 3
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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619097
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Drummond et al. (1995) and Palombo et al. (1995) showed that the mismatch-binding factor is a heterodimer of the 100-kD MSH2 (609309) and a 160-kD polypeptide called GTBP (for G/T binding protein). Sequence analysis identified GTBP as a new member of the MutS homolog family. Both proteins are required for mismatch-specific binding, a result consistent with the finding that tumor-derived cell lines devoid of either protein are also devoid of mismatch-binding activity. </p><p>Nicolaides et al. (1996) described the 5-prime end of the GTBP gene, thus allowing definition of the entire coding region. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>All homologs of the MutS proteins contain a highly conserved region of approximately 150 amino acids that encompasses a helix-turn-helix domain associated with an adenine nucleotide and magnesium binding motif, termed Walker-A motif. This part of the molecule has ATPase activity. Gradia et al. (1997) found that this ATPase activity and the associated adenine nucleotide-binding domain functions to regulate mismatch binding as a molecular switch. The MSH2-MSH6 complex is 'on' (binds mismatched nucleotides) in the ADP-bound form and 'off' in the ATP-bound form. Hydrolysis of ATP results in the recovery of mismatch binding, while ADP-to-ATP exchange results in mismatch dissociation. These results suggested to Gradia et al. (1997) a new model for the function of MutS proteins during mismatch repair in which the switch determines the timing of downstream events. Gradia et al. (1999) showed that ATP-induced release of MSH2-MSH6 from mismatched DNA is prevented if the ends are blocked or if the DNA is circular. The authors demonstrated that mismatched DNA provokes ADP-to-ATP exchange, resulting in a conformational transition that converts MSH2-MSH6 into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. These results suggested to Gradia et al. (1999) a model for bidirectional mismatch repair in which stochastic loading of multiple ATP-bound MSH2-MSH6 sliding clamps onto mismatch-containing DNA leads to activation of the repair machinery and/or other signaling effectors similar to G protein switches. </p><p>Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1 (113705)-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (607585), BLM (604610), MSH2, MSH6, MLH1, the RAD50 (604040)-MRE11 (600814)-NBS1 (602667) complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. </p><p>Hombauer et al. (2011) fused S. cerevisiae Msh6 with cyclins to restrict the availability of the Msh2-Msh6 mismatch recognition complex to either S phase or G2/M phase of the cell cycle. The Msh6-S cyclin fusion was proficient for suppressing mutations at 3 loci that replicate at mid-S phase, whereas the Msh6-G2/M cyclin fusion was defective. However, the Msh6-G2/M cyclin fusion was functional for mismatch repair at a very late-replicating region of the genome. In contrast, the heteroduplex rejection function of mismatch repair during recombination was partially functional during both S phase and G2/M phase. Hombauer et al. (2011) concluded that their results indicate a temporal coupling of mismatch repair, but not heteroduplex rejection, to DNA replication. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Papadopoulos et al. (1995) localized the GTBP gene to 2p16 by PCR evaluation of a panel of somatic cell hybrids containing segments of chromosome 2. They found that GTBP resides in the same YAC as MSH2; on the basis of the size of this YAC, GTBP was inferred to reside within 1 Mb of MSH2. The localization was confirmed by fluorescence in situ hybridization. From the colocalization of fluorescent signals, the maximum distance separating GTBP and MSH2 was estimated at 0.5 Mb. Thus, MSH2 and GTBP may have been produced by duplication of a primordial mutS repair gene. Adjacency of duplicated genes is not uncommon in the mammalian genome. Although MSH2 and GTBP exist in the cell as a heterodimer, the functions of these 2 proteins seem distinguishable. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Lynch Syndrome 5</em></strong></p><p>
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Papadopoulos et al. (1995) stated that whereas germline mutations of MSH2 account for about 50% of all cases of hereditary nonpolyposis colon cancer (Lynch syndrome; see 120435), germline GTBP mutations in HNPCC, if they occur at all, are rare. They hypothesized that GTBP mutations may not cause sufficient genetic instability to result in predisposition to tumor formation. Alternatively, GTBP may participate in processes other than mismatch repair, and the haploinsufficiency that would be associated with its germline mutation might be incompatible with normal embryogenesis or development. </p><p>Papadopoulos et al. (1995) found the GTBP gene to be inactivated in 3 hypermutable cell lines. Unlike cells defective in other mismatch repair genes, which display widespread alterations in mononucleotide, dinucleotide, and other simple repeated sequences, the GTBP-deficient cells showed alterations primarily in mononucleotide tracts. One of the cell lines found to carry a GTBP mutation was the HCT-15 colorectal tumor cell line, which is selectively defective in the repair of base-base and single-nucleotide insertion-deletion mismatches (Drummond et al., 1995). Such defects had been shown to be corrected by GTBP by Drummond