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Entry
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- *600259 - PMS1 HOMOLOG 2, MISMATCH REPAIR SYSTEM COMPONENT; PMS2
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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">*600259</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600259">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 role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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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=ENSG00000122512;t=ENST00000265849" 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=5395" 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=600259" 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=ENSG00000122512;t=ENST00000265849" 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_000535,NM_001322003,NM_001322004,NM_001322005,NM_001322006,NM_001322007,NM_001322008,NM_001322009,NM_001322010,NM_001322011,NM_001322012,NM_001322013,NM_001322014,NM_001322015,NM_001406866,NM_001406868,NM_001406869,NM_001406870,NM_001406871,NM_001406872,NM_001406873,NM_001406874,NM_001406875,NM_001406876,NM_001406877,NM_001406878,NM_001406879,NM_001406880,NM_001406881,NM_001406882,NM_001406883,NM_001406884,NM_001406885,NM_001406886,NM_001406887,NM_001406888,NM_001406889,NM_001406890,NM_001406891,NM_001406892,NM_001406893,NM_001406894,NM_001406895,NM_001406896,NM_001406897,NM_001406898,NM_001406899,NM_001406900,NM_001406901,NM_001406902,NM_001406903,NM_001406904,NM_001406905,NM_001406906,NM_001406907,NM_001406908,NM_001406909,NM_001406910,NM_001406911,NM_001406912,NR_136154,XM_047420482,XM_047420483,XM_047420484,XM_047420486" 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_000535" 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=600259" 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=02598&isoform_id=02598_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/PMS2" 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/535515,557470,31873629,41350089,58737033,58737035,58737039,58737041,58737043,62739886,119575457,148357340,189065468,194378162,317373266,1015125298,1015130027,1015148760,1015158154,1015158971,1015172279,1015172281,1015172283,1015172287,1015172289,1015172291,1015172293,1015177035,1015181836,2217367467,2217367469,2217367471,2217367476,2243203114,2243203128,2243203597,2243203785,2243203920,2243204174,2243204297,2243205408,2243205856,2243206271,2243206404,2243206508,2243206656,2243206766,2243207642,2244985382,2244985386,2244985404,2244985408,2244985434,2244985449,2244985460,2244985462,2244985490,2244985500,2244985517,2244985529,2244985537,2244985551,2244985572,2244985605,2244985623,2244985639,2244985682,2244986453,2244986475,2244986499,2244986521,2244986525,2244986531,2244986543,2244986553,2244986567,2244986586,2244986598,2244986637,2462614844,2462614846,2462614848,2462614850,2462614852,2462614854,2462614856,2462614858,2462614860,2462614862,2462614864" 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/P54278" 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=5395" 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=ENSG00000122512;t=ENST00000265849" 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=PMS2" 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=PMS2" 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+5395" 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/PMS2" 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:5395" 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/5395" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr7&hgg_gene=ENST00000265849.12&hgg_start=5970925&hgg_end=6009106&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:9122" 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:9122" 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/pms2" 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=600259[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=600259[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000122512" 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=PMS2" 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=PMS2" 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=PMS2" 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=PMS2" title="Zhejiang University-Adinovo Center PMS2 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.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>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PMS2&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/PA33448" 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:9122" 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/FBgn0011660.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:104288" 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/PMS2#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:104288" 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/5395/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=5395" 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=WBGene00004064;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-030131-686" 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:5395" 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=PMS2&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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600259
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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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PMS1 HOMOLOG 2, MISMATCH REPAIR SYSTEM COMPONENT; PMS2
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</span>
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</h3>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
POSTMEIOTIC SEGREGATION INCREASED, S. CEREVISIAE, 2<br />
|
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MISMATCH REPAIR GENE PMSL2; PMSL2
|
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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=PMS2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PMS2</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>
|
|
Cytogenetic location: <a href="/geneMap/7/51?start=-3&limit=10&highlight=51">7p22.1</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:5970925-6009106&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">7:5,970,925-6,009,106</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
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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>
|
|
</span>
|
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</div>
|
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<div>
|
|
<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=614337,619101" 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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<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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<p>In screening a database of human genes identified by the expressed sequence tag (EST) method (<a href="#1" class="mim-tip-reference" title="Adams, M. D., Kelley, J. M., Gocayne, J. D., Dubnick, M., Polymeropoulos, M. H., Xiao, H., Merril, C. R., Wu, A., Olde, B., Moreno, R. F., Kerlavage, A. R., McCombie, W. R., Venter, J. C. <strong>Complementary DNA sequencing: expressed sequence tags and human genome project.</strong> Science 252: 1651-1656, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2047873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2047873</a>] [<a href="https://doi.org/10.1126/science.2047873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2047873">Adams et al., 1991</a>), <a href="#29" class="mim-tip-reference" title="Papadopoulos, N., Nicolaides, N. C., Wei, Y.-F., Ruben, S. M., Carter, K. C., Rosen, C. A., Haseltine, W. A., Fleischmann, R. D., Fraser, C. M., Adams, M. D., Venter, J. C., Hamilton, S. R., Petersen, G. M., Watson, P., Lynch, H. T., Peltomaki, P., Mecklin, J.-P., de la Chapelle, A., Kinzler, K. W., Vogelstein, B. <strong>Mutation of a mutL homolog in hereditary colon cancer.</strong> Science 263: 1625-1629, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8128251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8128251</a>] [<a href="https://doi.org/10.1126/science.8128251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8128251">Papadopoulos et al. (1994)</a> identified 2 human ESTs with homology to the yeast PMS1 gene: the human genes were designated PMS1 (<a href="/entry/600258">600258</a>) and PMS2. Sequence analysis of the human PMS2 clone predicted an 862-residue protein with 32% identity to yeast PMS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8128251+2047873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the process of characterizing PMS2 cDNA and its promoter region, <a href="#25" class="mim-tip-reference" title="Nicolaides, N. C., Kinzler, K. W., Vogelstein, B. <strong>Analysis of the 5-prime region of PMS2 reveals heterogeneous transcripts and a novel overlapping gene.</strong> Genomics 29: 329-334, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8666379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8666379</a>] [<a href="https://doi.org/10.1006/geno.1995.9997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8666379">Nicolaides et al. (1995)</a> discovered another gene, provisionally called JTV1 (AIMP2; <a href="/entry/600859">600859</a>), which is transcribed from the opposite DNA strand and overlaps with PMS2. The genes lie in a head-to-head arrangement and both are ubiquitously expressed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8666379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Hypermutable H6 colorectal tumor cells are defective in strand-specific mismatch repair and bear defects in both alleles of the human MLH1 gene (<a href="/entry/120436">120436</a>). <a href="#18" class="mim-tip-reference" title="Li, G.-M., Modrich, P. <strong>Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs.</strong> Proc. Nat. Acad. Sci. 92: 1950-1954, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7892206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7892206</a>] [<a href="https://doi.org/10.1073/pnas.92.6.1950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7892206">Li and Modrich (1995)</a> purified to near homogeneity an activity from HeLa cells that complemented H6 nuclear extracts to restore repair proficiency on a set of heteroduplex DNAs representing the 8 base-base mismatches as well as a number of slipped-strand, insertion/deletion mispairs. The activity behaved as a single species during fractionation and copurified with proteins of 85 and 100 kD. Microsequence analysis demonstrated both of these proteins to be homologs of bacterial MutL, with the former corresponding to the human MLH1 product and the latter to the product of human PMS2 or a closely related gene. The 1:1 molar stoichiometry of the 2 polypeptides and their hydrodynamic behavior indicated formation of a heterodimer. These observations indicated that interactions between members of the family of the human MutL homologs may be restricted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7892206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>MutL-alpha is a heterodimer of MLH1 and PMS2 and is required for mismatch repair. <a href="#15" class="mim-tip-reference" title="Kadyrov, F. A., Dzantiev, L., Constantin, N., Modrich, P. <strong>Endonucleolytic function of MutL-alpha in human mismatch repair.</strong> Cell 126: 297-308, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16873062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16873062</a>] [<a href="https://doi.org/10.1016/j.cell.2006.05.039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16873062">Kadyrov et al. (2006)</a> identified human MutL-alpha as a latent endonuclease activated in a DNA mismatch-, MutS-alpha (see <a href="/entry/609309">609309</a>)-, RFC (see <a href="/entry/102579">102579</a>)-, PCNA (<a href="/entry/176740">176740</a>)-, and ATP-dependent manner. Incision of a nicked heteroduplex by this 4-protein system was strongly biased to the nicked strand. A mismatch-containing DNA segment spanned by 2 strand breaks was then removed by the 5-prime-to-3-prime activity of MutS-alpha-activated exonuclease-1 (EXO1; <a href="/entry/606063">606063</a>). By mutation analysis, <a href="#15" class="mim-tip-reference" title="Kadyrov, F. A., Dzantiev, L., Constantin, N., Modrich, P. <strong>Endonucleolytic function of MutL-alpha in human mismatch repair.</strong> Cell 126: 297-308, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16873062/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16873062</a>] [<a href="https://doi.org/10.1016/j.cell.2006.05.039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16873062">Kadyrov et al. (2006)</a> mapped the endonuclease active site to a conserved motif in PMS2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16873062" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 human MLH1-deficient cells, <a href="#33" class="mim-tip-reference" title="Shimodaira, H., Yoshioka-Yamashita, A., Kolodner, R. D., Wang, J. Y. J. <strong>Interaction of mismatch repair protein PMS2 and the p53-related transcription factor p73 in apoptosis response to cisplatin.</strong> Proc. Nat. Acad. Sci. 100: 2420-2425, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12601175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12601175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12601175[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.0438031100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12601175">Shimodaira et al. (2003)</a> found that PMS2 interacted with and stabilized the apoptotic protein p73 (TP73; <a href="/entry/601990">601990</a>) and that the interaction caused redistribution of PMS2 to the nuclear compartment. Treatment with the DNA crosslinking agent cisplatin resulted in increased association of the 2 molecules and enhanced apoptotic function of p73. The findings demonstrated a role for PMS2 in DNA damage-induced apoptosis as well as in DNA repair. <a href="#21" class="mim-tip-reference" title="Marinovic-Terzic, I., Yoshioka-Yamashita, A., Shimodaira, H., Avdievich, E., Hunton, I. C., Kolodner, R. D., Edelmann, W., Wang, J. Y. J. <strong>Apoptotic function of human PMS2 compromised by the nonsynonymous single-nucleotide polymorphic variant R20Q.</strong> Proc. Nat. Acad. Sci. 105: 13993-13998, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18768816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18768816</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18768816[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.0806435105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18768816">Marinovic-Terzic et al. (2008)</a> showed that a polymorphism in the PMS2 gene, resulting in an arg20-to-gln (R20Q) substitution, interfered with the interaction of PMS2 and p73 and resulted in a decreased apoptotic response to cisplatin when expressed in mouse fibroblasts. The findings suggested that this polymorphic PMS2 allele may modulate tumor responses to cisplatin among cancer patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18768816+12601175" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#24" class="mim-tip-reference" title="Nicolaides, N. C., Carter, K. C., Shell, B. K., Papadopoulos, N., Vogelstein, B., Kinzler, K. W. <strong>Genomic organization of the human PMS2 gene family.</strong> Genomics 30: 195-206, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8586419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8586419</a>] [<a href="https://doi.org/10.1006/geno.1995.9885" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8586419">Nicolaides et al. (1995)</a> found that the PMS2 gene encompasses 16 kb and contains 15 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8586419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#27" class="mim-tip-reference" title="Nicolaides, N. C., Papadopoulos, N., Liu, B., Wei, Y.-F., Carter, K. C., Ruben, S. M., Rosen, C. A., Haseltine, W. A., Fleischmann, R. D., Fraser, C. M., Adams, M. D., Venter, J. C., Dunlop, M. G., Hamilton, S. R., Petersen, G. M., de la Chapelle, A., Vogelstein, B., Kinzler, K. W. <strong>Mutations of two PMS homologues in hereditary nonpolyposis colon cancer.</strong> Nature 371: 75-80, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8072530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8072530</a>] [<a href="https://doi.org/10.1038/371075a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8072530">Nicolaides et al. (1994)</a> mapped the PMS2 gene to chromosome 7 by analysis of somatic cell hybrids and to chromosome 7p22 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8072530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Pseudogenes</em></strong></p><p>
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<a href="#27" class="mim-tip-reference" title="Nicolaides, N. C., Papadopoulos, N., Liu, B., Wei, Y.-F., Carter, K. C., Ruben, S. M., Rosen, C. A., Haseltine, W. A., Fleischmann, R. D., Fraser, C. M., Adams, M. D., Venter, J. C., Dunlop, M. G., Hamilton, S. R., Petersen, G. M., de la Chapelle, A., Vogelstein, B., Kinzler, K. W. <strong>Mutations of two PMS homologues in hereditary nonpolyposis colon cancer.</strong> Nature 371: 75-80, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8072530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8072530</a>] [<a href="https://doi.org/10.1038/371075a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8072530">Nicolaides et al. (1994)</a> and <a href="#8" class="mim-tip-reference" title="De Vos, M., Hayward, B. E., Picton, S., Sheridan, E., Bonthron, D. T. <strong>Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.</strong> Am. J. Hum. Genet. 74: 954-964, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15077197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15077197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15077197[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/10.1086/420796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15077197">De Vos et al. (2004)</a> identified 14 PMS2 pseudogenes that contain copies of some or all of PMS2 exons 1 to 5. Another pseudogene, PMS2CL, is transcribed and corresponds to exons 9 and 11 to 15 of the PMS2 gene. It is embedded in a 100-kb inverted duplication located about 700 kb centromeric to the PMS2 gene. <a href="#13" class="mim-tip-reference" title="Hayward, B. E., De Vos, M., Valleley, E. M. A., Charlton, R. S., Taylor, G. R., Sheridan, E., Bonthron, D. T. <strong>Extensive gene conversion at the PMS2 DNA mismatch repair locus.</strong> Hum. Mutat. 28: 424-430, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17253626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17253626</a>] [<a href="https://doi.org/10.1002/humu.20457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17253626">Hayward et al. (2007)</a> demonstrated that sequence transfer, or a type of 'gene conversion,' between the PMS2 and PMS2CL is an ongoing process that leads to allelic diversity of the PMS2 gene and creates difficulty in mutation analysis. <a href="#13" class="mim-tip-reference" title="Hayward, B. E., De Vos, M., Valleley, E. M. A., Charlton, R. S., Taylor, G. R., Sheridan, E., Bonthron, D. T. <strong>Extensive gene conversion at the PMS2 DNA mismatch repair locus.</strong> Hum. Mutat. 28: 424-430, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17253626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17253626</a>] [<a href="https://doi.org/10.1002/humu.20457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17253626">Hayward et al. (2007)</a> stated that it is 'unsafe' to rely on PCR primer-site selectivity for generating PMS2 amplicons for mutation analysis, but noted that exon 10 is absent from the PMS2CL pseudogene and could be used as an anchor point. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15077197+8072530+17253626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 4</em></strong></p><p>
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In a patient with a family history of hereditary nonpolyposis colorectal cancer (LYNCH4; <a href="/entry/614337">614337</a>), <a href="#27" class="mim-tip-reference" title="Nicolaides, N. C., Papadopoulos, N., Liu, B., Wei, Y.-F., Carter, K. C., Ruben, S. M., Rosen, C. A., Haseltine, W. A., Fleischmann, R. D., Fraser, C. M., Adams, M. D., Venter, J. C., Dunlop, M. G., Hamilton, S. R., Petersen, G. M., de la Chapelle, A., Vogelstein, B., Kinzler, K. W. <strong>Mutations of two PMS homologues in hereditary nonpolyposis colon cancer.</strong> Nature 371: 75-80, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8072530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8072530</a>] [<a href="https://doi.org/10.1038/371075a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8072530">Nicolaides et al. (1994)</a> identified a germline deletion in the PMS2 gene. A second deletion was found in the patient's tumor sample. The tumor from this patient exhibited microsatellite instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8072530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Parsons, R., Li, G.-M., Longley, M., Modrich, P., Liu, B., Berk, T., Hamilton, S. R., Kinzler, K. W., Vogelstein, B. <strong>Mismatch repair deficiency in phenotypically normal human cells.</strong> Science 268: 738-740, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7632227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7632227</a>] [<a href="https://doi.org/10.1126/science.7632227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7632227">Parsons et al. (1995)</a> found that HNPCC patients with germline mutations of either PMS2 or MLH1 had widespread mutations not only in their tumors but also in their nonneoplastic cells. Although these patients had numerous mutations in all the tissues examined, they had very few tumors. The hypermutability was associated with a profound defect in MMR at the biochemical level. The findings suggested that MMR deficiency is compatible with normal human development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7632227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Ma, A.-H., Xia, L., Littman, S. J., Swinler, S., Lader, G., Polinkovsky, A., Olechnowicz, J., Kasturi, L., Lutterbaugh, J., Modrich, P., Veigl, M. L., Markowitz, S. D., Sedwick, W. D. <strong>Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability.</strong> Oncogene 19: 2249-2256, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10822375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10822375</a>] [<a href="https://doi.org/10.1038/sj.onc.1203568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10822375">Ma et al. (2000)</a> reported that in the Vaco481 human colon cancer cell line, the PMS2 gene is inactivated by somatic mutations of both PMS2 alleles. The cell line derived from this tumor was functionally deficient in DNA mismatch repair. The cell line demonstrated microsatellite instability, an elevated HPRT gene (<a href="/entry/308000">308000</a>) mutation rate, and resistance to the cytotoxicity of the alkylator N-methyl-N-prime-nitronitrosoguanidine (MNNG). <a href="#20" class="mim-tip-reference" title="Ma, A.-H., Xia, L., Littman, S. J., Swinler, S., Lader, G., Polinkovsky, A., Olechnowicz, J., Kasturi, L., Lutterbaugh, J., Modrich, P., Veigl, M. L., Markowitz, S. D., Sedwick, W. D. <strong>Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability.</strong> Oncogene 19: 2249-2256, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10822375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10822375</a>] [<a href="https://doi.org/10.1038/sj.onc.1203568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10822375">Ma et al. (2000)</a> concluded that somatic inactivation of PMS2 can play a role in development of sporadic microsatellite unstable colon cancer expressing the full range of cancer phenotypes associated with inactivation of the mismatch repair system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10822375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#40" class="mim-tip-reference" title="Yuan, Z. Q., Gottlieb, B., Beitel, L. K., Wong, N., Gordon, P. H., Wang, Q., Puisieux, A., Foulkes, W. D., Trifiro, M. <strong>Polymorphisms and HNPCC: PMS2-MLH1 protein interactions diminished by single nucleotide polymorphisms.</strong> Hum. Mutat. 19: 108-113, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11793469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11793469</a>] [<a href="https://doi.org/10.1002/humu.10040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11793469">Yuan et al. (2002)</a> noted that the MLH1 (<a href="/entry/120436">120436</a>) and MSH2 (<a href="/entry/609309">609309</a>) proteins interact with PMS1, PMS2, and MSH6 (<a href="/entry/600678">600678</a>) proteins, and that missense mutations in specific regions of MLH1 have been shown to lead to defects in protein-protein interactions with PMS2. They reported that 3 missense alterations previously identified as single-nucleotide polymorphisms (SNPs) in PMS2 (P511K, T597S, and M622I) cause defective protein-protein interactions with MLH1, even though the alterations are not in the previously reported interaction domain. These SNPs can result in gene alterations that have a functional effect on protein phenotype and thus may represent variants carrying an increased risk for tumorigenesis in HNPCC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11793469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Nakagawa, H., Lockman, J. C., Frankel, W. L., Hampel, H., Steenblock, K., Burgart, L. J., Thibodeau, S. N., de la Chapelle, A. <strong>Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation.</strong> Cancer Res. 64: 4721-4727, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15256438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15256438</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-03-2879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15256438">Nakagawa et al. (2004)</a> identified heterozygous germline mutations in the PMS2 gene in 2 unrelated patients with colon cancer without a family history of the disorder. Loss of heterozygosity was detected in the tumor tissue in both cases. Abrogation of the PMS2 protein from 1 allele was seen in 2 additional patients in whom PMS2 mutations could not be detected. <a href="#22" class="mim-tip-reference" title="Nakagawa, H., Lockman, J. C., Frankel, W. L., Hampel, H., Steenblock, K., Burgart, L. J., Thibodeau, S. N., de la Chapelle, A. <strong>Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation.</strong> Cancer Res. 64: 4721-4727, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15256438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15256438</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-03-2879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15256438">Nakagawa et al. (2004)</a> noted that there is a family of PMS2 genes that are highly homologous to the 5-prime region of PMS2. The findings indicated that PMS2 behaves according to the 2-hit Knudson model, but that mutations may be overlooked due to the existence of numerous related genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15256438" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a family with HNPCC meeting the Amsterdam criteria, <a href="#35" class="mim-tip-reference" title="Thompson, E., Meldrum, C. J., Crooks, R., McPhillips, M., Thomas, L., Spigelman, A. D., Scott, R. J. <strong>Hereditary non-polyposis colorectal cancer and the role of hPMS2 and hEXO1 mutations.</strong> Clin. Genet. 65: 215-225, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756672</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00214.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14756672">Thompson et al. (2004)</a> identified a mutation in the PMS2 gene (<a href="#0006">600259.0006</a>) that segregated with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14756672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Worthley, D. L., Walsh, M. D., Barker, M., Ruszkiewicz, A., Bennett, G., Phillips, K., Suthers, G. <strong>Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.</strong> Gastroenterology 128: 1431-1436, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15887124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15887124</a>] [<a href="https://doi.org/10.1053/j.gastro.2005.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15887124">Worthley et al. (2005)</a> tested a cohort of tumor samples from patients with features suggestive of HNPCC for microsatellite instability and exclusive loss of expression of the PMS2 gene in tumor tissue. A kindred was identified with HNPCC due to a heterozygous loss-of-function mutation in the PMS2 gene (<a href="#0007">600259.0007</a>). The authors stated that this was the first description of autosomal dominant HNPCC due to mutation in the PMS2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15887124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hendriks, Y. M. C., Jagmohan-Changur, S., Van der Klift, H. M., Morreau, H., Van Puijenbroek, M., Tops, C., Van Os, T., Wagner, A., Ausems, M. G. F. M., Gomez, E., Breuning, M. J., Brocker-Vriends, A. H. J. T., Vasen, H. F. A., Wijnen, J. T. <strong>Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome).</strong> Gastroenterology 130: 312-322, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16472587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16472587</a>] [<a href="https://doi.org/10.1053/j.gastro.2005.10.052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16472587">Hendriks et al. (2006)</a> analyzed the PMS2 gene in 112 patients from MLH1-, MSH2- and MSH6-negative HNPCC-like families and in 775 tumors from patients with familial colorectal cancer. They identified 4 genomic rearrangements and 3 truncating point mutations (<a href="#0008">600259.0008</a>-<a href="#0010">600259.0010</a>). The pattern of inheritance was autosomal dominant, and mutations segregated with disease. The most common cancer was colorectal carcinoma, followed by endometrial and ovarian carcinomas. The phenotype was milder compared to that of families with MLH1 or MSH2 mutations: the mean age at diagnosis of colorectal carcinoma was 52 years, 7 to 8 years later than that associated with MLH1 and MSH2 mutations. Analysis of tumors from proven carriers showed high microsatellite instability and loss of PMS2 protein expression in all tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16472587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Niessen, R. C., Kleibeuker, J. H., Westers, H., Jager, P. O. J., Rozeveld, D., Bos, K. K., Boersma-van Ek, W., Hollema, H., Sijmons, R. H., Hofstra, R. M. W. <strong>PMS2 involvement in patients suspected of Lynch syndrome.</strong> Genes Chromosomes Cancer 48: 322-329, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19132747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19132747</a>] [<a href="https://doi.org/10.1002/gcc.20642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19132747">Niessen et al. (2009)</a> identified PMS2 mutations in 4 (4%) of 97 patients with early-onset microsatellite-unstable colorectal or endometrial cancer or multiple Lynch-associated tumors. In tumor tissue available from 1 of the mutation carriers, no PMS2 immunoreactivity was detected. None of the 97 patients carried mutations in the MLH1, MSH2, or MSH6 genes. <a href="#28" class="mim-tip-reference" title="Niessen, R. C., Kleibeuker, J. H., Westers, H., Jager, P. O. J., Rozeveld, D., Bos, K. K., Boersma-van Ek, W., Hollema, H., Sijmons, R. H., Hofstra, R. M. W. <strong>PMS2 involvement in patients suspected of Lynch syndrome.</strong> Genes Chromosomes Cancer 48: 322-329, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19132747/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19132747</a>] [<a href="https://doi.org/10.1002/gcc.20642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19132747">Niessen et al. (2009)</a> commented that the frequency of PMS2 mutations in Lynch syndrome patients may be higher than previously expected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19132747" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#32" 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 (<a href="/entry/600678">600678</a>), and 124 in PMS2. 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="#32" 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 2 MMR genes MSH6 and PMS2, mutations in which cause HNPCC5 (<a href="/entry/614350">614350</a>) and HNPCC4, 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 4</em></strong></p><p>
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Mismatch repair cancer syndrome-4 (MMRCS4; <a href="/entry/619101">619101</a>) is characterized classically by the concurrence of a primary brain tumor and multiple colorectal adenomas; this association is also sometimes referred to as Turcot syndrome. In a patient with glioblastoma and colonic adenomas, <a href="#12" class="mim-tip-reference" title="Hamilton, S. R., Liu, B., Parsons, R. E., Papadopoulos, N., Jen, J., Powell, S. M., Krush, A. J., Berk, T., Cohen, Z., Tetu, B., Burger, P. C., Wood, P. A., Taqi, F., Booker, S. V., Petersen, G. M., Offerhaus, G. J. A., Tersmette, A. C., Giardiello, F. M., Vogelstein, B., Kinzler, K. W. <strong>The molecular basis of Turcot's syndrome.</strong> New Eng. J. Med. 332: 839-847, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7661930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7661930</a>] [<a href="https://doi.org/10.1056/NEJM199503303321302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7661930">Hamilton et al. (1995)</a> identified a mutation in the PMS2 gene (R134X; <a href="#0001">600259.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7661930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Trimbath, J. D., Petersen, G. M., Erdman, S. H., Ferre, M., Luce, M. C., Giardiello, F. M. <strong>Cafe-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC?</strong> Fam. Cancer 1: 101-105, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14574005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14574005</a>] [<a href="https://doi.org/10.1023/a:1013881832014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14574005">Trimbath et al. (2001)</a> identified a homozygous mutation in the PMS2 gene (<a href="#0013">600259.0013</a>) in affected members of a consanguineous Guyanese family with variable expression of colorectal adenocarcinoma, acute leukemia, brain tumors, and cafe-au-lait spots. The authors noted that the phenotype of mismatch repair deficiency should include cafe-au-lait spots and hematologic malignancies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14574005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 affected members of a consanguineous family with early-onset brain tumors, <a href="#8" class="mim-tip-reference" title="De Vos, M., Hayward, B. E., Picton, S., Sheridan, E., Bonthron, D. T. <strong>Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.</strong> Am. J. Hum. Genet. 74: 954-964, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15077197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15077197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15077197[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/10.1086/420796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15077197">De Vos et al. (2004)</a> identified a homozygous mutation in exon 14 of the PMS2 gene (R802X; <a href="#0004">600259.0004</a>). Heterozygous family members had no cancer predisposition. Genome searches revealed a previously unrecognized pseudogene PMS2CL, corresponding to exons 9-15, within a 100-kb inverted duplication situated 600 kb centromeric from PMS2 itself. Furthermore, in the family with Turcot syndrome (<a href="#12" class="mim-tip-reference" title="Hamilton, S. R., Liu, B., Parsons, R. E., Papadopoulos, N., Jen, J., Powell, S. M., Krush, A. J., Berk, T., Cohen, Z., Tetu, B., Burger, P. C., Wood, P. A., Taqi, F., Booker, S. V., Petersen, G. M., Offerhaus, G. J. A., Tersmette, A. C., Giardiello, F. M., Vogelstein, B., Kinzler, K. W. <strong>The molecular basis of Turcot's syndrome.</strong> New Eng. J. Med. 332: 839-847, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7661930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7661930</a>] [<a href="https://doi.org/10.1056/NEJM199503303321302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7661930">Hamilton et al., 1995</a>) in which the first inherited PMS2 mutation (R134X; <a href="#0001">600259.0001</a>) was described, a truncating mutation was identified on the other allele (<a href="#0005">600259.0005</a>). The findings indicated autosomal recessive inheritance of the disorder. <a href="#8" class="mim-tip-reference" title="De Vos, M., Hayward, B. E., Picton, S., Sheridan, E., Bonthron, D. T. <strong>Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.</strong> Am. J. Hum. Genet. 74: 954-964, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15077197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15077197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15077197[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/10.1086/420796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15077197">De Vos et al. (2004)</a> found that the complexity of PMS2 pseudogenes is greater than appreciated and may have hindered previous mutation studies. Several previously reported PMS2 polymorphisms may, in fact, be pseudogene sequence variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15077197+7661930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sisters with mismatch repair cancer syndrome, <a href="#2" 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 PMS2 gene (<a href="#0011">600259.0011</a>, <a href="#0012">600259.0012</a>). Both patients had colon cancer; 1 also had oligodendroglioma and the other also had endometrial cancer and cafe-au-lait spots. <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><p><a href="#9" class="mim-tip-reference" title="Etzler, J., Peyrl, A., Zatkova, A., Schildhaus, H.-U., Ficek, A., Merkelbach-Bruse, S., Kratz, C. P., Attarbaschi, A., Hainfellner, J. A., Yao, S., Messiaen, L., Slavc, I., Wimmer, K. <strong>RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference.</strong> Hum. Mutat. 29: 299-305, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18030674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18030674</a>] [<a href="https://doi.org/10.1002/humu.20657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18030674">Etzler et al. (2008)</a> developed an RNA-based assay using direct cDNA sequencing of RT-PCR products to identify a homozygous mutation in the PMS2 gene (<a href="#0014">600259.0014</a>) in a patient with mismatch repair deficiency who had glioblastoma multiforme. Studies of an unrelated healthy individual confirmed the utility of the RNA technique to correctly distinguish PMS2 from its PMS2CL pseudogene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18030674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Peron, S., Metin, A., Gardes, P., Alyanakian, M.-A., Sheridan, E., Kratz, C. P., Fischer, A., Durandy, A. <strong>Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination.</strong> J. Exp. Med. 205: 2465-2472, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824584</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824584[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/10.1084/jem.20080789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824584">Peron et al. (2008)</a> reported that 3 patients with mismatch repair cancer syndrome due to different homozygous mutations in the PMS2 gene exhibited Ig class switch recombination (CSR) deficiency. Two of the patients had been previously reported by <a href="#7" class="mim-tip-reference" title="De Vos, M., Hayward, B. E., Charlton, R., Taylor, G. R., Glaser, A. W., Picton, S., Cole, T. R., Maher, E. R., McKeown, C. M. E., Mann, J. R., Yates, J. R., Baralle, D., Rankin, J., Bonthron, D. T., Sheridan, E. <strong>PMS2 mutations in childhood cancer.</strong> J. Nat. Cancer Inst. 98: 358-361, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16507833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16507833</a>] [<a href="https://doi.org/10.1093/jnci/djj073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16507833">De Vos et al. (2006)</a> and <a href="#17" class="mim-tip-reference" title="Kratz, C. P., Niemeyer, C. M., Juttner, E., Kartal, M., Weninger, A., Schmitt-Graeff, A., Kontny, U., Lauten, M., Utzolino, S., Radecke, J., Fonatsch, C., Wimmer, K. <strong>Childhood T-cell non-Hodgkin's lymphoma, colorectal carcinoma and brain tumor in association with cafe-au-lait spots caused by a novel homozygous PMS2 mutation. (Letter)</strong> Leukemia 22: 1078-1080, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18007577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18007577</a>] [<a href="https://doi.org/10.1038/sj.leu.2405008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18007577">Kratz et al. (2008)</a> and carried homozygous R802X and frameshift (<a href="#0017">600259.0017</a>) mutations, respectively. The patient who had not been previously reported, a 12-year-old Turkish girl, had a homozygous deletion of exons 11 through 14 and an 18-nucleotide frameshift insertion and stop codon at the beginning of exon 15 (<a href="#0018">600259.0018</a>). Her consanguineous parents were heterozygous for the mutation. In vitro analysis showed that the CSR defect was characterized by the occurrence of double-strand DNA breaks (DSBs) in switch regions and abnormal formation of switch junctions. <a href="#31" class="mim-tip-reference" title="Peron, S., Metin, A., Gardes, P., Alyanakian, M.-A., Sheridan, E., Kratz, C. P., Fischer, A., Durandy, A. <strong>Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination.</strong> J. Exp. Med. 205: 2465-2472, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824584</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824584[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/10.1084/jem.20080789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824584">Peron et al. (2008)</a> proposed that PMS2 has a role in CSR-induced DSB generation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16507833+18007577+18824584" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>PMS2 Mutation Detection</em></strong></p><p>