et al. (1995). Papadopoulos et al. (1995) observed what appeared to be truncation of both alleles due to frameshift mutations: they detected a 1-bp deletion at codon 222 which changed a leucine to a termination codon and a 5-bp deletion/substitution at codon 1103 that created a new termination codon 9-bp downstream. MT1, an alkylation-resistant lymphoblastoid cell line with a biochemical deficiency similar to that of HCT-15, was shown to have 2 mutations in GTBP: an A-to-T transversion at codon 1145, resulting in the substitution of valine for aspartic acid in the highly conserved domain of GTBP, and a G-to-A transition at codon 1192, resulting in the substitution of isoleucine for valine. Cloning of the RT-PCR products revealed that the 2 mutations were on separate alleles. Neither of these mutations were present in the mismatch repair-proficient and alkylation-sensitive cells from which the MT1 cells were derived. </p><p>Nicolaides et al. (1996) identified several polymorphisms within the 5-prime end of the GTBP gene. </p><p>Risinger et al. (1996) demonstrated a missense mutation in the MSH6 gene in an endometrial carcinoma cell line that also contained a mutation in the MSH3 gene (600887). </p><p>Miyaki et al. (1997) stated that the following germline mutations of DNA mismatch repair genes had been identified in HNPCC families: more than 50 in MSH2 (609309), nearly 60 in MLH1 (120436), 1 in PMS1 (600258), and 2 in PMS2 (600259). They had identified 8 germline mutations of MSH2 and MLH1 in Japanese HNPCC families, but mutation of these genes could not be found in 5 other HNPCC families. Even in cases of HNPCC in which germline mutations had not yet been identified, tumors showed a replication error, RER(+) phenotype, suggesting that these cases have germline mutations in other mismatch repair genes. They studied 5 Japanese HNPCC families in which germline mutations of MSH2 or MLH1 could not be detected and found that 1 had a germline mutation in GTBP (600678.0004). </p><p>Wijnen et al. (1999) found that 7 of 10 germline mutations in MSH6 had been identified in atypical HNPCC families not fulfilling the Amsterdam criteria. </p><p>Germline mutations in mismatch repair (MMR) genes are rarely found in families with HNPCC or suspected HNPCC that do not show microsatellite instability (MSI), i.e., the MSI-low phenotype. Therefore, an MSI-high phenotype is often used as an inclusion criterion for mutation testing of MMR genes. Correction of base-base mismatches is a major function of MSH6. Since mismatches present with an MSI-low phenotype, Wu et al. (1999) assumed that the phenotype in patients with HNPCC-related tumors might be associated with MSH6 germline mutations. They detected presumably causative mutations in the MSH6 gene in 4 of 18 patients (22%) who had suspected HNPCC and MSI-low tumors. In a group of 18 patients who had suspected HNPCC and MSI-high tumors, 1 MSH6 missense mutation was found, but the same patient also had an MLH1 mutation, which may explain the MSI-high phenotype. The results suggested that MSH6 may be involved in a substantial proportion of patients with HNPCC or suspected HNPCC and MSI-low tumors. Furthermore, the data emphasized that an MSI-low phenotype cannot be considered an exclusion criterion for mutation testing of MMR genes in general. </p><p>Verma et al. (1999) identified a subset of individuals with early-onset (before age 50 years) colorectal cancer whose tumors showed microsatellite instability for mono- but not dinucleotide repeat markers. Six of 7 of these tumors were left-sided. Sequence analysis of DNA from the blood of 5 of the individuals with this subgroup of tumors identified a germline nonsense mutation in MSH6 in an isolated case of early-onset (43 years) colorectal cancer. </p><p>Wagner et al. (2001) reported a large Dutch family with atypical HNPCC not meeting Amsterdam criteria in which they found a frameshift mutation in MSH6 (600678.0005). </p><p>Huang et al. (2001) screened for mutations in the MSH6 and MSH3 genes in 90 HNPCC families in which germline mutations of MSH2 and MLH1 had been excluded. Although MSH3 was not involved in any family, a large family that fulfilled Amsterdam I criteria and had late-onset HNPCC showed a novel germline mutation in MSH6 (3052_3053delCT; 600678.0008). Huang et al. (2001) also sequenced the entire MSH6 gene exon by exon in families with frameshift mutations in the (C)8 tract in tumors, previously suggested as a predictor of MSH6 germline mutations; no mutations were found. They concluded that MSH6 and MSH3 are rarely involved in genetic predisposition to HNPCC. </p><p>Berends et al. (2002) searched for MSH6 germline mutations in 316 individuals who were known or suspected to have HNPCC. They described the molecular and clinical features of 25 index patients and 8 relatives with MSH6 variants. Five truncating MSH6 mutations, one of which was found 7 times, were detected in 12 index patients, and 10 MSH6 variants with unknown pathogenicity were found in 13 index patients. Based on these and other findings, Berends et al. (2002) concluded that MSH6 mutation analysis should be considered in all patients suspected to have HNPCC. Neither microsatellite instability nor immunohistochemistry should be a definitive selection criterion for MSH6 mutation analysis. </p><p>To determine whether and how MSH6 mutations cause susceptibility to HNPCC, Kariola et al. (2002) studied heterodimerization of 4 MSH6 variants with MSH2 and the functionality of these MutS complexes in an in vitro MMR assay. All