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The 3-prime end of the PMS2 gene contains the transcribed PMS2CL pseudogene. PMS2 mutation detection is complicated by the occurrence of sequence exchange events between the duplicated regions of PMS2 and PMS2CL, consisting of exons 9 and 11 to 15 (<a href="#13" class="mim-tip-reference" title="Hayward, B. E., De Vos, M., Valleley, E. M. A., Charlton, R. S., Taylor, G. R., Sheridan, E., Bonthron, D. T. <strong>Extensive gene conversion at the PMS2 DNA mismatch repair locus.</strong> Hum. Mutat. 28: 424-430, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17253626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17253626</a>] [<a href="https://doi.org/10.1002/humu.20457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17253626">Hayward et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17253626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Ganster, C., Wernstedt, A., Kehrer-Sawatzki, H., Messiaen, L., Schmidt, K., Rahner, N., Heinimann, K., Fonatsch, C., Zschocke, J., Wimmer, K. <strong>Functional PMS2 hybrid alleles containing a pseudogene-specific missense variant trace back to a single ancient intrachromosomal recombination event.</strong> Hum. Mutat. 31: 552-560, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20186689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20186689</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20186689[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20186689">Ganster et al. (2010)</a> genotyped exons 11 to 15 of the PMS2 gene in 192 individuals from different ethnic backgrounds. About one-third of individuals carried hybrid alleles of PMS2 with pseudogene-specific variants (PSV). Depending on the population, 14 to 60% of these hybrid alleles carried PMS2CL-specific sequences in exons 13 to 15, with the remainder only in exon 15. These exon 13-15 hybrid alleles, which they called H1 hybrid alleles, constituted different haplotypes that could be traced back to a single ancient intrachromosomal recombination event with crossover. <a href="#10" class="mim-tip-reference" title="Ganster, C., Wernstedt, A., Kehrer-Sawatzki, H., Messiaen, L., Schmidt, K., Rahner, N., Heinimann, K., Fonatsch, C., Zschocke, J., Wimmer, K. <strong>Functional PMS2 hybrid alleles containing a pseudogene-specific missense variant trace back to a single ancient intrachromosomal recombination event.</strong> Hum. Mutat. 31: 552-560, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20186689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20186689</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20186689[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20186689">Ganster et al. (2010)</a> developed a genomic DNA-based PCR assay that could be used to identify H1 hybrid allele carriers with high sensitivity and specificity (100% and 99%, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20186689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="van der Klift, H. M., Tops, C. M. J., Bik, E. C., Boogaard, M. W., Borgstein, A.-M., Hansson, K. B. M., Ausems, M. G. E. M., Gomez Garcia, E., Green, A., Hes, F. J., Izatt, L., van Hest, L. P., Alonso, A. M., Vriends, A. H. J. T., Wagner, A., van Zelst-Stams, W. A. G., Vasen, H. F. A., Morreau, H., Devilee, P., Wijnen, J. T. <strong>Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients.</strong> Hum. Mutat. 31: 578-587, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20186688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20186688</a>] [<a href="https://doi.org/10.1002/humu.21229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20186688">Van der Klift et al. (2010)</a> identified sequence transfers between the PMS2CL pseudogene and the PMS2 gene involving intron 12 to the 3-prime end of the PMS2 gene in 4 to 52% of DNA samples. Overall, sequence exchanges between PMS2 and PMS2CL were observed in 69% (83 of 120) of individuals. There was no significant difference in sequence transfer between 25 controls and 95 patients with colorectal cancer, suggesting that these variants have only a mild or neutral effect on gene function. However, these sequence events may influence genetic testing. <a href="#37" class="mim-tip-reference" title="van der Klift, H. M., Tops, C. M. J., Bik, E. C., Boogaard, M. W., Borgstein, A.-M., Hansson, K. B. M., Ausems, M. G. E. M., Gomez Garcia, E., Green, A., Hes, F. J., Izatt, L., van Hest, L. P., Alonso, A. M., Vriends, A. H. J. T., Wagner, A., van Zelst-Stams, W. A. G., Vasen, H. F. A., Morreau, H., Devilee, P., Wijnen, J. T. <strong>Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients.</strong> Hum. Mutat. 31: 578-587, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20186688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20186688</a>] [<a href="https://doi.org/10.1002/humu.21229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20186688">Van der Klift et al. (2010)</a> presented an RNA-based mutation detection strategy to improve reliability. Using this strategy, 19 different putative pathogenic PMS2 mutations were identified, 4 (21%) of which were in the region with frequent sequence transfer, and had been missed or incorrectly interpreted as homozygous with other detection methods. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20186688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Vaughn, C. P., Robles, J., Swensen, J. J., Miller, C. E., Lyon, E., Mao, R., Bayrak-Toydemir, P., Samowitz, W. S. <strong>Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes.</strong> Hum. Mutat. 31: 588-593, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20205264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20205264</a>] [<a href="https://doi.org/10.1002/humu.21230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20205264">Vaughn et al. (2010)</a> identified pathogenic mutations in the PMS2 gene in 22 (37%) of 59 patients with colorectal cancer who showed loss of PMS2 protein expression by immunohistochemistry. The mutations were detected using a long-range PCR product spanning exons 11 to 15 of the PMS2 gene, with the forward primer anchored in exon 10, which is not shared by the PMS2CL pseudogene. An additional 3 patients with PMS2 mutations were found among 53 colorectal samples without immunohistochemical studies. Ten (37%) of the 27 mutations detected were large deletions encompassing 1 or more exons. <a href="#38" class="mim-tip-reference" title="Vaughn, C. P., Robles, J., Swensen, J. J., Miller, C. E., Lyon, E., Mao, R., Bayrak-Toydemir, P., Samowitz, W. S. <strong>Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes.</strong> Hum. Mutat. 31: 588-593, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20205264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20205264</a>] [<a href="https://doi.org/10.1002/humu.21230" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20205264">Vaughn et al. (2010)</a> emphasized the importance of using methods that can reliably distinguish between PMS2 and its PMS2CL pseudogene in the diagnosis of mutations at the 3-prime end of PMS2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20205264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using gene targeting in embryonic stem cells, <a href="#3" class="mim-tip-reference" title="Baker, S. M., Bronner, C. E., Zhang, L., Plug, A. W., Robatzek, M., Warren, G., Elliott, E. A., Yu, J., Ashley, T., Arnheim, N., Flavell, R. A., Liskay, R. M. <strong>Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis.</strong> Cell 82: 309-319, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7628019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7628019</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90318-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7628019">Baker et al. (1995)</a> generated a line of mice with a null mutation in the Pms2 gene. They observed microsatellite instability in the male germline and in tumor DNA of Pms2-deficient animals. They concluded, therefore, that Pms2 is involved in DNA mismatch repair in a variety of tissues. The deficient animals appeared prone to sarcomas and lymphomas. Pms2-deficient males were infertile, producing only abnormal spermatozoa. Analysis of axial element and synaptonemal complex formation during prophase of meiosis I indicated abnormalities in chromosome synapsis. These observations suggested links among MMR, genetic recombination, and chromosome synapsis in meiosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7628019" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 the effect of Pms2 inactivation on genomic integrity in vivo, <a href="#23" class="mim-tip-reference" title="Narayanan, L., Fritzell, J. A., Baker, S. M., Liskay, R. M., Glazer, P. M. <strong>Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2.</strong> Proc. Nat. Acad. Sci. 94: 3122-3127, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9096356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9096356</a>] [<a href="https://doi.org/10.1073/pnas.94.7.3122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9096356">Narayanan et al. (1997)</a> constructed hybrid transgenic mice that carry targeted disruptions at the Pms2 locus along with a chromosomally integrated mutation reporter gene. In the absence of any mutagenic treatment, mice nullizygous for Pms2 showed a 100-fold elevation in mutation frequency in all tissues examined compared with both wildtype and heterozygous littermates. The mutation pattern in the nullizygotes was notable for frequent 1-bp deletions and insertions within mononucleotide repeat sequences, consistent with an essential role for PMS2 in the repair of replication slippage errors. Further, the results demonstrated that high rates of mutagenesis in multiple tissues are compatible with normal development and life and are not necessarily associated with accelerated aging. Also, the finding of genetic instability in all tissues tested contrasted with the limited tissue distribution of cancers in the animals, raising important questions regarding the role of mutagenesis in carcinogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9096356" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Gomes-Pereira, M., Fortune, M. T., Ingram, L., McAbney, J. P., Monckton, D. G. <strong>Pms2 is a genetic enhancer of trinucleotide CAG/CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion.</strong> Hum. Molec. Genet. 13: 1815-1825, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15198993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15198993</a>] [<a href="https://doi.org/10.1093/hmg/ddh186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15198993">Gomes-Pereira et al. (2004)</a> determined that the rate of somatic expansion of a transgenic CAG/CTG repeat in Pms2 -/- mice was reduced by 50% compared to Pms2 +/- mice. A higher frequency of rare, but very large, deletions was also detected in these animals. No significant differences were observed between Pms2 +/+ and Pms2 +/- mice, suggesting that a single functional Pms2 allele is sufficient to generate normal levels of somatic mosaicism. <a href="#11" class="mim-tip-reference" title="Gomes-Pereira, M., Fortune, M. T., Ingram, L., McAbney, J. P., Monckton, D. G. <strong>Pms2 is a genetic enhancer of trinucleotide CAG/CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion.</strong> Hum. Molec. Genet. 13: 1815-1825, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15198993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15198993</a>] [<a href="https://doi.org/10.1093/hmg/ddh186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15198993">Gomes-Pereira et al. (2004)</a> hypothesized that, in addition to MMR enzymes that directly bind mismatched DNA, proteins that are subsequently recruited to the complex may also play a central role in the accumulation of repeat-length changes. They suggested that somatic expansion results not by replication slippage, single-stranded annealing, or simple MutS-mediated stabilization of secondary structures, but rather by inappropriate DNA mismatch repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15198993" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 order to study mismatch repair in response to dysfunctional telomeres, <a href="#34" class="mim-tip-reference" title="Siegl-Cachedenier, I., Munoz, P., Flores, J. M., Klatt, P., Blasco, M. A. <strong>Deficient mismatch repair improves organismal fitness and survival of mice with dysfunctional telomeres.</strong> Genes Dev. 21: 2234-2247, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17785530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17785530</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17785530[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.430107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17785530">Siegl-Cachedenier et al. (2007)</a> generated mice deficient for both telomerase (TERC; <a href="/entry/602322">602322</a>) and Pms2. Pms2 deficiency prolonged the mean life span and median survival of telomerase-deficient mice concomitant with rescue of degenerative pathologies. Rescue of survival was independent of changes in telomere length, sister telomere recombination, and microsatellite instability. Pms2 deficiency rescued cell proliferation defects but not apoptotic defects in vivo, concomitant with a decreased p21 (CDKN1A; <a href="/entry/116899">116899</a>) induction in response to short telomeres. The proliferative advantage conferred to telomerase-deficient cells by ablation of Pms2 did not produce increased tumors; indeed, Terc-null/Pms2-null mice showed reduced tumors compared with Pms2-null mice. <a href="#34" class="mim-tip-reference" title="Siegl-Cachedenier, I., Munoz, P., Flores, J. M., Klatt, P., Blasco, M. A. <strong>Deficient mismatch repair improves organismal fitness and survival of mice with dysfunctional telomeres.</strong> Genes Dev. 21: 2234-2247, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17785530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17785530</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17785530[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.430107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17785530">Siegl-Cachedenier et al. (2007)</a> concluded that deficiency in mismatch repair rescues organismal survival and proliferation in telomerase-deficient mice by attenuating the antiproliferative response associated with short telomeres. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17785530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an 18-year-old man (family 12) with colonic adenomas, lymphoma of the rectum, glioblastoma, and multiple cafe-au-lait spots consistent with mismatch repair cancer syndrome (MMRCS4; <a href="/entry/619101">619101</a>), <a href="#12" class="mim-tip-reference" title="Hamilton, S. R., Liu, B., Parsons, R. E., Papadopoulos, N., Jen, J., Powell, S. M., Krush, A. J., Berk, T., Cohen, Z., Tetu, B., Burger, P. C., Wood, P. A., Taqi, F., Booker, S. V., Petersen, G. M., Offerhaus, G. J. A., Tersmette, A. C., Giardiello, F. M., Vogelstein, B., Kinzler, K. W. <strong>The molecular basis of Turcot's syndrome.</strong> New Eng. J. Med. 332: 839-847, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7661930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7661930</a>] [<a href="https://doi.org/10.1056/NEJM199503303321302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7661930">Hamilton et al. (1995)</a> identified a heterozygous C-to-T transition in the PMS2 gene, resulting in an arg134-to-ter (R134X) substitution. His sister had colonic carcinoma and cafe-au-lait spots. In this family, <a href="#8" class="mim-tip-reference" title="De Vos, M., Hayward, B. E., Picton, S., Sheridan, E., Bonthron, D. T. <strong>Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.</strong> Am. J. Hum. Genet. 74: 954-964, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15077197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15077197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15077197[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/10.1086/420796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15077197">De Vos et al. (2004)</a> identified a second mutation in the PMS2 gene: a heterozygous 2-bp deletion in exon 13, within a repeated dinucleotide (CTCT) at codon 728-729 (<a href="#0005">600259.0005</a>). The findings were consistent with autosomal recessive inheritance of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15077197+7661930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Nicolaides, N. C., Littman, S. J., Modrich, P., Kinzler, K. W., Vogelstein, B. <strong>A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype.</strong> Molec. Cell. Biol. 18: 1635-1641, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9488480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9488480</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9488480[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/10.1128/MCB.18.3.1635" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9488480">Nicolaides et al. (1998)</a> presented experimental evidence that the R134X substitution was sufficient to reduce mismatch repair and induce microsatellite instability in cells containing a wildtype PMS2 allele, suggesting that it could act in a dominant-negative manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9488480" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000009816 OR RCV000076802 OR RCV002228025 OR RCV003298029" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009816, RCV000076802, RCV002228025, RCV003298029" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009816...</a>
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<p>In a girl with early-onset brain tumor and colorectal cancer (MMRCS4; <a href="/entry/619101">619101</a>), <a href="#6" class="mim-tip-reference" title="De Rosa, M., Fasano, C., Panariello, L., Scarano, M. I., Belli, G., Iannelli, A., Ciciliano, F., Izzo, P. <strong>Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.</strong> Oncogene 19: 1719-1723, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10763829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10763829</a>] [<a href="https://doi.org/10.1038/sj.onc.1203447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10763829">De Rosa et al. (2000)</a> identified 2 germline mutations in the PMS2 gene: a 1-bp deletion (1221delG) in exon 11 and a 4-bp deletion in exon 14 (2361delCTTC; <a href="#0003">600259.0003</a>). The former mutation was inherited from the mother and the latter from the father. Both mutations resulted in loss of the MLH1 interaction domain of PMS2. The patient died at the age of 18 years. Her sister, whose DNA was not available for analysis, had a neuroblastoma of the brain at the age of 13 years and died at the age of 14 years. The first sister had marked microsatellite instability in both tumor and normal colon mucosa. The tumor also had somatic mutations in the TGFBR2 (<a href="/entry/190182">190182</a>) and APC (<a href="/entry/611731">611731</a>) genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10763829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267608160 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608160;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=rs267608160" 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=rs267608160" 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=RCV000009817 OR RCV000076853 OR RCV000572699 OR RCV000629975 OR RCV000657184 OR RCV003452991" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009817, RCV000076853, RCV000572699, RCV000629975, RCV000657184, RCV003452991" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009817...</a>