mutations occurred in putative HNPCC patients lacking known MSH2 or MLH1 mutations, and were not found among more than 185 healthy controls. Irrespective of the type or the site of the amino acid substitutions, all the variants repaired GT mismatches to AT comparable to wildtype MSH6 protein. However, the MSH6 protein carrying a mutation in the MSH2/MSH6 interaction region was poorly expressed, suggesting problems in its stability. The authors recommended caution in interpretation of mutation data in those putative HNPCC families that do not fulfill the Amsterdam criteria, and suggested that the pathogenicity of mutations in putative HNPCC families may be linked to other biochemical events. </p><p>Endometrial cancer is the most common gynecologic malignancy in the United States and the most frequent extracolonic tumor in hereditary nonpolyposis colorectal cancer. Sporadic endometrial cancers exhibit microsatellite instability (MSI), usually associated with methylation of the MLH1 promoter. Germline MSH6 mutations, which are rare in HNPCC, have been reported in several families with multiple members affected with endometrial carcinoma (see, e.g., 600678.0005). Goodfellow et al. (2003) reasoned that MSH6 mutation might account for loss of MMR in MSI-positive endometrial cancers in which the cause of MSI was unknown. They therefore investigated MSI and MLH1 promoter methylation in 441 endometrial cancer patients unselected for age or personal and family history of cancers. Evaluation for MSH6 defects was performed in 100 cases (23% of the entire series). Inactivating germline MSH6 mutations were identified in 7 women with MSI-positive, MLH1 promoter unmethylated cancers. Most of the MSI in these cases was seen with mononucleotide repeat markers. MSH6 mutation carriers were significantly younger than the rest of the population (mean age 54.8 vs 64.6, P = 0.04). Somatic mutations were seen in 17 tumors, all of which had MSI. The minimum estimate of the prevalence of inherited MSH6 mutation in endometrial cancer was placed at 1.6% (7 of 441), comparable with the predicted prevalence for patients with colorectal cancer. </p><p>A substantial fraction of germline mutations in the mismatch repair genes MLH1 and MSH2 represent genomic rearrangements. See, for example, the Alu-mediated deletions of the former (120436.0004) and the latter (609309.0017). In 2 patients with HNPCC who developed tumors with loss of MSH6 expression, Plaschke et al. (2003) identified an Alu-mediated deletion (600678.0010) in 1 and a 4.9-kb duplication (600678.0011) in the other. </p><p>Without preselection and regardless of family history, Barnetson et al. (2006) recruited 870 patients under the age of 55 years soon after they received the diagnosis of colorectal cancer. They studied these patients for germline mutations in DNA mismatch-repair genes MLH1, MSH2, and MSH6 and developed a 2-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes. Stage 1 of the model incorporated only clinical variables; stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability. The model was validated in an independent population of patients. Furthermore, they analyzed 2,938 patient-years of follow-up to determine whether genotype influenced survival. Among the 870 participants, 38 mutations were found: 15 in MLH1, 16 in MSH2, and 7 in MSH6. Carrier frequencies in men (6%) and women (3%) differed significantly (P less than 0.04). Survival among carriers was not significantly different from that among noncarriers. </p><p>Cyr and Heinen (2008) showed that 5 HNPCC-associated MSH6 missense mutations, including the V878A mutation (600678.0006), disrupted DNA mismatch-stimulated ATP hydrolysis activity, providing functional evidence that these mutations contribute to disease. The R976H and H1248D mutations affected mismatch recognition. The V878A, G566R, and D803G mutations uncoupled mismatch binding and ATP hydrolysis activities of the MSH2/MSH6 heterodimer and altered ATP-dependent conformation changes of the MSH2/MSH6 heterodimer. None of the mutations affected heterodimer formation with MSH2, and most showed normal binding to mismatched DNA. </p><p>To investigate the association of MMR genes with breast cancer, Roberts et al. (2018) conducted a retrospective review of personal and family cancer history in 423 women with pathogenic or likely pathogenic germline variants in MMR genes identified via clinical multigene hereditary cancer testing: 65 in MLH1 (120436), 94 in MSH2 (609309), 140 in MSH6, and 124 in PMS2 (600259). Standard incidence ratios (SIRs) of breast cancer were calculated by comparing breast cancer frequencies in the study population with those in the general population. When evaluating by gene, the age-standardized breast cancer risks for MSH6 (SIR = 2.11; 95% CI, 1.56-2.86) and PMS2 (SIR = 2.92; 95% CI, 2.17-3.92) were associated with a statistically significant risk for breast cancer, whereas MLH1 and MSH2 were not. Roberts et al. (2018) concluded that the MMR genes MSH6 and PMS2, mutations in which cause HNPCC5 and HNPCC4 (614334), respectively, should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer. </p><p><strong><em>Mismatch Repair Cancer Syndrome 3</em></strong></p><p>
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In 2 sibs with mismatch repair cancer syndrome-3 (MMRCS3; 619097), also known as brain tumor-polyposis syndrome-1 or Turcot syndrome, Ostergaard et al. (2005) identified compound heterozygosity for 2 mutations in the MSH6 gene (600678.0012, 600678.0013). One sib developed an anaplastic astrocytoma at age 9.4 years and later developed a T-cell lymphoma. His sister had a glioblastoma of the spinal cord at age 2 years. Both children had multiple cafe-au-lait spots without other features of neurofibromatosis I (NF1; 162200). Three additional heterozygous family members had colon and/or endometrial cancer. </p><p>In patients with childhood onset of colonic adenocarcinoma, lymphoma, and brain tumors, Menko et al. (2004) and Hegde et al. (2005) identified homozygous mutations in the MSH6 gene (600678.0014 and 600678.0015, respectively). </p>
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</span>
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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>Edelmann et al. (1997) used gene targeting to generate mice carrying a null mutation in the murine mismatch repair gene Msh6. The PGKneo expression cassette was inserted into the fourth exon of the gene. Cells that were homozygous for the mutation did not produce any detectable MSH6 protein, and extracts prepared from these cells were defective for repair of single nucleotide mismatches. Repair of 1-, 2-, and 4-nucleotide insertion/deletion mismatches was unaffected. Mice that were homozygous for the mutation had a reduced life span. The mice developed a spectrum of tumors, predominantly gastrointestinal tumors and B- and T-cell lymphomas. The tumors did not show any microsatellite instability. Edelmann et al. (1997) concluded that MSH6 mutations, like those in some other members of the family of mismatch repair genes, lead to cancer susceptibility, and that germline mutations in this gene may be associated with a cancer predisposition syndrome that does not show microsatellite instability. </p><p>De Wind et al. (1999) inactivated the mouse Msh3 and Msh6 genes by targeted disruption. Msh6-deficient mice were prone to cancer. Most animals developed lymphomas or epithelial tumors originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in a Msh6-deficient background, loss of Msh3 accelerated intestinal tumorigenesis. The frequency of lymphomas was not affected. Furthermore, mismatch-directed antirecombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of mismatch repair functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3. </p><p>Oxidation of G in DNA yields 8-oxo-G (GO), a mutagenic lesion that leads to misincorporation of A opposite GO. In S. cerevisiae, Ni et al. (1999) found that mutations in the MSH2 or MSH6 genes caused a synergistic increase in mutation rate when in combination with mutations in the OGG1 gene (601982), resulting in a 140- to 218-fold increase in the G:C-to-T:A transversion rate. Consistent with this, MSH2-MSH6 complex bound with high affinity and specificity to GO:A mispairs and GO:C basepairs. These data indicated that in S. cerevisiae, MSH2-MSH6-dependent mismatch repair is the major mechanism by which misincorporation of A opposite GO is corrected. </p>
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</span>
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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>18 Selected Examples):</strong>
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</h4>
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<h4>
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<span class="mim-font">
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<strong>.0001 LYNCH SYNDROME 5</strong>
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<span class="mim-text-font">
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MSH6, 1-BP DEL, LEU222TER
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<br />
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ClinVar: RCV000009484
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<div>
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<span class="mim-text-font">
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<p>Papadopoulos et al. (1995) found a 1-bp deletion mutation of the MSH6 gene in the HCT-15 colorectal cancer cell line (LYNCH5; 614350) at codon 222, which changed a leucine to a termination codon. They also found a 5-bp deletion/substitution at codon 1103 (TTGATAGAGT to TTTGT), which created a new termination codon 9-bp downstream. </p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 REMOVED FROM DATABASE</strong>
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</span>
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</h4>
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<span class="mim-font">
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<strong>.0003 REMOVED FROM DATABASE</strong>
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</span>
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<h4>
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<span class="mim-font">
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<strong>.0004 LYNCH SYNDROME 5</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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MSH6, 1-BP DEL, FS570TER
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<br />
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SNP: rs63751234,
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gnomAD: rs63751234,
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ClinVar: RCV000009488
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</span>
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<div>
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<span class="mim-text-font">