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<p>For discussion of the 4-bp deletion in the PMS2 gene (2361delCTTC) that was found in compound heterozygous state in 2 sisters with early-onset brain tumors (MMRCS4; <a href="/entry/619101">619101</a>) by <a href="#6" class="mim-tip-reference" title="De Rosa, M., Fasano, C., Panariello, L., Scarano, M. I., Belli, G., Iannelli, A., Ciciliano, F., Izzo, P. <strong>Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.</strong> Oncogene 19: 1719-1723, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10763829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10763829</a>] [<a href="https://doi.org/10.1038/sj.onc.1203447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10763829">De Rosa et al. (2000)</a>, see <a href="#0002">600259.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10763829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0004 MISMATCH REPAIR CANCER SYNDROME 4</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"><span class="text-primary">●</span> rs63751466 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63751466;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/rs63751466?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=rs63751466" 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=rs63751466" 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=RCV000009818 OR RCV000076858 OR RCV000129304 OR RCV000409056 OR RCV000413126 OR RCV000524467 OR RCV001257544 OR RCV001267876 OR RCV002265552 OR RCV003415681 OR RCV004691719 OR RCV005031433" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009818, RCV000076858, RCV000129304, RCV000409056, RCV000413126, RCV000524467, RCV001257544, RCV001267876, RCV002265552, RCV003415681, RCV004691719, RCV005031433" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009818...</a>
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<p>In affected sibs of a consanguineous family with cutaneous cafe-au-lait spots and early-onset brain tumors (MMRCS4; <a href="/entry/619101">619101</a>), <a href="#8" class="mim-tip-reference" title="De Vos, M., Hayward, B. E., Picton, S., Sheridan, E., Bonthron, D. T. <strong>Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.</strong> Am. J. Hum. Genet. 74: 954-964, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15077197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15077197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15077197[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/10.1086/420796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15077197">De Vos et al. (2004)</a> identified a homozygous 2428C-to-T transition in exon 14 of the PMS2 gene, resulting in an arg802-to-ter (R802X) substitution. The oldest sib developed a cerebral high grade B-cell non-Hodgkin lymphoma at age 10 years. The next younger sib had a cerebral primitive neuroectodermal tumor (PNET) at age 9 years. The third sib had mild learning difficulties and a supratentorial primitive neuroectodermal tumor (SPNET) at age 14 years. A pair of double first cousins, aged 10 years, had cafe-au-lait spots and mild learning difficulties, but no history of cancer. No Lisch nodules or additional features of NF1 (<a href="/entry/162200">162200</a>) were present in any of the affected individuals or in the parents. There was no family history of colorectal or endometrial adenocarcinoma. Colonoscopy in the parents of the 3 affected sibs was normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15077197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="De Vos, M., Hayward, B. E., Charlton, R., Taylor, G. R., Glaser, A. W., Picton, S., Cole, T. R., Maher, E. R., McKeown, C. M. E., Mann, J. R., Yates, J. R., Baralle, D., Rankin, J., Bonthron, D. T., Sheridan, E. <strong>PMS2 mutations in childhood cancer.</strong> J. Nat. Cancer Inst. 98: 358-361, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16507833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16507833</a>] [<a href="https://doi.org/10.1093/jnci/djj073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16507833">De Vos et al. (2006)</a> identified homozygosity for the R802X mutation in 11 patients from 5 consanguineous families of Pakistani origin living in the UK. All 5 families were from the northeastern Mirpur region of Pakistan, but there was no known blood relationship among them. Further analysis of polymorphisms suggested an ancestral founder effect for the mutation. The patients had cafe-au-lait skin patches and hematologic, brain, and/or colorectal cancers in childhood or adolescence that resulted in death in 8 of the patients. <a href="#7" class="mim-tip-reference" title="De Vos, M., Hayward, B. E., Charlton, R., Taylor, G. R., Glaser, A. W., Picton, S., Cole, T. R., Maher, E. R., McKeown, C. M. E., Mann, J. R., Yates, J. R., Baralle, D., Rankin, J., Bonthron, D. T., Sheridan, E. <strong>PMS2 mutations in childhood cancer.</strong> J. Nat. Cancer Inst. 98: 358-361, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16507833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16507833</a>] [<a href="https://doi.org/10.1093/jnci/djj073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16507833">De Vos et al. (2006)</a> proposed that early accurate diagnosis of this cancer syndrome is important to optimize the therapeutic response and to manage the risk to sibs of tumor development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16507833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0005 MISMATCH REPAIR CANCER SYNDROME 4</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"><span class="text-primary">●</span> rs587779335 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587779335;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/rs587779335?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=rs587779335" 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=rs587779335" 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=RCV000009819 OR RCV000172821 OR RCV000365642 OR RCV000544078 OR RCV000573464 OR RCV000778109 OR RCV001267877 OR RCV001293420 OR RCV001353688 OR RCV002267843 OR RCV003415835 OR RCV003436927 OR RCV003492428" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009819, RCV000172821, RCV000365642, RCV000544078, RCV000573464, RCV000778109, RCV001267877, RCV001293420, RCV001353688, RCV002267843, RCV003415835, RCV003436927, RCV003492428" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009819...</a>
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<p>In the family with mismatch repair cancer syndrome (MMRCS4; <a href="/entry/619101">619101</a>) in which <a href="#12" class="mim-tip-reference" title="Hamilton, S. R., Liu, B., Parsons, R. E., Papadopoulos, N., Jen, J., Powell, S. M., Krush, A. J., Berk, T., Cohen, Z., Tetu, B., Burger, P. C., Wood, P. A., Taqi, F., Booker, S. V., Petersen, G. M., Offerhaus, G. J. A., Tersmette, A. C., Giardiello, F. M., Vogelstein, B., Kinzler, K. W. <strong>The molecular basis of Turcot's syndrome.</strong> New Eng. J. Med. 332: 839-847, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7661930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7661930</a>] [<a href="https://doi.org/10.1056/NEJM199503303321302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7661930">Hamilton et al. (1995)</a> first demonstrated a heterozygous mutation in the PMS2 gene (<a href="#0001">600259.0001</a>), <a href="#8" class="mim-tip-reference" title="De Vos, M., Hayward, B. E., Picton, S., Sheridan, E., Bonthron, D. T. <strong>Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.</strong> Am. J. Hum. Genet. 74: 954-964, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15077197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15077197</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15077197[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/10.1086/420796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15077197">De Vos et al. (2004)</a> found a second heterozygous 2-bp deletion in exon 13, within a repeated dinucleotide (CTCT) at codon 728-729 (2184delTC) in both affected sibs. Thus, the sibs were compound heterozygotes, indicating autosomal recessive inheritance of the disorder. The deletion was inherited from the mother. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15077197+7661930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0006 LYNCH SYNDROME 4</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"><span class="text-primary">●</span> rs267608159 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608159;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/rs267608159?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=rs267608159" 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=rs267608159" 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=RCV000009820" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009820" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009820</a>
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<p>In a family with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria (LYNCH4; <a href="/entry/614337">614337</a>), <a href="#35" class="mim-tip-reference" title="Thompson, E., Meldrum, C. J., Crooks, R., McPhillips, M., Thomas, L., Spigelman, A. D., Scott, R. J. <strong>Hereditary non-polyposis colorectal cancer and the role of hPMS2 and hEXO1 mutations.</strong> Clin. Genet. 65: 215-225, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756672</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00214.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14756672">Thompson et al. (2004)</a> identified a 3-bp deletion in exon 11 of the PMS2 gene, resulting in deletion of lysine-412 (lys412del). The mutation segregated with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14756672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs63750049 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63750049;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=rs63750049" 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=rs63750049" 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=RCV000009821 OR RCV000076793 OR RCV000220282 OR RCV000530149 OR RCV000570955 OR RCV001375488" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009821, RCV000076793, RCV000220282, RCV000530149, RCV000570955, RCV001375488" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009821...</a>
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<p>In a family fulfilling the Amsterdam II criteria for a clinical diagnosis of hereditary nonpolyposis colorectal cancer (LYNCH4; <a href="/entry/614337">614337</a>), <a href="#39" class="mim-tip-reference" title="Worthley, D. L., Walsh, M. D., Barker, M., Ruszkiewicz, A., Bennett, G., Phillips, K., Suthers, G. <strong>Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.</strong> Gastroenterology 128: 1431-1436, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15887124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15887124</a>] [<a href="https://doi.org/10.1053/j.gastro.2005.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15887124">Worthley et al. (2005)</a> identified heterozygosity for a 1021delA mutation in exon 10 of the PMS2 gene, resulting in a frameshift and a stop codon at position 355. The proband was diagnosed with cancer of the transverse colon at age 49 and underwent hemicolectomy and adjuvant chemotherapy; 2 years later he developed and subsequently died of metastatic esophageal carcinoma. His mutation-positive mother developed endometrial cancer at 60 years of age, had 3 polyps identified in her proximal colon in her early 70s, and subsequently developed carcinoma of the cecum at age 80. His maternal grandfather had colorectal cancer at 66 years of age, while a maternal great-uncle developed colorectal cancer at 45 years of age. The proband's brother, who also had the mutation, had 2 sessile polyps removed from the sigmoid colon at 47 and 49 years of age, respectively; the tissue was unavailable for histology. A maternal uncle who died of metastatic squamous cell carcinoma of the esophagus did not carry the mutation; nor, presumably, did his daughter who was diagnosed with breast cancer at 25 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15887124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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PMS2, IVS10, T-A, +2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608158 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608158;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=rs267608158" 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=rs267608158" 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=RCV000009822 OR RCV000076796" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009822, RCV000076796" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009822...</a>
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<p>In a family (family 5) with hereditary nonpolyposis colorectal cancer (LYNCH4; <a href="/entry/614337">614337</a>), <a href="#14" class="mim-tip-reference" title="Hendriks, Y. M. C., Jagmohan-Changur, S., Van der Klift, H. M., Morreau, H., Van Puijenbroek, M., Tops, C., Van Os, T., Wagner, A., Ausems, M. G. F. M., Gomez, E., Breuning, M. J., Brocker-Vriends, A. H. J. T., Vasen, H. F. A., Wijnen, J. T. <strong>Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome).</strong> Gastroenterology 130: 312-322, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16472587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16472587</a>] [<a href="https://doi.org/10.1053/j.gastro.2005.10.052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16472587">Hendriks et al. (2006)</a> identified heterozygosity for a mutation in intron 10 of the PMS2 gene (c.1144+2T-A) that was predicted to affect correct splicing. The mutation cosegregated with disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16472587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 4</strong>
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PMS2, ARG628TER
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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> rs63750451 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63750451;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/rs63750451?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=rs63750451" 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=rs63750451" 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=RCV000009823 OR RCV000076834 OR RCV000218575 OR RCV000220439 OR RCV000524451 OR RCV001193819" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009823, RCV000076834, RCV000218575, RCV000220439, RCV000524451, RCV001193819" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009823...</a>
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<p>In a family with hereditary nonpolyposis colorectal cancer (LYNCH4; <a href="/entry/614337">614337</a>), <a href="#14" class="mim-tip-reference" title="Hendriks, Y. M. C., Jagmohan-Changur, S., Van der Klift, H. M., Morreau, H., Van Puijenbroek, M., Tops, C., Van Os, T., Wagner, A., Ausems, M. G. F. M., Gomez, E., Breuning, M. J., Brocker-Vriends, A. H. J. T., Vasen, H. F. A., Wijnen, J. T. <strong>Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome).</strong> Gastroenterology 130: 312-322, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16472587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16472587</a>] [<a href="https://doi.org/10.1053/j.gastro.2005.10.052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16472587">Hendriks et al. (2006)</a> identified heterozygosity for a 1882C-T transition in exon 11 of the PMS2 gene, predicted to result in an arg628-to-ter (R628X) substitution. The mutation cosegregated with disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16472587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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PMS2, 1-BP DEL, 856G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057515571 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057515571;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=rs1057515571" 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=rs1057515571" 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=RCV000009824" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009824" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009824</a>
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<p>In a family with hereditary nonpolyposis colorectal cancer (LYNCH4; <a href="/entry/614337">614337</a>), <a href="#14" class="mim-tip-reference" title="Hendriks, Y. M. C., Jagmohan-Changur, S., Van der Klift, H. M., Morreau, H., Van Puijenbroek, M., Tops, C., Van Os, T., Wagner, A., Ausems, M. G. F. M., Gomez, E., Breuning, M. J., Brocker-Vriends, A. H. J. T., Vasen, H. F. A., Wijnen, J. T. <strong>Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome).</strong> Gastroenterology 130: 312-322, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16472587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16472587</a>] [<a href="https://doi.org/10.1053/j.gastro.2005.10.052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16472587">Hendriks et al. (2006)</a> identified heterozygosity for a 1-bp deletion (856delG) in exon 8 of the PMS2 gene, predicted to cause a frameshift and a premature stop at aspartic acid-286. The mutation cosegregated with disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16472587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0011 MISMATCH REPAIR CANCER SYNDROME 4</strong>
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PMS2, LYS577FS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057515572 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057515572;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=rs1057515572" 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=rs1057515572" 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=RCV000009825 OR RCV000657177 OR RCV000678287 OR RCV001012887 OR RCV001357852 OR RCV003478973" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009825, RCV000657177, RCV000678287, RCV001012887, RCV001357852, RCV003478973" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009825...</a>
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<p>In 2 sisters with mismatch repair cancer syndrome (MMRCS4; <a href="/entry/619101">619101</a>), <a href="#2" 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 PMS2 gene: S46I (<a href="#0012">600259.0012</a>) and a frameshift at lys577 resulting from a gene conversion event with the paralogous pseudogene PMS2CL. The converted tract was estimated to be no longer than 23 nucleotides. Both patients had colon cancer; one also had oligodendroglioma and the other also had endometrial cancer and cafe-au-lait spots. <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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<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> rs121434629 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434629;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/rs121434629?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=rs121434629" 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=rs121434629" 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=RCV000009826 OR RCV000056324 OR RCV000076807 OR RCV000115657 OR RCV000200994 OR RCV000524432 OR RCV000722017 OR RCV001267878 OR RCV001353458 OR RCV001797999 OR RCV001804723 OR RCV002476951 OR RCV003335023 OR RCV003390667 OR RCV004555831 OR RCV004691720" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009826, RCV000056324, RCV000076807, RCV000115657, RCV000200994, RCV000524432, RCV000722017, RCV001267878, RCV001353458, RCV001797999, RCV001804723, RCV002476951, RCV003335023, RCV003390667, RCV004555831, RCV004691720" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009826...</a>
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In 2 sisters with mismatch repair cancer syndrome (MMRCS4; <a href="/entry/619101">619101</a>), <a href="#2" 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 PMS2 gene: a 137G-T transversion in exon 2, resulting in a ser46-to-ile (S46I) substitution, and a frameshift (<a href="#0011">600259.0011</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><p><strong><em>Lynch Syndrome 4</em></strong></p><p>
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<a href="#4" class="mim-tip-reference" title="Borras, E., Pineda, M., Cadinanos, J., del Valle, J., Brieger, A., Hinrichsen, I., Cabanillas, R., Navarro, M., Brunet, J., Sanjuan, X., Musulen, E., van der Klift, H., Lazaro, C., Plotz, G., Blanco, I., Capella, G. <strong>Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants.</strong> J. Med. Genet. 50: 552-563, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23709753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23709753</a>] [<a href="https://doi.org/10.1136/jmedgenet-2012-101511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23709753">Borras et al. (2013)</a> identified a heterozygous S46I mutation in 2 members of a Spanish family with hereditary nonpolyposis colorectal cancer-4 (LYNCH4; <a href="/entry/614337">614337</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23709753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>One patient had colorectal cancer and the other had 3 skin tumors. An unrelated Spanish patient with bladder cancer also carried the mutation. The substitution is located within the nucleotide binding pocket of the ATPase domain, suggesting an interference with the ATPase function. In vitro functional expression studies showed that the mutant protein had significantly reduced MMR activity (about 13%) compared to controls, confirming its pathogenicity.</p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000009827 OR RCV000076801" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009827, RCV000076801" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009827...</a>
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<p>In affected members of a consanguineous Guyanese family with variable expression of colorectal adenocarcinoma, acute leukemia, brain tumors, and cafe-au-lait spots (MMRCS4; <a href="/entry/619101">619101</a>), <a href="#36" class="mim-tip-reference" title="Trimbath, J. D., Petersen, G. M., Erdman, S. H., Ferre, M., Luce, M. C., Giardiello, F. M. <strong>Cafe-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC?</strong> Fam. Cancer 1: 101-105, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14574005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14574005</a>] [<a href="https://doi.org/10.1023/a:1013881832014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14574005">Trimbath et al. (2001)</a> identified a homozygous 20-bp insertion at nucleotide 1169 of the PMS2 gene (1169ins20), resulting in a truncation of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14574005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0014 MISMATCH REPAIR CANCER SYNDROME 4</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"><span class="text-primary">●</span> rs63750793 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63750793;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/rs63750793?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=rs63750793" 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=rs63750793" 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=RCV000009828 OR RCV000076829 OR RCV002514362 OR RCV003452987 OR RCV004943751" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009828, RCV000076829, RCV002514362, RCV003452987, RCV004943751" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009828...</a>
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<p>In a Turkish patient (patient 3) who developed glioblastoma multiforme at age 10 years and who had cafe-au-lait spots (MMRCS4; <a href="/entry/619101">619101</a>), <a href="#9" class="mim-tip-reference" title="Etzler, J., Peyrl, A., Zatkova, A., Schildhaus, H.-U., Ficek, A., Merkelbach-Bruse, S., Kratz, C. P., Attarbaschi, A., Hainfellner, J. A., Yao, S., Messiaen, L., Slavc, I., Wimmer, K. <strong>RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference.</strong> Hum. Mutat. 29: 299-305, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18030674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18030674</a>] [<a href="https://doi.org/10.1002/humu.20657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18030674">Etzler et al. (2008)</a> identified a homozygous 1-bp deletion (c.182delA, NM_000535.4) in exon 3 of the PMS2 gene. The parents were consanguineous. Immunohistochemical analysis showed loss of PMS2 expression in the tumor and nonneoplastic tissue. <a href="#9" class="mim-tip-reference" title="Etzler, J., Peyrl, A., Zatkova, A., Schildhaus, H.-U., Ficek, A., Merkelbach-Bruse, S., Kratz, C. P., Attarbaschi, A., Hainfellner, J. A., Yao, S., Messiaen, L., Slavc, I., Wimmer, K. <strong>RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference.</strong> Hum. Mutat. 29: 299-305, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18030674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18030674</a>] [<a href="https://doi.org/10.1002/humu.20657" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18030674">Etzler et al. (2008)</a> used an RNA-based assay to avoid the detection of pseudogene sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18030674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs267608150 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608150;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=rs267608150" 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=rs267608150" 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=RCV000009829 OR RCV000076885 OR RCV000115703 OR RCV000235196 OR RCV000722010 OR RCV000763590 OR RCV001201395 OR RCV001254933 OR RCV001353497 OR RCV001804827 OR RCV003149759 OR RCV003915043" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009829, RCV000076885, RCV000115703, RCV000235196, RCV000722010, RCV000763590, RCV001201395, RCV001254933, RCV001353497, RCV001804827, RCV003149759, RCV003915043" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009829...</a>
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<p>In 12 presumably unrelated patients with hereditary nonpolyposis colorectal cancer-4 (LYNCH4; <a href="/entry/614337">614337</a>), <a href="#5" class="mim-tip-reference" title="Clendenning, M., Senter, L., Hampel, H., Robinson, K. L., Sun, S., Buchanan, D., Walsh, M. D., Nilbert, M., Green, J., Potter, J., Lindblom, A., de la Chapelle, A. <strong>A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome.</strong> J. Med. Genet. 45: 340-345, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18178629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18178629</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18178629[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2007.056150" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18178629">Clendenning et al. (2008)</a> identified a heterozygous insertion/deletion mutation (736_741del6ins11) in the PMS2 gene, resulting in an alteration of the protein sequence from residue 246 with premature termination at residue 249, which is about 614 amino acids before the wildtype stop codon. Family history suggested reduced penetrance. Haplotype analysis indicated a common founder, and the age of the mutation was estimated at 1,625 years, suggesting that this indel mutation arose sometime during the first millennium. The mutation was enriched in patients of British and Swedish ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18178629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs121434630 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434630;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=rs121434630" 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=rs121434630" 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=RCV000009830" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009830" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009830</a>
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<p>In 9-year-old boy with mismatch repair cancer syndrome (MMRCS4; <a href="/entry/619101">619101</a>) manifest as rhabdomyosarcoma at age 3 years and colonic adenocarcinoma at age 8 years, <a href="#16" class="mim-tip-reference" title="Kratz, C. P., Holter, S., Etzler, J., Lauten, M., Pollett, A., Niemeyer, C. M., Gallinger, S., Wimmer, K. <strong>Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome.</strong> J. Med. Genet. 46: 418-420, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19293170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19293170</a>] [<a href="https://doi.org/10.1136/jmg.2008.064212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19293170">Kratz et al. (2009)</a> identified a homozygous 219T-A transversion in exon 3 of the PMS2 gene, resulting in a cys73-to-ter (C73X) substitution. He was born of unaffected consanguineous parents, but there was a history of cancer in the family. Cafe-au-lait spots were observed in the proband. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19293170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs63750106 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63750106;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=rs63750106" 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=rs63750106" 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=RCV000076805 OR RCV004576920" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000076805, RCV004576920" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000076805...</a>
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<p><a href="#17" class="mim-tip-reference" title="Kratz, C. P., Niemeyer, C. M., Juttner, E., Kartal, M., Weninger, A., Schmitt-Graeff, A., Kontny, U., Lauten, M., Utzolino, S., Radecke, J., Fonatsch, C., Wimmer, K. <strong>Childhood T-cell non-Hodgkin's lymphoma, colorectal carcinoma and brain tumor in association with cafe-au-lait spots caused by a novel homozygous PMS2 mutation. (Letter)</strong> Leukemia 22: 1078-1080, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18007577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18007577</a>] [<a href="https://doi.org/10.1038/sj.leu.2405008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18007577">Kratz et al. (2008)</a> reported a Turkish girl with mismatch repair cancer syndrome (MMRCS4; <a href="/entry/619101">619101</a>) who had been successfully treated for non-Hodgkin lymphoma at age 6 years and who presented at age 16 years with colorectal carcinomas. The patient's sister had cafe-au-lait spots and died from a supratentorial primitive neuroectodermal tumor at age 9 years. The parents and 4 sibs were healthy and without cancer history at time of report, although 1 sib also had cafe-au-lait spots. Microsatellite, immunohistochemical, and sequence analysis that avoided pseudogene interference showed that the patient had a homozygous 1-bp duplication (c.1306dupA) in exon 11 of the PMS2 gene, resulting in a frameshift at ser436 and premature termination (Ser436LysfsX22). Genomic DNA sequencing confirmed the mutation. The patient's parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18007577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0018 MISMATCH REPAIR CANCER SYNDROME 4</strong>
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PMS2, EX11-EX14 DEL/18-BP INS
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000029205 OR RCV000076800" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000029205, RCV000076800" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000029205...</a>
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<p><a href="#31" class="mim-tip-reference" title="Peron, S., Metin, A., Gardes, P., Alyanakian, M.-A., Sheridan, E., Kratz, C. P., Fischer, A., Durandy, A. <strong>Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination.</strong> J. Exp. Med. 205: 2465-2472, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824584</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824584[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/10.1084/jem.20080789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824584">Peron et al. (2008)</a> reported a 12-year-old Turkish girl (patient 1) with mismatch repair cancer syndrome (MMRCS4; <a href="/entry/619101">619101</a>) who exhibited Ig class switch recombination (CSR) deficiency. She presented with multiple cafe-au-lait spots and suffered from recurrent infections from the age of 1 year, leading to an immunodeficiency diagnosis at 9 years of age. A year later, she developed a colorectal adenocarcinoma. By genomic DNA analysis, followed by cDNA confirmation, <a href="#31" class="mim-tip-reference" title="Peron, S., Metin, A., Gardes, P., Alyanakian, M.-A., Sheridan, E., Kratz, C. P., Fischer, A., Durandy, A. <strong>Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination.</strong> J. Exp. Med. 205: 2465-2472, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18824584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18824584</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18824584[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/10.1084/jem.20080789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18824584">Peron et al. (2008)</a> identified a homozygous deletion of exons 11 through 14 of the patient's PMS2 gene and an 18-nucleotide frameshift insertion and stop codon at the beginning of exon 15. Her consanguineous parents were heterozygous for the mutation. In vitro analysis showed that the CSR defect was characterized by the occurrence of double-strand DNA breaks in switch regions and abnormal formation of switch junctions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18824584" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs869320619 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320619;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=rs869320619" 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=rs869320619" 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=RCV000172908 OR RCV000630142 OR RCV001179765 OR RCV001284205 OR RCV001804905 OR RCV003454446" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000172908, RCV000630142, RCV001179765, RCV001284205, RCV001804905, RCV003454446" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000172908...</a>
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<p>In 13 individuals from 7 unrelated families of Inuit origin with an attenuated form of mismatch repair cancer syndrome (MMRCS4; <a href="/entry/619101">619101</a>), <a href="#19" class="mim-tip-reference" title="Li, L., Hamel, N., Baker, K., McGuffin, M. J., Couillard, M., Gologan, A., Marcus, V. A., Chodirker, B., Chudley, A., Stefanovici, C., Durandy, A., Hegele, R. A., and 10 others. <strong>A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.</strong> J. Med. Genet. 52: 348-352, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25691505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25691505</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25691505">Li et al. (2015)</a> identified a homozygous c.2002A-G transition (c.2002A-G, NM_000535.5) in the PMS2 gene. The mutation was predicted to result in an ile668-to-val (I668V) substitution, but analysis of patient cells showed that it altered a 5-prime splice site for intron 11, causing aberrant RNA splicing with a 5-bp deletion, and resulting in nonsense-mediated mRNA decay. Patient cells showed only a minor amount of full-length transcripts and some residual normal full-length protein. Haplotype analysis indicated a founder effect estimated to have appeared late in the 11th century. The age at cancer onset in individuals homozygous for the c.2002A-G mutation was significantly later (median age 22 years) compared to individuals homozygous for truncating PMS2 mutations (8 years). There was also a difference in the tumor spectrum, with brain tumors being significantly less prevalent in c.2002A-G homozygotes (15%) compared to truncating homozygotes (67%). <a href="#19" class="mim-tip-reference" title="Li, L., Hamel, N., Baker, K., McGuffin, M. J., Couillard, M., Gologan, A., Marcus, V. A., Chodirker, B., Chudley, A., Stefanovici, C., Durandy, A., Hegele, R. A., and 10 others. <strong>A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.</strong> J. Med. Genet. 52: 348-352, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25691505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25691505</a>] [<a href="https://doi.org/10.1136/jmedgenet-2014-102934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25691505">Li et al. (2015)</a> concluded that even a low level of PMS2 expression likely delays cancer onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25691505" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Adams, M. D., Kelley, J. M., Gocayne, J. D., Dubnick, M., Polymeropoulos, M. H., Xiao, H., Merril, C. R., Wu, A., Olde, B., Moreno, R. F., Kerlavage, A. R., McCombie, W. R., Venter, J. C.
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<strong>Complementary DNA sequencing: expressed sequence tags and human genome project.</strong>
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Science 252: 1651-1656, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2047873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2047873</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2047873" 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.2047873" target="_blank">Full Text</a>]
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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.
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<strong>Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation.</strong>
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Hum. Mutat. 28: 1084-1090, 2007.
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20569" target="_blank">Full Text</a>]
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Baker, S. M., Bronner, C. E., Zhang, L., Plug, A. W., Robatzek, M., Warren, G., Elliott, E. A., Yu, J., Ashley, T., Arnheim, N., Flavell, R. A., Liskay, R. M.
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<strong>Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis.</strong>
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Cell 82: 309-319, 1995.
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[<a href="https://doi.org/10.1016/0092-8674(95)90318-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2012-101511" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2007.056150" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.onc.1203447" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/jnci/djj073" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/420796" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20657" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.21223" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh186" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20457" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1053/j.gastro.2005.10.052" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2014-102934" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17785530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17785530</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17785530[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=17785530" 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/10.1101/gad.430107" target="_blank">Full Text</a>]
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</p>
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<a id="35" class="mim-anchor"></a>
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<a id="Thompson2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thompson, E., Meldrum, C. J., Crooks, R., McPhillips, M., Thomas, L., Spigelman, A. D., Scott, R. J.
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|
<strong>Hereditary non-polyposis colorectal cancer and the role of hPMS2 and hEXO1 mutations.</strong>
|
|
Clin. Genet. 65: 215-225, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756672</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14756672" 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/j.1399-0004.2004.00214.x" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="36" class="mim-anchor"></a>
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<a id="Trimbath2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Trimbath, J. D., Petersen, G. M., Erdman, S. H., Ferre, M., Luce, M. C., Giardiello, F. M.
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<strong>Cafe-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC?</strong>
|
|
Fam. Cancer 1: 101-105, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14574005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14574005</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14574005" 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/10.1023/a:1013881832014" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="37" class="mim-anchor"></a>
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<a id="van der Klift2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van der Klift, H. M., Tops, C. M. J., Bik, E. C., Boogaard, M. W., Borgstein, A.-M., Hansson, K. B. M., Ausems, M. G. E. M., Gomez Garcia, E., Green, A., Hes, F. J., Izatt, L., van Hest, L. P., Alonso, A. M., Vriends, A. H. J. T., Wagner, A., van Zelst-Stams, W. A. G., Vasen, H. F. A., Morreau, H., Devilee, P., Wijnen, J. T.
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|
<strong>Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients.</strong>
|
|
Hum. Mutat. 31: 578-587, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20186688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20186688</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20186688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.21229" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="38" class="mim-anchor"></a>
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<a id="Vaughn2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vaughn, C. P., Robles, J., Swensen, J. J., Miller, C. E., Lyon, E., Mao, R., Bayrak-Toydemir, P., Samowitz, W. S.
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<strong>Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes.</strong>
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Hum. Mutat. 31: 588-593, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20205264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20205264</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20205264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.21230" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="39" class="mim-anchor"></a>
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<a id="Worthley2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Worthley, D. L., Walsh, M. D., Barker, M., Ruszkiewicz, A., Bennett, G., Phillips, K., Suthers, G.