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<p>Miyaki et al. (1997) demonstrated an MHS6 germline mutation in an HNPCC family (LYNCH5; 614350) in which no mutation could be identified in the MSH2 (609309) or MLH1 (120436) genes. Carcinoma of the transverse colon in a 52-year-old member of the family showed alterations in 5 of 7 dinucleotide repeat loci and all 4 mononucleotide repeat loci analyzed. Mutations were also identified in TGFBR2 (190182), BAX (600040), and APC (611731), but did not exhibit loss of heterozygosity at 5q, 8p, 17p, and 18q, or mutations of the TP53 (191170) and KRAS2 (190070) genes. At age 53 this patient also had an endometrial carcinoma, which exhibited RER(+) at 3 of 4 dinucleotide repeats and 3 of 4 mononucleotide repeats. PCR-SSCP analysis of DNA from the colon and endometrial carcinoma and normal tissues detected a mutant band for MSH6. Direct sequencing of the mutant band revealed a C deletion at codon 534 of the MSH6 gene, predicting premature stop at codon 570 and truncation of the MSH6 protein. The same germline mutation was also detected in the patient's sister, who presented with endometrial carcinoma at the age of 53 years. Other sisters who had had endometrial or ovarian carcinoma were assumed to have the same germline mutation, as it was detected in their offspring. In addition to the germline mutation, somatic mutations of MSH6 were detected in carcinomas from the proband in this family, including a T deletion at codon 128 in the colon carcinoma and a C deletion at codon 1085 in the endometrial carcinoma, both of which led to stop codons. These somatic mutations were presumably in the alleles without the germline mutation, suggesting that inactivation of both alleles of MSH6 was the cause of the RER(+) phenotype and the stimulus for neoplasia. Although this family did not fulfill the Amsterdam criteria, patients in the family had colonic, endometrial, ovarian, and pancreatic carcinomas. Miyaki et al. (1997) considered it noteworthy that endometrial and ovarian carcinomas were predominant in this family, in contrast to the predominance of colorectal carcinomas in families with MSH2 or MLH1 germline mutations. The mean age for carcinoma formation in this family was 58 years, which is somewhat later than the mean age of 41 years for the first appearance of cancer in the usual HNPCC families with germline mutation of MSH2 or MLH1. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 LYNCH SYNDROME 5</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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MSH6, 1-BP DEL, 594T
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<br />
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ClinVar: RCV000009485
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 10 families with atypical HNPCC in which endometrial cancer was the leading feature (LYNCH5; 614350), Wijnen et al. (1999) identified germline mutations of the MSH6 gene; one of the families had deletion of a T at nucleotide 594, resulting in frameshift and stop at codon 609. Ovarian, endometrial, and urothelial tumors were found in this family, but only one instance of rectal tumor and one instance of colonic tumor. </p><p>Wagner et al. (2001) reported this mutation in a Dutch family with atypical HNPCC. Colorectal tumors were uncommon, while endometrial tumors and urinary tract tumours were more prevalent; the age of onset was delayed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MSH6, VAL878ALA
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<br />
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SNP: rs2020912,
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gnomAD: rs2020912,
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ClinVar: RCV000009486, RCV000030264, RCV000034495, RCV000121581, RCV000148644, RCV000157763, RCV001080582, RCV001269491, RCV001353988, RCV001797998, RCV002490347
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>This variant, formerly designated COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 5, DIGENIC, has been reclassified based on a review of ClinVar on December 7, 2016 by Hamosh (2016).</p><p>In a patient with hereditary nonpolyposis colorectal cancer (see LYNCH5, 614350) who had a mutation in the MLH3 gene (E1451K; 604395.0005), Wu et al. (2001) also found a heterozygous val878-to-ala (V878A) mutation in the MSH6 gene. </p>
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</span>
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</div>
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<div>
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<br />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 LYNCH SYNDROME 5</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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MSH6, 1-BP INS, 650T
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<br />
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SNP: rs63750955,
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ClinVar: RCV000009487, RCV000075018, RCV000202569, RCV000235180, RCV000524211, RCV001804722, RCV002223129, RCV002288477, RCV002496313, RCV004739299
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Wu et al. (2001) identified a 1-bp insertion in the MSH6 gene (650insT) in a patient with hereditary nonpolyposis colorectal cancer (see LYNCH5, 614350). This patient also had a mutation in the MLH3 gene (E1451K; 604395.0005). </p>
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</span>
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</div>