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<strong>Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.</strong>
|
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Gastroenterology 128: 1431-1436, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15887124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15887124</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15887124" 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/10.1053/j.gastro.2005.04.008" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="40" class="mim-anchor"></a>
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<a id="Yuan2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yuan, Z. Q., Gottlieb, B., Beitel, L. K., Wong, N., Gordon, P. H., Wang, Q., Puisieux, A., Foulkes, W. D., Trifiro, M.
|
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<strong>Polymorphisms and HNPCC: PMS2-MLH1 protein interactions diminished by single nucleotide polymorphisms.</strong>
|
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Hum. Mutat. 19: 108-113, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11793469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11793469</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11793469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.10040" target="_blank">Full Text</a>]
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</p>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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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 : 6/8/2015<br>Cassandra L. Kniffin - updated : 9/23/2013<br>Matthew B. Gross - updated : 7/24/2012<br>Paul J. Converse - updated !$ : 7/11/2012<br>Cassandra L. Kniffin - updated : 8/30/2010<br>Cassandra L. Kniffin - updated : 9/21/2009<br>Cassandra L. Kniffin - updated : 6/17/2009<br>Cassandra L. Kniffin - updated : 3/19/2009<br>Cassandra L. Kniffin - updated : 10/2/2008<br>Cassandra L. Kniffin - updated : 3/11/2008<br>Patricia A. Hartz - updated : 9/25/2007<br>Patricia A. Hartz - updated : 2/5/2007<br>George E. Tiller - updated : 1/16/2007<br>Marla J. F. O'Neill - updated : 8/28/2006<br>Victor A. McKusick - updated : 10/20/2004<br>Victor A. McKusick - updated : 4/27/2004<br>Victor A. McKusick - updated : 2/21/2002<br>Victor A. McKusick - updated : 8/24/2000<br>Victor A. McKusick - updated : 6/1/2000<br>Victor A. McKusick - updated : 3/15/1999<br>Victor A. McKusick - updated : 10/27/1997<br>Victor A. McKusick - updated : 5/13/1997<br>Alan F. Scott - updated : 10/17/1995
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="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 : 12/21/1994
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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="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 11/15/2022
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</span>
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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>alopez : 12/27/2016<br>carol : 09/09/2015<br>mcolton : 8/12/2015<br>carol : 6/10/2015<br>mcolton : 6/9/2015<br>ckniffin : 6/8/2015<br>carol : 10/9/2013<br>ckniffin : 9/23/2013<br>mgross : 7/24/2012<br>terry : 7/11/2012<br>alopez : 11/9/2011<br>wwang : 9/3/2010<br>ckniffin : 8/30/2010<br>wwang : 9/25/2009<br>ckniffin : 9/21/2009<br>wwang : 7/17/2009<br>ckniffin : 6/17/2009<br>wwang : 3/30/2009<br>ckniffin : 3/19/2009<br>wwang : 10/8/2008<br>ckniffin : 10/2/2008<br>carol : 7/8/2008<br>wwang : 3/13/2008<br>ckniffin : 3/11/2008<br>wwang : 2/27/2008<br>ckniffin : 2/5/2008<br>carol : 1/15/2008<br>ckniffin : 1/7/2008<br>wwang : 10/2/2007<br>terry : 9/25/2007<br>mgross : 2/5/2007<br>wwang : 1/24/2007<br>terry : 1/16/2007<br>carol : 8/28/2006<br>carol : 2/28/2006<br>mgross : 4/15/2005<br>mgross : 4/14/2005<br>tkritzer : 10/21/2004<br>terry : 10/20/2004<br>alopez : 4/29/2004<br>terry : 4/27/2004<br>alopez : 3/17/2004<br>cwells : 2/25/2002<br>terry : 2/21/2002<br>carol : 10/23/2001<br>mcapotos : 8/30/2000<br>mcapotos : 8/29/2000<br>carol : 8/28/2000<br>terry : 8/24/2000<br>carol : 6/8/2000<br>terry : 6/1/2000<br>carol : 3/18/1999<br>terry : 3/15/1999<br>alopez : 9/4/1998<br>dkim : 7/7/1998<br>terry : 6/4/1998<br>mark : 10/28/1997<br>jenny : 10/28/1997<br>terry : 10/27/1997<br>mark : 8/15/1997<br>jenny : 5/13/1997<br>terry : 5/7/1997<br>mark : 1/11/1996<br>mark : 10/15/1995<br>mimadm : 9/23/1995<br>mark : 5/15/1995<br>terry : 3/29/1995
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600259
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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PMS1 HOMOLOG 2, MISMATCH REPAIR SYSTEM COMPONENT; PMS2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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POSTMEIOTIC SEGREGATION INCREASED, S. CEREVISIAE, 2<br />
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MISMATCH REPAIR GENE PMSL2; PMSL2
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PMS2</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 7p22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:5,970,925-6,009,106 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
|
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<span class="mim-font">
|
|
7p22.1
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Lynch syndrome 4
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
614337
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
|
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Mismatch repair cancer syndrome 4
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
619101
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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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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<strong>Cloning and Expression</strong>
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</h4>
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<p>In screening a database of human genes identified by the expressed sequence tag (EST) method (Adams et al., 1991), Papadopoulos et al. (1994) identified 2 human ESTs with homology to the yeast PMS1 gene: the human genes were designated PMS1 (600258) and PMS2. Sequence analysis of the human PMS2 clone predicted an 862-residue protein with 32% identity to yeast PMS1. </p><p>In the process of characterizing PMS2 cDNA and its promoter region, Nicolaides et al. (1995) discovered another gene, provisionally called JTV1 (AIMP2; 600859), which is transcribed from the opposite DNA strand and overlaps with PMS2. The genes lie in a head-to-head arrangement and both are ubiquitously expressed. </p>
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<h4>
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<strong>Gene Function</strong>
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</h4>
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<p>Hypermutable H6 colorectal tumor cells are defective in strand-specific mismatch repair and bear defects in both alleles of the human MLH1 gene (120436). Li and Modrich (1995) purified to near homogeneity an activity from HeLa cells that complemented H6 nuclear extracts to restore repair proficiency on a set of heteroduplex DNAs representing the 8 base-base mismatches as well as a number of slipped-strand, insertion/deletion mispairs. The activity behaved as a single species during fractionation and copurified with proteins of 85 and 100 kD. Microsequence analysis demonstrated both of these proteins to be homologs of bacterial MutL, with the former corresponding to the human MLH1 product and the latter to the product of human PMS2 or a closely related gene. The 1:1 molar stoichiometry of the 2 polypeptides and their hydrodynamic behavior indicated formation of a heterodimer. These observations indicated that interactions between members of the family of the human MutL homologs may be restricted. </p><p>MutL-alpha is a heterodimer of MLH1 and PMS2 and is required for mismatch repair. Kadyrov et al. (2006) identified human MutL-alpha as a latent endonuclease activated in a DNA mismatch-, MutS-alpha (see 609309)-, RFC (see 102579)-, PCNA (176740)-, and ATP-dependent manner. Incision of a nicked heteroduplex by this 4-protein system was strongly biased to the nicked strand. A mismatch-containing DNA segment spanned by 2 strand breaks was then removed by the 5-prime-to-3-prime activity of MutS-alpha-activated exonuclease-1 (EXO1; 606063). By mutation analysis, Kadyrov et al. (2006) mapped the endonuclease active site to a conserved motif in PMS2. </p><p>In human MLH1-deficient cells, Shimodaira et al. (2003) found that PMS2 interacted with and stabilized the apoptotic protein p73 (TP73; 601990) and that the interaction caused redistribution of PMS2 to the nuclear compartment. Treatment with the DNA crosslinking agent cisplatin resulted in increased association of the 2 molecules and enhanced apoptotic function of p73. The findings demonstrated a role for PMS2 in DNA damage-induced apoptosis as well as in DNA repair. Marinovic-Terzic et al. (2008) showed that a polymorphism in the PMS2 gene, resulting in an arg20-to-gln (R20Q) substitution, interfered with the interaction of PMS2 and p73 and resulted in a decreased apoptotic response to cisplatin when expressed in mouse fibroblasts. The findings suggested that this polymorphic PMS2 allele may modulate tumor responses to cisplatin among cancer patients. </p>
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<h4>
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<strong>Gene Structure</strong>
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<p>Nicolaides et al. (1995) found that the PMS2 gene encompasses 16 kb and contains 15 exons. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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<p>Nicolaides et al. (1994) mapped the PMS2 gene to chromosome 7 by analysis of somatic cell hybrids and to chromosome 7p22 by fluorescence in situ hybridization. </p><p><strong><em>Pseudogenes</em></strong></p><p>
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Nicolaides et al. (1994) and De Vos et al. (2004) identified 14 PMS2 pseudogenes that contain copies of some or all of PMS2 exons 1 to 5. Another pseudogene, PMS2CL, is transcribed and corresponds to exons 9 and 11 to 15 of the PMS2 gene. It is embedded in a 100-kb inverted duplication located about 700 kb centromeric to the PMS2 gene. Hayward et al. (2007) demonstrated that sequence transfer, or a type of 'gene conversion,' between the PMS2 and PMS2CL is an ongoing process that leads to allelic diversity of the PMS2 gene and creates difficulty in mutation analysis. Hayward et al. (2007) stated that it is 'unsafe' to rely on PCR primer-site selectivity for generating PMS2 amplicons for mutation analysis, but noted that exon 10 is absent from the PMS2CL pseudogene and could be used as an anchor point. </p>
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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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<p><strong><em>Lynch Syndrome 4</em></strong></p><p>
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In a patient with a family history of hereditary nonpolyposis colorectal cancer (LYNCH4; 614337), Nicolaides et al. (1994) identified a germline deletion in the PMS2 gene. A second deletion was found in the patient's tumor sample. The tumor from this patient exhibited microsatellite instability. </p><p>Parsons et al. (1995) found that HNPCC patients with germline mutations of either PMS2 or MLH1 had widespread mutations not only in their tumors but also in their nonneoplastic cells. Although these patients had numerous mutations in all the tissues examined, they had very few tumors. The hypermutability was associated with a profound defect in MMR at the biochemical level. The findings suggested that MMR deficiency is compatible with normal human development. </p><p>Ma et al. (2000) reported that in the Vaco481 human colon cancer cell line, the PMS2 gene is inactivated by somatic mutations of both PMS2 alleles. The cell line derived from this tumor was functionally deficient in DNA mismatch repair. The cell line demonstrated microsatellite instability, an elevated HPRT gene (308000) mutation rate, and resistance to the cytotoxicity of the alkylator N-methyl-N-prime-nitronitrosoguanidine (MNNG). Ma et al. (2000) concluded that somatic inactivation of PMS2 can play a role in development of sporadic microsatellite unstable colon cancer expressing the full range of cancer phenotypes associated with inactivation of the mismatch repair system. </p><p>Yuan et al. (2002) noted that the MLH1 (120436) and MSH2 (609309) proteins interact with PMS1, PMS2, and MSH6 (600678) proteins, and that missense mutations in specific regions of MLH1 have been shown to lead to defects in protein-protein interactions with PMS2. They reported that 3 missense alterations previously identified as single-nucleotide polymorphisms (SNPs) in PMS2 (P511K, T597S, and M622I) cause defective protein-protein interactions with MLH1, even though the alterations are not in the previously reported interaction domain. These SNPs can result in gene alterations that have a functional effect on protein phenotype and thus may represent variants carrying an increased risk for tumorigenesis in HNPCC. </p><p>Nakagawa et al. (2004) identified heterozygous germline mutations in the PMS2 gene in 2 unrelated patients with colon cancer without a family history of the disorder. Loss of heterozygosity was detected in the tumor tissue in both cases. Abrogation of the PMS2 protein from 1 allele was seen in 2 additional patients in whom PMS2 mutations could not be detected. Nakagawa et al. (2004) noted that there is a family of PMS2 genes that are highly homologous to the 5-prime region of PMS2. The findings indicated that PMS2 behaves according to the 2-hit Knudson model, but that mutations may be overlooked due to the existence of numerous related genes. </p><p>In a family with HNPCC meeting the Amsterdam criteria, Thompson et al. (2004) identified a mutation in the PMS2 gene (600259.0006) that segregated with the disease. </p><p>Worthley et al. (2005) tested a cohort of tumor samples from patients with features suggestive of HNPCC for microsatellite instability and exclusive loss of expression of the PMS2 gene in tumor tissue. A kindred was identified with HNPCC due to a heterozygous loss-of-function mutation in the PMS2 gene (600259.0007). The authors stated that this was the first description of autosomal dominant HNPCC due to mutation in the PMS2 gene. </p><p>Hendriks et al. (2006) analyzed the PMS2 gene in 112 patients from MLH1-, MSH2- and MSH6-negative HNPCC-like families and in 775 tumors from patients with familial colorectal cancer. They identified 4 genomic rearrangements and 3 truncating point mutations (600259.0008-600259.0010). The pattern of inheritance was autosomal dominant, and mutations segregated with disease. The most common cancer was colorectal carcinoma, followed by endometrial and ovarian carcinomas. The phenotype was milder compared to that of families with MLH1 or MSH2 mutations: the mean age at diagnosis of colorectal carcinoma was 52 years, 7 to 8 years later than that associated with MLH1 and MSH2 mutations. Analysis of tumors from proven carriers showed high microsatellite instability and loss of PMS2 protein expression in all tumors. </p><p>Niessen et al. (2009) identified PMS2 mutations in 4 (4%) of 97 patients with early-onset microsatellite-unstable colorectal or endometrial cancer or multiple Lynch-associated tumors. In tumor tissue available from 1 of the mutation carriers, no PMS2 immunoreactivity was detected. None of the 97 patients carried mutations in the MLH1, MSH2, or MSH6 genes. Niessen et al. (2009) commented that the frequency of PMS2 mutations in Lynch syndrome patients may be higher than previously expected. </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 (600678), and 124 in PMS2. 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 2 MMR genes MSH6 and PMS2, mutations in which cause HNPCC5 (614350) and HNPCC4, 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 4</em></strong></p><p>
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Mismatch repair cancer syndrome-4 (MMRCS4; 619101) is characterized classically by the concurrence of a primary brain tumor and multiple colorectal adenomas; this association is also sometimes referred to as Turcot syndrome. In a patient with glioblastoma and colonic adenomas, Hamilton et al. (1995) identified a mutation in the PMS2 gene (R134X; 600259.0001). </p><p>Trimbath et al. (2001) identified a homozygous mutation in the PMS2 gene (600259.0013) in affected members of a consanguineous Guyanese family with variable expression of colorectal adenocarcinoma, acute leukemia, brain tumors, and cafe-au-lait spots. The authors noted that the phenotype of mismatch repair deficiency should include cafe-au-lait spots and hematologic malignancies. </p><p>In affected members of a consanguineous family with early-onset brain tumors, De Vos et al. (2004) identified a homozygous mutation in exon 14 of the PMS2 gene (R802X; 600259.0004). Heterozygous family members had no cancer predisposition. Genome searches revealed a previously unrecognized pseudogene PMS2CL, corresponding to exons 9-15, within a 100-kb inverted duplication situated 600 kb centromeric from PMS2 itself. Furthermore, in the family with Turcot syndrome (Hamilton et al., 1995) in which the first inherited PMS2 mutation (R134X; 600259.0001) was described, a truncating mutation was identified on the other allele (600259.0005). The findings indicated autosomal recessive inheritance of the disorder. De Vos et al. (2004) found that the complexity of PMS2 pseudogenes is greater than appreciated and may have hindered previous mutation studies. Several previously reported PMS2 polymorphisms may, in fact, be pseudogene sequence variants. </p><p>In 2 sisters with mismatch repair cancer syndrome, Auclair et al. (2007) identified compound heterozygosity for 2 mutations in the PMS2 gene (600259.0011, 600259.0012). Both patients had colon cancer; 1 also had oligodendroglioma and the other also had endometrial cancer and cafe-au-lait spots. </p><p>Etzler et al. (2008) developed an RNA-based assay using direct cDNA sequencing of RT-PCR products to identify a homozygous mutation in the PMS2 gene (600259.0014) in a patient with mismatch repair deficiency who had glioblastoma multiforme. Studies of an unrelated healthy individual confirmed the utility of the RNA technique to correctly distinguish PMS2 from its PMS2CL pseudogene. </p><p>Peron et al. (2008) reported that 3 patients with mismatch repair cancer syndrome due to different homozygous mutations in the PMS2 gene exhibited Ig class switch recombination (CSR) deficiency. Two of the patients had been previously reported by De Vos et al. (2006) and Kratz et al. (2008) and carried homozygous R802X and frameshift (600259.0017) mutations, respectively. The patient who had not been previously reported, a 12-year-old Turkish girl, had a homozygous deletion of exons 11 through 14 and an 18-nucleotide frameshift insertion and stop codon at the beginning of exon 15 (600259.0018). Her consanguineous parents were heterozygous for the mutation. In vitro analysis showed that the CSR defect was characterized by the occurrence of double-strand DNA breaks (DSBs) in switch regions and abnormal formation of switch junctions. Peron et al. (2008) proposed that PMS2 has a role in CSR-induced DSB generation. </p><p><strong><em>PMS2 Mutation Detection</em></strong></p><p>
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The 3-prime end of the PMS2 gene contains the transcribed PMS2CL pseudogene. PMS2 mutation detection is complicated by the occurrence of sequence exchange events between the duplicated regions of PMS2 and PMS2CL, consisting of exons 9 and 11 to 15 (Hayward et al., 2007). </p><p>Ganster et al. (2010) genotyped exons 11 to 15 of the PMS2 gene in 192 individuals from different ethnic backgrounds. About one-third of individuals carried hybrid alleles of PMS2 with pseudogene-specific variants (PSV). Depending on the population, 14 to 60% of these hybrid alleles carried PMS2CL-specific sequences in exons 13 to 15, with the remainder only in exon 15. These exon 13-15 hybrid alleles, which they called H1 hybrid alleles, constituted different haplotypes that could be traced back to a single ancient intrachromosomal recombination event with crossover. Ganster et al. (2010) developed a genomic DNA-based PCR assay that could be used to identify H1 hybrid allele carriers with high sensitivity and specificity (100% and 99%, respectively). </p><p>Van der Klift et al. (2010) identified sequence transfers between the PMS2CL pseudogene and the PMS2 gene involving intron 12 to the 3-prime end of the PMS2 gene in 4 to 52% of DNA samples. Overall, sequence exchanges between PMS2 and PMS2CL were observed in 69% (83 of 120) of individuals. There was no significant difference in sequence transfer between 25 controls and 95 patients with colorectal cancer, suggesting that these variants have only a mild or neutral effect on gene function. However, these sequence events may influence genetic testing. Van der Klift et al. (2010) presented an RNA-based mutation detection strategy to improve reliability. Using this strategy, 19 different putative pathogenic PMS2 mutations were identified, 4 (21%) of which were in the region with frequent sequence transfer, and had been missed or incorrectly interpreted as homozygous with other detection methods. </p><p>Vaughn et al. (2010) identified pathogenic mutations in the PMS2 gene in 22 (37%) of 59 patients with colorectal cancer who showed loss of PMS2 protein expression by immunohistochemistry. The mutations were detected using a long-range PCR product spanning exons 11 to 15 of the PMS2 gene, with the forward primer anchored in exon 10, which is not shared by the PMS2CL pseudogene. An additional 3 patients with PMS2 mutations were found among 53 colorectal samples without immunohistochemical studies. Ten (37%) of the 27 mutations detected were large deletions encompassing 1 or more exons. Vaughn et al. (2010) emphasized the importance of using methods that can reliably distinguish between PMS2 and its PMS2CL pseudogene in the diagnosis of mutations at the 3-prime end of PMS2. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Using gene targeting in embryonic stem cells, Baker et al. (1995) generated a line of mice with a null mutation in the Pms2 gene. They observed microsatellite instability in the male germline and in tumor DNA of Pms2-deficient animals. They concluded, therefore, that Pms2 is involved in DNA mismatch repair in a variety of tissues. The deficient animals appeared prone to sarcomas and lymphomas. Pms2-deficient males were infertile, producing only abnormal spermatozoa. Analysis of axial element and synaptonemal complex formation during prophase of meiosis I indicated abnormalities in chromosome synapsis. These observations suggested links among MMR, genetic recombination, and chromosome synapsis in meiosis. </p><p>To determine the effect of Pms2 inactivation on genomic integrity in vivo, Narayanan et al. (1997) constructed hybrid transgenic mice that carry targeted disruptions at the Pms2 locus along with a chromosomally integrated mutation reporter gene. In the absence of any mutagenic treatment, mice nullizygous for Pms2 showed a 100-fold elevation in mutation frequency in all tissues examined compared with both wildtype and heterozygous littermates. The mutation pattern in the nullizygotes was notable for frequent 1-bp deletions and insertions within mononucleotide repeat sequences, consistent with an essential role for PMS2 in the repair of replication slippage errors. Further, the results demonstrated that high rates of mutagenesis in multiple tissues are compatible with normal development and life and are not necessarily associated with accelerated aging. Also, the finding of genetic instability in all tissues tested contrasted with the limited tissue distribution of cancers in the animals, raising important questions regarding the role of mutagenesis in carcinogenesis. </p><p>Gomes-Pereira et al. (2004) determined that the rate of somatic expansion of a transgenic CAG/CTG repeat in Pms2 -/- mice was reduced by 50% compared to Pms2 +/- mice. A higher frequency of rare, but very large, deletions was also detected in these animals. No significant differences were observed between Pms2 +/+ and Pms2 +/- mice, suggesting that a single functional Pms2 allele is sufficient to generate normal levels of somatic mosaicism. Gomes-Pereira et al. (2004) hypothesized that, in addition to MMR enzymes that directly bind mismatched DNA, proteins that are subsequently recruited to the complex may also play a central role in the accumulation of repeat-length changes. They suggested that somatic expansion results not by replication slippage, single-stranded annealing, or simple MutS-mediated stabilization of secondary structures, but rather by inappropriate DNA mismatch repair. </p><p>In order to study mismatch repair in response to dysfunctional telomeres, Siegl-Cachedenier et al. (2007) generated mice deficient for both telomerase (TERC; 602322) and Pms2. Pms2 deficiency prolonged the mean life span and median survival of telomerase-deficient mice concomitant with rescue of degenerative pathologies. Rescue of survival was independent of changes in telomere length, sister telomere recombination, and microsatellite instability. Pms2 deficiency rescued cell proliferation defects but not apoptotic defects in vivo, concomitant with a decreased p21 (CDKN1A; 116899) induction in response to short telomeres. The proliferative advantage conferred to telomerase-deficient cells by ablation of Pms2 did not produce increased tumors; indeed, Terc-null/Pms2-null mice showed reduced tumors compared with Pms2-null mice. Siegl-Cachedenier et al. (2007) concluded that deficiency in mismatch repair rescues organismal survival and proliferation in telomerase-deficient mice by attenuating the antiproliferative response associated with short telomeres. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>19 Selected Examples):</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>.0001 MISMATCH REPAIR CANCER SYNDROME 4</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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PMS2, ARG134TER
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<br />
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SNP: rs63750871,
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gnomAD: rs63750871,
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ClinVar: RCV000009815, RCV000076872, RCV000115695, RCV000212842, RCV000524474, RCV000576870, RCV001196700, RCV001310204, RCV003162222, RCV005042023
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<span class="mim-text-font">
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<p>In an 18-year-old man (family 12) with colonic adenomas, lymphoma of the rectum, glioblastoma, and multiple cafe-au-lait spots consistent with mismatch repair cancer syndrome (MMRCS4; 619101), Hamilton et al. (1995) identified a heterozygous C-to-T transition in the PMS2 gene, resulting in an arg134-to-ter (R134X) substitution. His sister had colonic carcinoma and cafe-au-lait spots. In this family, De Vos et al. (2004) identified a second mutation in the PMS2 gene: a heterozygous 2-bp deletion in exon 13, within a repeated dinucleotide (CTCT) at codon 728-729 (600259.0005). The findings were consistent with autosomal recessive inheritance of the disorder. </p><p>Nicolaides et al. (1998) presented experimental evidence that the R134X substitution was sufficient to reduce mismatch repair and induce microsatellite instability in cells containing a wildtype PMS2 allele, suggesting that it could act in a dominant-negative manner. </p>
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</span>
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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 MISMATCH REPAIR CANCER SYNDROME 4</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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PMS2, 1-BP DEL, 1221G
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<br />
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SNP: rs587776715,
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ClinVar: RCV000009816, RCV000076802, RCV002228025, RCV003298029
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a girl with early-onset brain tumor and colorectal cancer (MMRCS4; 619101), De Rosa et al. (2000) identified 2 germline mutations in the PMS2 gene: a 1-bp deletion (1221delG) in exon 11 and a 4-bp deletion in exon 14 (2361delCTTC; 600259.0003). The former mutation was inherited from the mother and the latter from the father. Both mutations resulted in loss of the MLH1 interaction domain of PMS2. The patient died at the age of 18 years. Her sister, whose DNA was not available for analysis, had a neuroblastoma of the brain at the age of 13 years and died at the age of 14 years. The first sister had marked microsatellite instability in both tumor and normal colon mucosa. The tumor also had somatic mutations in the TGFBR2 (190182) and APC (611731) genes. </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>.0003 MISMATCH REPAIR CANCER SYNDROME 4</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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PMS2, 4-BP DEL, 2361CTTC
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SNP: rs267608160,
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ClinVar: RCV000009817, RCV000076853, RCV000572699, RCV000629975, RCV000657184, RCV003452991
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</span>
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<span class="mim-text-font">
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<p>For discussion of the 4-bp deletion in the PMS2 gene (2361delCTTC) that was found in compound heterozygous state in 2 sisters with early-onset brain tumors (MMRCS4; 619101) by De Rosa et al. (2000), see 600259.0002. </p>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 MISMATCH REPAIR CANCER SYNDROME 4</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PMS2, ARG802TER
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<br />
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SNP: rs63751466,
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gnomAD: rs63751466,
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ClinVar: RCV000009818, RCV000076858, RCV000129304, RCV000409056, RCV000413126, RCV000524467, RCV001257544, RCV001267876, RCV002265552, RCV003415681, RCV004691719, RCV005031433
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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 affected sibs of a consanguineous family with cutaneous cafe-au-lait spots and early-onset brain tumors (MMRCS4; 619101), De Vos et al. (2004) identified a homozygous 2428C-to-T transition in exon 14 of the PMS2 gene, resulting in an arg802-to-ter (R802X) substitution. The oldest sib developed a cerebral high grade B-cell non-Hodgkin lymphoma at age 10 years. The next younger sib had a cerebral primitive neuroectodermal tumor (PNET) at age 9 years. The third sib had mild learning difficulties and a supratentorial primitive neuroectodermal tumor (SPNET) at age 14 years. A pair of double first cousins, aged 10 years, had cafe-au-lait spots and mild learning difficulties, but no history of cancer. No Lisch nodules or additional features of NF1 (162200) were present in any of the affected individuals or in the parents. There was no family history of colorectal or endometrial adenocarcinoma. Colonoscopy in the parents of the 3 affected sibs was normal. </p><p>De Vos et al. (2006) identified homozygosity for the R802X mutation in 11 patients from 5 consanguineous families of Pakistani origin living in the UK. All 5 families were from the northeastern Mirpur region of Pakistan, but there was no known blood relationship among them. Further analysis of polymorphisms suggested an ancestral founder effect for the mutation. The patients had cafe-au-lait skin patches and hematologic, brain, and/or colorectal cancers in childhood or adolescence that resulted in death in 8 of the patients. De Vos et al. (2006) proposed that early accurate diagnosis of this cancer syndrome is important to optimize the therapeutic response and to manage the risk to sibs of tumor development. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 MISMATCH REPAIR CANCER SYNDROME 4</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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PMS2, 2-BP DEL, 2184TC
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<br />
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SNP: rs587779335,
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gnomAD: rs587779335,
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ClinVar: RCV000009819, RCV000172821, RCV000365642, RCV000544078, RCV000573464, RCV000778109, RCV001267877, RCV001293420, RCV001353688, RCV002267843, RCV003415835, RCV003436927, RCV003492428
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In the family with mismatch repair cancer syndrome (MMRCS4; 619101) in which Hamilton et al. (1995) first demonstrated a heterozygous mutation in the PMS2 gene (600259.0001), De Vos et al. (2004) found a second heterozygous 2-bp deletion in exon 13, within a repeated dinucleotide (CTCT) at codon 728-729 (2184delTC) in both affected sibs. Thus, the sibs were compound heterozygotes, indicating autosomal recessive inheritance of the disorder. The deletion was inherited from the mother. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 LYNCH SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
|
PMS2, 3-BP DEL, LYS412DEL
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<br />
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SNP: rs267608159,
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|
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gnomAD: rs267608159,
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|
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ClinVar: RCV000009820
|
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria (LYNCH4; 614337), Thompson et al. (2004) identified a 3-bp deletion in exon 11 of the PMS2 gene, resulting in deletion of lysine-412 (lys412del). The mutation segregated with the disease. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0007 LYNCH SYNDROME 4</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PMS2, 1-BP DEL, 1021A
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<br />
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SNP: rs63750049,
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|
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ClinVar: RCV000009821, RCV000076793, RCV000220282, RCV000530149, RCV000570955, RCV001375488
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family fulfilling the Amsterdam II criteria for a clinical diagnosis of hereditary nonpolyposis colorectal cancer (LYNCH4; 614337), Worthley et al. (2005) identified heterozygosity for a 1021delA mutation in exon 10 of the PMS2 gene, resulting in a frameshift and a stop codon at position 355. The proband was diagnosed with cancer of the transverse colon at age 49 and underwent hemicolectomy and adjuvant chemotherapy; 2 years later he developed and subsequently died of metastatic esophageal carcinoma. His mutation-positive mother developed endometrial cancer at 60 years of age, had 3 polyps identified in her proximal colon in her early 70s, and subsequently developed carcinoma of the cecum at age 80. His maternal grandfather had colorectal cancer at 66 years of age, while a maternal great-uncle developed colorectal cancer at 45 years of age. The proband's brother, who also had the mutation, had 2 sessile polyps removed from the sigmoid colon at 47 and 49 years of age, respectively; the tissue was unavailable for histology. A maternal uncle who died of metastatic squamous cell carcinoma of the esophagus did not carry the mutation; nor, presumably, did his daughter who was diagnosed with breast cancer at 25 years of age. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LYNCH SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PMS2, IVS10, T-A, +2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267608158,
|
|
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|
|
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|
|
ClinVar: RCV000009822, RCV000076796
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family (family 5) with hereditary nonpolyposis colorectal cancer (LYNCH4; 614337), Hendriks et al. (2006) identified heterozygosity for a mutation in intron 10 of the PMS2 gene (c.1144+2T-A) that was predicted to affect correct splicing. The mutation cosegregated with disease. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
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|
<div>
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LYNCH SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PMS2, ARG628TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs63750451,
|
|
|
|
|
|
gnomAD: rs63750451,
|
|
|
|
|
|
ClinVar: RCV000009823, RCV000076834, RCV000218575, RCV000220439, RCV000524451, RCV001193819
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with hereditary nonpolyposis colorectal cancer (LYNCH4; 614337), Hendriks et al. (2006) identified heterozygosity for a 1882C-T transition in exon 11 of the PMS2 gene, predicted to result in an arg628-to-ter (R628X) substitution. The mutation cosegregated with disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LYNCH SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PMS2, 1-BP DEL, 856G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057515571,
|
|
|
|
|
|
|
|
ClinVar: RCV000009824
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family with hereditary nonpolyposis colorectal cancer (LYNCH4; 614337), Hendriks et al. (2006) identified heterozygosity for a 1-bp deletion (856delG) in exon 8 of the PMS2 gene, predicted to cause a frameshift and a premature stop at aspartic acid-286. The mutation cosegregated with disease. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 MISMATCH REPAIR CANCER SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PMS2, LYS577FS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057515572,
|
|
|
|
|
|
|
|
ClinVar: RCV000009825, RCV000657177, RCV000678287, RCV001012887, RCV001357852, RCV003478973