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<div>
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<br />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 LYNCH SYNDROME 5</strong>
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</span>
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</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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|
MSH6, 2-BP DEL, 3052CT
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|
<br />
|
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|
|
SNP: rs63751407,
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|
|
ClinVar: RCV000009489, RCV000074799, RCV001018330, RCV002514331, RCV003460675
|
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|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>Huang et al. (2001) described a 2-bp deletion (CT) at nucleotide 3052 in exon 4 of the MSH6 gene in a large family that met Amsterdam I criteria and had late-onset HNPCC (LYNCH5, 614350). </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
<div>
|
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|
|
<div>
|
|
<h4>
|
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<span class="mim-font">
|
|
<strong>.0009 LYNCH SYNDROME 5</strong>
|
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</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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MSH6, 2-BP DEL, 3311TT
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<br />
|
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SNP: rs267608092,
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|
|
ClinVar: RCV000009490, RCV000074837, RCV000202034, RCV000223509, RCV000630139, RCV003460681
|
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|
|
|
</span>
|
|
</div>
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|
<div>
|
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<span class="mim-text-font">
|
|
<p>In a Polish family, Suchy et al. (2002) described a woman in whom bilateral ovarian cancer of the endometrioid type was diagnosed at the age of 49 years and who had a positive family history for both colon cancer (614350) and endometrial cancer (608089). The 3311_3312delTT mutation created a termination codon at 1106 and removed a C-terminal MSH2 (609309) interaction region and a nucleotide-binding region. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LYNCH SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
|
MSH6, 13-KB DEL
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<br />
|
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|
|
ClinVar: RCV000009491
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with hereditary nonpolyposis colon cancer (LYNCH5; 614350) with loss of MSH6 expression in tumors and no germline mutations, Plaschke et al. (2003) identified an Alu repeat-mediated deletion of 13 kb affecting the promoter region, exon 1, and exon 2 of the MSH6 gene. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 LYNCH SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MSH6, 4.9-KB DUP
|
|
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|
|
|
<br />
|
|
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|
|
|
|
ClinVar: RCV000009492
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with hereditary nonpolyposis colorectal cancer (LYNCH5; 614350) with loss of MSH6 expression in tumors and no germline mutations, Plaschke et al. (2003) identified a duplication of 4.9 kb of the MSH6 gene containing 1.6 kb of the 3-prime end of exon 4 and exon 5, integrated into intron 5. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 MISMATCH REPAIR CANCER SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LYNCH SYNDROME 5, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MSH6, TRP1024TER
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs587779252,
|
|
|
|
|
|
|
|
ClinVar: RCV000009493, RCV000074796, RCV000202503, RCV002433574, RCV004696679
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with mismatch repair cancer syndrome (MMRCS3; 619097), Ostergaard et al. (2005) identified compound heterozygosity for 2 mutations in the MSH6 gene: a c.3073G-A transition resulting in a trp1024-to-ter (W1024X) substitution, and a 4-bp deletion (c.3609_3612del; 600678.0013). One sib developed an anaplastic astrocytoma at age 9.4 years and later developed a T-cell lymphoma. His sister had a glioblastoma of the spinal cord at age 2 years. Both children had multiple cafe-au-lait spots without other features of neurofibromatosis I (162200). Three additional heterozygous family members had colon and/or endometrial cancer (LYNCH5; 614350). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 MISMATCH REPAIR CANCER SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MSH6, 4-BP DEL, NT3609
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587779274,
|
|
|
|
|
|
|
|
ClinVar: RCV000074893, RCV002267831, RCV002514332, RCV003450975, RCV004537279, RCV004576919
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 4-bp deletion (c.3609_3612del) in the MSH6 gene that was found in compound heterozygous state in 2 sibs with mismatch repair cancer syndrome (MMRCS3; 619097) by Ostergaard et al. (2005), see 600678.0012. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 MISMATCH REPAIR CANCER SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MSH6, 3-BP DEL, 3386GTG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776705,
|
|
|
|
|
|
|
|
ClinVar: RCV000009496
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with mismatch repair cancer syndrome (MMRCS3; 619097), who was born of healthy consanguineous parents, Menko et al. (2004) identified a homozygous 3-bp deletion (c.3386_3388delGTG) in exon 5 of the MSH6 gene, resulting in a frameshift. The boy developed a malignant oligodendroglioma at age 10 years and a colonic adenocarcinoma at age 12 years. Tissue from the rectal cancer showed absence of MSH6 staining and high microsatellite instability, whereas tissue from the brain tumor showed MSH6-positive cells and microsatellite stability, suggesting different pathways of carcinogenesis. Although physical examination of the patient showed multiple cafe-au-lait spots, germline mutations in the NF1 gene (613113) were not identified. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 MISMATCH REPAIR CANCER SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MSH6, 1-BP INS, 3634T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776706,
|
|
|
|
|
|
|
|
ClinVar: RCV000009497, RCV000507938, RCV000774609, RCV001069945, RCV001355519, RCV003450623, RCV003996081
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Pakistani girl with mismatch repair cancer syndrome (MMRCS3; 619097) manifest as childhood onset of glioblastoma multiforme and early death, Hegde et al. (2005) identified a homozygous 1-bp insertion (c.3634insT, NM_000179) in exon 7 of the MSH6 gene, resulting in a truncated protein missing the last 179 amino acids. Her brother, who died at age 9 years, had colonic adenocarcinoma and lymphoma. Both children had cafe-au-lait spots and axillary freckling. Tumor tissue from the girl showed increased microsatellite instability. The unaffected parents were heterozygous for the mutation and denied consanguinity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 MISMATCH REPAIR CANCER SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MSH6, 1-BP DUP, 1596T
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587779217,
|
|
|
|
|
|
|
|
ClinVar: RCV000009498, RCV000074668
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with multiple colonic polyps and cafe-au-lait spots (MMRCS3; 619097), Auclair et al. (2007) identified compound heterozygosity for 2 mutations in the MSH6 gene: a 1-bp duplication (c.1596_1597dupT, NM_000179.1) in exon 4 and a 1-bp deletion (3261delC; 600678.0017) in exon 5. Both mutations resulted in frameshift and premature termination of the protein (Glu533fs and Pro1087fs, respectively). A sister had died of glioblastoma at age 7 years; she also had cafe-au-lait spots. Each unaffected parent was heterozygous for 1 of the mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 MISMATCH REPAIR CANCER SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MSH6, 1-BP DEL, 3261C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267608078,
|
|
|
|
|
|
gnomAD: rs267608078,
|
|
|
|
|
|
ClinVar: RCV000009499, RCV000074830, RCV000115411, RCV000202045, RCV000524165, RCV001249957, RCV001353984, RCV001762178, RCV001824596, RCV002498358, RCV003162476
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1-bp deletion in the MSH6 gene (c.3261delC, NM_000179.1) that was found in compound heterozygous state in a patient with mismatch repair cancer syndrome (MMRCS3; 619097) by Auclair et al. (2007), see 600678.0016. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 LYNCH SYNDROME 5</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MSH6, GLN4TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786201042,
|
|
|
|
|
|
gnomAD: rs786201042,
|
|
|
|
|
|
ClinVar: RCV000162425, RCV000199142, RCV000202232, RCV000202528, RCV000524100, RCV001254934, RCV001353573, RCV001798562, RCV002478495, RCV003462113, RCV004528905
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 11 probands of French Canadian descent in the Province of Quebec with hereditary nonpolyposis colorectal cancer type 5 (LYNCH5; 614350), Castellsague et al. (2015) identified a heterozygous c.10C-T transition in the MSH6 gene, resulting in a gln4-to-ter (Q4X) substitution. Analysis of 27 additional family members indicated that the mutation cosegregated with cancer in 15 of 23 carriers, consistent with incomplete penetrance. Heterozygous carriers had an average age of cancer diagnosis at 44.2 years; 1 homozygous carrier had onset at age 10 years. Haplotype analysis indicated a founder effect in this population, and the mutation was estimated to have occurred about 513 years ago. The carrier rate in this population was estimated at about 1 in 400. All evaluable tumors showed loss of MSH6 protein and microsatellite instability (MSI); no loss of heterozygosity (LOH) was identified in any of the evaluated tumors, but the authors suggested that the gene was likely inactivated by point mutations or deletions. Among all families, 8 (73%) of 11 affected carrier females had endometrial cancer, suggesting that this is a typical presenting MSH6-related cancer in women. Analysis of this mutation among a larger population-based cohort of French Canadians showed that only 1 of 187 patients with colorectal cancer had the mutation, whereas 7 of 381 patients with endometrial cancer carried the mutation, yielding an odds ratio (OR) of 7.5 (p less than 0.0001). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
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|
|
|
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|
|
</div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Auclair, J., Leroux, D., Desseigne, F., Lasset, C., Saurin, J. C., Joly, M. O., Pinson, S., Xu, X. L., Montmain, G., Ruano, E., Navarro, C., Puisieux, A., Wang, Q.