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters with mismatch repair cancer syndrome (MMRCS4; 619101), Auclair et al. (2007) identified compound heterozygosity for 2 mutations in the PMS2 gene: S46I (600259.0012) and a frameshift at lys577 resulting from a gene conversion event with the paralogous pseudogene PMS2CL. The converted tract was estimated to be no longer than 23 nucleotides. Both patients had colon cancer; one also had oligodendroglioma and the other also had endometrial cancer and cafe-au-lait spots. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 MISMATCH REPAIR CANCER SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LYNCH SYNDROME 4, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PMS2, SER46ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121434629,
|
|
|
|
|
|
gnomAD: rs121434629,
|
|
|
|
|
|
ClinVar: RCV000009826, RCV000056324, RCV000076807, RCV000115657, RCV000200994, RCV000524432, RCV000722017, RCV001267878, RCV001353458, RCV001797999, RCV001804723, RCV002476951, RCV003335023, RCV003390667, RCV004555831, RCV004691720
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Mismatch Repair Cancer Syndrome 4</em></strong></p><p>
|
|
In 2 sisters with mismatch repair cancer syndrome (MMRCS4; 619101), Auclair et al. (2007) identified compound heterozygosity for 2 mutations in the PMS2 gene: a 137G-T transversion in exon 2, resulting in a ser46-to-ile (S46I) substitution, and a frameshift (600259.0011). </p><p><strong><em>Lynch Syndrome 4</em></strong></p><p>
|
|
Borras et al. (2013) identified a heterozygous S46I mutation in 2 members of a Spanish family with hereditary nonpolyposis colorectal cancer-4 (LYNCH4; 614337). </p><p>One patient had colorectal cancer and the other had 3 skin tumors. An unrelated Spanish patient with bladder cancer also carried the mutation. The substitution is located within the nucleotide binding pocket of the ATPase domain, suggesting an interference with the ATPase function. In vitro functional expression studies showed that the mutant protein had significantly reduced MMR activity (about 13%) compared to controls, confirming its pathogenicity.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 MISMATCH REPAIR CANCER SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PMS2, 20-BP INS, NT1169
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000009827, RCV000076801
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a consanguineous Guyanese family with variable expression of colorectal adenocarcinoma, acute leukemia, brain tumors, and cafe-au-lait spots (MMRCS4; 619101), Trimbath et al. (2001) identified a homozygous 20-bp insertion at nucleotide 1169 of the PMS2 gene (1169ins20), resulting in a truncation of the protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 MISMATCH REPAIR CANCER SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PMS2, 1-BP DEL, 182A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs63750793,
|
|
|
|
|
|
gnomAD: rs63750793,
|
|
|
|
|
|
ClinVar: RCV000009828, RCV000076829, RCV002514362, RCV003452987, RCV004943751
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Turkish patient (patient 3) who developed glioblastoma multiforme at age 10 years and who had cafe-au-lait spots (MMRCS4; 619101), Etzler et al. (2008) identified a homozygous 1-bp deletion (c.182delA, NM_000535.4) in exon 3 of the PMS2 gene. The parents were consanguineous. Immunohistochemical analysis showed loss of PMS2 expression in the tumor and nonneoplastic tissue. Etzler et al. (2008) used an RNA-based assay to avoid the detection of pseudogene sequences. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 LYNCH SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PMS2, 6-BP DEL/11-BP INS, NT736
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267608150,
|
|
|
|
|
|
|
|
ClinVar: RCV000009829, RCV000076885, RCV000115703, RCV000235196, RCV000722010, RCV000763590, RCV001201395, RCV001254933, RCV001353497, RCV001804827, RCV003149759, RCV003915043
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 12 presumably unrelated patients with hereditary nonpolyposis colorectal cancer-4 (LYNCH4; 614337), Clendenning et al. (2008) identified a heterozygous insertion/deletion mutation (736_741del6ins11) in the PMS2 gene, resulting in an alteration of the protein sequence from residue 246 with premature termination at residue 249, which is about 614 amino acids before the wildtype stop codon. Family history suggested reduced penetrance. Haplotype analysis indicated a common founder, and the age of the mutation was estimated at 1,625 years, suggesting that this indel mutation arose sometime during the first millennium. The mutation was enriched in patients of British and Swedish ancestry. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 MISMATCH REPAIR CANCER SYNDROME 4</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PMS2, CYS73TER
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<br />
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SNP: rs121434630,
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ClinVar: RCV000009830
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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 9-year-old boy with mismatch repair cancer syndrome (MMRCS4; 619101) manifest as rhabdomyosarcoma at age 3 years and colonic adenocarcinoma at age 8 years, Kratz et al. (2009) identified a homozygous 219T-A transversion in exon 3 of the PMS2 gene, resulting in a cys73-to-ter (C73X) substitution. He was born of unaffected consanguineous parents, but there was a history of cancer in the family. Cafe-au-lait spots were observed in the proband. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0017 MISMATCH REPAIR CANCER SYNDROME 4</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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PMS2, 1-BP DUP, 1306A
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<br />
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SNP: rs63750106,
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ClinVar: RCV000076805, RCV004576920
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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>Kratz et al. (2008) reported a Turkish girl with mismatch repair cancer syndrome (MMRCS4; 619101) who had been successfully treated for non-Hodgkin lymphoma at age 6 years and who presented at age 16 years with colorectal carcinomas. The patient's sister had cafe-au-lait spots and died from a supratentorial primitive neuroectodermal tumor at age 9 years. The parents and 4 sibs were healthy and without cancer history at time of report, although 1 sib also had cafe-au-lait spots. Microsatellite, immunohistochemical, and sequence analysis that avoided pseudogene interference showed that the patient had a homozygous 1-bp duplication (c.1306dupA) in exon 11 of the PMS2 gene, resulting in a frameshift at ser436 and premature termination (Ser436LysfsX22). Genomic DNA sequencing confirmed the mutation. The patient's parents were heterozygous for the mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0018 MISMATCH REPAIR CANCER SYNDROME 4</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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PMS2, EX11-EX14 DEL/18-BP INS
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<br />
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ClinVar: RCV000029205, RCV000076800
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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>Peron et al. (2008) reported a 12-year-old Turkish girl (patient 1) with mismatch repair cancer syndrome (MMRCS4; 619101) who exhibited Ig class switch recombination (CSR) deficiency. She presented with multiple cafe-au-lait spots and suffered from recurrent infections from the age of 1 year, leading to an immunodeficiency diagnosis at 9 years of age. A year later, she developed a colorectal adenocarcinoma. By genomic DNA analysis, followed by cDNA confirmation, Peron et al. (2008) identified a homozygous deletion of exons 11 through 14 of the patient's PMS2 gene and an 18-nucleotide frameshift insertion and stop codon at the beginning of exon 15. Her consanguineous parents were heterozygous for the mutation. In vitro analysis showed that the CSR defect was characterized by the occurrence of double-strand DNA breaks in switch regions and abnormal formation of switch junctions. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0019 MISMATCH REPAIR CANCER SYNDROME 4</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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PMS2, 2002A-G
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<br />
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SNP: rs869320619,
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ClinVar: RCV000172908, RCV000630142, RCV001179765, RCV001284205, RCV001804905, RCV003454446
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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 13 individuals from 7 unrelated families of Inuit origin with an attenuated form of mismatch repair cancer syndrome (MMRCS4; 619101), Li et al. (2015) identified a homozygous c.2002A-G transition (c.2002A-G, NM_000535.5) in the PMS2 gene. The mutation was predicted to result in an ile668-to-val (I668V) substitution, but analysis of patient cells showed that it altered a 5-prime splice site for intron 11, causing aberrant RNA splicing with a 5-bp deletion, and resulting in nonsense-mediated mRNA decay. Patient cells showed only a minor amount of full-length transcripts and some residual normal full-length protein. Haplotype analysis indicated a founder effect estimated to have appeared late in the 11th century. The age at cancer onset in individuals homozygous for the c.2002A-G mutation was significantly later (median age 22 years) compared to individuals homozygous for truncating PMS2 mutations (8 years). There was also a difference in the tumor spectrum, with brain tumors being significantly less prevalent in c.2002A-G homozygotes (15%) compared to truncating homozygotes (67%). Li et al. (2015) concluded that even a low level of PMS2 expression likely delays cancer onset. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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Adams, M. D., Kelley, J. M., Gocayne, J. D., Dubnick, M., Polymeropoulos, M. H., Xiao, H., Merril, C. R., Wu, A., Olde, B., Moreno, R. F., Kerlavage, A. R., McCombie, W. R., Venter, J. C.
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<strong>Complementary DNA sequencing: expressed sequence tags and human genome project.</strong>
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Science 252: 1651-1656, 1991.
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[PubMed: 2047873]
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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.
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<strong>Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation.</strong>
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Hum. Mutat. 28: 1084-1090, 2007.
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Baker, S. M., Bronner, C. E., Zhang, L., Plug, A. W., Robatzek, M., Warren, G., Elliott, E. A., Yu, J., Ashley, T., Arnheim, N., Flavell, R. A., Liskay, R. M.
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<strong>Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis.</strong>
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Cell 82: 309-319, 1995.
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Borras, E., Pineda, M., Cadinanos, J., del Valle, J., Brieger, A., Hinrichsen, I., Cabanillas, R., Navarro, M., Brunet, J., Sanjuan, X., Musulen, E., van der Klift, H., Lazaro, C., Plotz, G., Blanco, I., Capella, G.
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<strong>Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants.</strong>
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Clendenning, M., Senter, L., Hampel, H., Robinson, K. L., Sun, S., Buchanan, D., Walsh, M. D., Nilbert, M., Green, J., Potter, J., Lindblom, A., de la Chapelle, A.
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<strong>A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome.</strong>
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De Rosa, M., Fasano, C., Panariello, L., Scarano, M. I., Belli, G., Iannelli, A., Ciciliano, F., Izzo, P.
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<strong>Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.</strong>
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Oncogene 19: 1719-1723, 2000.
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[PubMed: 10763829]
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De Vos, M., Hayward, B. E., Charlton, R., Taylor, G. R., Glaser, A. W., Picton, S., Cole, T. R., Maher, E. R., McKeown, C. M. E., Mann, J. R., Yates, J. R., Baralle, D., Rankin, J., Bonthron, D. T., Sheridan, E.
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<strong>PMS2 mutations in childhood cancer.</strong>
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De Vos, M., Hayward, B. E., Picton, S., Sheridan, E., Bonthron, D. T.
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<strong>Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.</strong>
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Am. J. Hum. Genet. 74: 954-964, 2004.
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<p class="mim-text-font">
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Etzler, J., Peyrl, A., Zatkova, A., Schildhaus, H.-U., Ficek, A., Merkelbach-Bruse, S., Kratz, C. P., Attarbaschi, A., Hainfellner, J. A., Yao, S., Messiaen, L., Slavc, I., Wimmer, K.
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Ganster, C., Wernstedt, A., Kehrer-Sawatzki, H., Messiaen, L., Schmidt, K., Rahner, N., Heinimann, K., Fonatsch, C., Zschocke, J., Wimmer, K.
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<strong>Functional PMS2 hybrid alleles containing a pseudogene-specific missense variant trace back to a single ancient intrachromosomal recombination event.</strong>
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Hum. Mutat. 31: 552-560, 2010.
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Hamilton, S. R., Liu, B., Parsons, R. E., Papadopoulos, N., Jen, J., Powell, S. M., Krush, A. J., Berk, T., Cohen, Z., Tetu, B., Burger, P. C., Wood, P. A., Taqi, F., Booker, S. V., Petersen, G. M., Offerhaus, G. J. A., Tersmette, A. C., Giardiello, F. M., Vogelstein, B., Kinzler, K. W.
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<strong>The molecular basis of Turcot's syndrome.</strong>
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<p class="mim-text-font">
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Hayward, B. E., De Vos, M., Valleley, E. M. A., Charlton, R. S., Taylor, G. R., Sheridan, E., Bonthron, D. T.
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<strong>Extensive gene conversion at the PMS2 DNA mismatch repair locus.</strong>
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Hum. Mutat. 28: 424-430, 2007.
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[PubMed: 17253626]
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[Full Text: https://doi.org/10.1002/humu.20457]
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<li>
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<p class="mim-text-font">
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Hendriks, Y. M. C., Jagmohan-Changur, S., Van der Klift, H. M., Morreau, H., Van Puijenbroek, M., Tops, C., Van Os, T., Wagner, A., Ausems, M. G. F. M., Gomez, E., Breuning, M. J., Brocker-Vriends, A. H. J. T., Vasen, H. F. A., Wijnen, J. T.
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<strong>Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome).</strong>
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Gastroenterology 130: 312-322, 2006.
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[PubMed: 16472587]
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[Full Text: https://doi.org/10.1053/j.gastro.2005.10.052]
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</p>
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<p class="mim-text-font">
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Kadyrov, F. A., Dzantiev, L., Constantin, N., Modrich, P.
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<strong>Endonucleolytic function of MutL-alpha in human mismatch repair.</strong>
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Cell 126: 297-308, 2006.
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[PubMed: 16873062]
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[Full Text: https://doi.org/10.1016/j.cell.2006.05.039]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kratz, C. P., Holter, S., Etzler, J., Lauten, M., Pollett, A., Niemeyer, C. M., Gallinger, S., Wimmer, K.
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<strong>Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome.</strong>
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J. Med. Genet. 46: 418-420, 2009.
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[PubMed: 19293170]
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[Full Text: https://doi.org/10.1136/jmg.2008.064212]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kratz, C. P., Niemeyer, C. M., Juttner, E., Kartal, M., Weninger, A., Schmitt-Graeff, A., Kontny, U., Lauten, M., Utzolino, S., Radecke, J., Fonatsch, C., Wimmer, K.
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<strong>Childhood T-cell non-Hodgkin's lymphoma, colorectal carcinoma and brain tumor in association with cafe-au-lait spots caused by a novel homozygous PMS2 mutation. (Letter)</strong>
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Leukemia 22: 1078-1080, 2008.
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[PubMed: 18007577]
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[Full Text: https://doi.org/10.1038/sj.leu.2405008]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Li, G.-M., Modrich, P.
|
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<strong>Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs.</strong>
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Proc. Nat. Acad. Sci. 92: 1950-1954, 1995.
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[PubMed: 7892206]
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[Full Text: https://doi.org/10.1073/pnas.92.6.1950]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Li, L., Hamel, N., Baker, K., McGuffin, M. J., Couillard, M., Gologan, A., Marcus, V. A., Chodirker, B., Chudley, A., Stefanovici, C., Durandy, A., Hegele, R. A., and 10 others.
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<strong>A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.</strong>
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J. Med. Genet. 52: 348-352, 2015.
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[PubMed: 25691505]
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[Full Text: https://doi.org/10.1136/jmedgenet-2014-102934]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Ma, A.-H., Xia, L., Littman, S. J., Swinler, S., Lader, G., Polinkovsky, A., Olechnowicz, J., Kasturi, L., Lutterbaugh, J., Modrich, P., Veigl, M. L., Markowitz, S. D., Sedwick, W. D.
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<strong>Somatic mutation of hPMS2 as a possible cause of sporadic human colon cancer with microsatellite instability.</strong>
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|
Oncogene 19: 2249-2256, 2000.
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[PubMed: 10822375]
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