|
|
<strong>Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation.</strong>
|
|
Hum. Mutat. 28: 1084-1090, 2007.
|
|
|
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|
|
[PubMed: 17557300]
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|
|
[Full Text: https://doi.org/10.1002/humu.20569]
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</p>
|
|
</li>
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Barnetson, R. A., Tenesa, A., Farrington, S. M., Nicholl, I. D., Cetnarskyj, R., Porteous, M. E., Campbell, H., Dunlop, M. G.
|
|
<strong>Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.</strong>
|
|
New Eng. J. Med. 354: 2751-2763, 2006.
|
|
|
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|
|
[PubMed: 16807412]
|
|
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|
|
[Full Text: https://doi.org/10.1056/NEJMoa053493]
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Berends, M. J. W., Wu, Y., Sijmons, R. H., Mensink, R. G. J., van der Sluis, T., Hordijk-Hos, J. M., de Vries, E. G. E., Hollema, H., Karrenbeld, A., Buys, C. H. C. M., van der Zee, A. G. J., Hofstra, R. M. W., Kleibeuker, J. H.
|
|
<strong>Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant.</strong>
|
|
Am. J. Hum. Genet. 70: 26-37, 2002.
|
|
|
|
|
|
[PubMed: 11709755]
|
|
|
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|
|
[Full Text: https://doi.org/10.1086/337944]
|
|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Castellsague, E., Liu, J., Volenik, A., Giroux, S., Gagne, R., Maranda, B., Roussel-Jobin, A., Latreille, J., Laframboise, R., Palma, L., Kasprzak, L., Marcus, V. A., and 14 others.
|
|
<strong>Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population.</strong>
|
|
Clin. Genet. 87: 536-542, 2015.
|
|
|
|
|
|
[PubMed: 25318681]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/cge.12526]
|
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|
|
</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
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</ol>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 05/27/2020<br>Cassandra L. Kniffin - updated : 12/7/2015<br>Ada Hamosh - updated : 2/7/2012<br>Cassandra L. Kniffin - updated : 7/28/2011<br>Cassandra L. Kniffin - updated : 12/22/2010<br>Cassandra L. Kniffin - updated : 3/23/2009<br>Cassandra L. Kniffin - updated : 1/7/2008<br>Victor A. McKusick - updated : 11/1/2006<br>Victor A. McKusick - updated : 5/21/2004<br>Victor A. McKusick - updated : 10/1/2003<br>Victor A. McKusick - updated : 6/19/2003<br>George E. Tiller - updated : 2/14/2003<br>Victor A. McKusick - updated : 1/7/2003<br>Victor A. McKusick - updated : 8/9/2002<br>Victor A. McKusick - updated : 1/22/2002<br>Michael J. Wright - updated : 6/5/2001<br>Paul J. Converse - updated : 11/16/2000<br>Michael J. Wright - updated : 12/16/1999<br>Victor A. McKusick - updated : 11/16/1999<br>Ada Hamosh - updated : 11/3/1999<br>Stylianos E. Antonarakis - updated : 10/7/1999<br>Victor A. McKusick - updated : 9/28/1999<br>Stylianos E. Antonarakis - updated : 3/22/1999<br>Stylianos E. Antonarakis - updated : 2/20/1998<br>Victor A. McKusick - updated : 10/27/1997
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</span>
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<span class="text-nowrap mim-text-font">
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Creation Date:
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