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Entry
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- *609644 - FANCM GENE; FANCM
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- OMIM
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<p>
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<span class="h4">*609644</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/609644">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 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>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<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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<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=ENSG00000187790;t=ENST00000267430" 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=57697" 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=609644" 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 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=ENSG00000187790;t=ENST00000267430" 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_001308133,NM_001308134,NM_020937,XM_011537034,XM_011537035,XM_011537037,XM_017021523,XM_047431631,XM_047431632,XM_047431633,XM_047431634" 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_020937" 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=609644" 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=13876&isoform_id=13876_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/FANCM" 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/10047267,21752288,23273574,71912519,74959747,78099254,119586185,119586186,119586187,119586188,187954507,219518301,767981198,767981200,767981205,815890934,815890936,1034587758,2217298158,2217298160,2217298162,2217298164,2462541138,2462541140,2462541142,2462541144,2462541146,2462541148,2462541150,2462541152" 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/Q8IYD8" 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=57697" 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=ENSG00000187790;t=ENST00000267430" 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=FANCM" 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=FANCM" 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+57697" 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/FANCM" 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:57697" 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/57697" 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=chr14&hgg_gene=ENST00000267430.10&hgg_start=45135930&hgg_end=45200890&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 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:23168" 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:23168" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=609644[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=609644[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/FANCM/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000187790" 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=FANCM" 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=FANCM" 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=FANCM" 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="http://www.rockefeller.edu/fanconi/mutate/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FANCM&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/PA134943156" 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:23168" 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/FBgn0038889.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:2442306" 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/FANCM#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:2442306" 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/57697/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=57697" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-090929-1" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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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:57697" 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=FANCM&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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609644
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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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FANCM GENE; FANCM
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
FANCONI ANEMIA-ASSOCIATED POLYPEPTIDE, 250-KD; FAAP250<br />
|
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KIAA1596
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FANCM" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FANCM</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/14/200?start=-3&limit=10&highlight=200">14q21.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr14:45135930-45200890&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'})">14:45,135,930-45,200,890</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>
|
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</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>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=618096,618086" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
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>
|
|
</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/14/200?start=-3&limit=10&highlight=200">
|
|
14q21.2
|
|
</a>
|
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</span>
|
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</td>
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Premature ovarian failure 15
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/618096"> 618096 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
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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>
|
|
<span class="mim-font">
|
|
Spermatogenic failure 28
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/618086"> 618086 </a>
|
|
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
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</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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<p>By sequencing clones obtained from a size-fractionated fetal brain cDNA library, <a href="#18" class="mim-tip-reference" title="Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong> DNA Res. 7: 273-281, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10997877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10997877</a>] [<a href="https://doi.org/10.1093/dnares/7.4.271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10997877">Nagase et al. (2000)</a> cloned FANCM, which they designated KIAA1596. RT-PCR ELISA detected low to moderate FANCM expression in testis and ovary, lower levels in fetal liver and adult brain, skeletal muscle, kidney, and spleen, and little to no expression in fetal brain and adult spinal cord, heart, lung, liver, and pancreas. Within specific adult brain regions, low to moderate expression was detected in amygdala, with lower levels in all other brain regions examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10997877" 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>Meetei et al. (<a href="#17" class="mim-tip-reference" title="Meetei, A. R., Sechi, S., Wallisch, M., Yang, D., Young, M. K., Joenje, H., Hoatlin, M. E., Wang, W. <strong>A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.</strong> Molec. Cell. Biol. 23: 3417-3426, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12724401[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.23.10.3417-3426.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12724401">2003</a>, <a href="#14" class="mim-tip-reference" " title="Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W. <strong>A novel ubiquitin ligase is deficient in Fanconi anemia.</strong> Nature Genet. 35: 165-170, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973351</a>] [<a href="https://doi.org/10.1038/ng1241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12973351">2003</a>, <a href="#15" class="mim-tip-reference" title="Meetei, A. R., Levitus, M., Xue, Y., Medhurst, A. L., Zwaan, M., Ling, C., Rooimans, M. A., Bier, P., Hoatlin, M., Pals, G., de Winter, J. P., Wang, W., Joenje, H. <strong>X-linked inheritance of Fanconi anemia complementation group B.</strong> Nature Genet. 36: 1219-1224, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15502827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15502827</a>] [<a href="https://doi.org/10.1038/ng1458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15502827">2004</a>) purified a Fanconi anemia core complex containing 7 Fanconi anemia-associated proteins each essential for monoubiquitination of FANCD2 (<a href="/entry/613984">613984</a>), a key reaction in the Fanconi anemia DNA damage-response pathway. Using mass spectrometry, <a href="#16" class="mim-tip-reference" title="Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W. <strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong> Nature Genet. 37: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[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/ng1626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116422">Meetei et al. (2005)</a> identified another component, FAAP250, as KIAA1596. Antibodies raised against KIAA1596 specifically recognized the 250-kD polypeptide of the Fanconi anemia core complex immunopurified using antibodies against FANCA (<a href="/entry/607139">607139</a>). FAAP250, or FANCM, has sequence similarity to DNA repair proteins, including archaeal Hef, yeast MPH1, and human ERCC4 (<a href="/entry/133520">133520</a>). The deduced 2,048-amino acid protein contains an N-terminal helicase domain homologous to those of DEAH box helicases (see <a href="/entry/607570">607570</a>) or DNA-stimulated ATPases. It also has a C-terminal endonuclease domain homologous to that of ERCC4, but sequence degeneracy suggests that it is inactive. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15502827+16116422+12973351+12724401" 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>By immunohistochemical analysis of human testicular tissue sections, <a href="#10" class="mim-tip-reference" title="Kasak, L., Punab, M., Nagirmaja, L., Grigorova, M., Minajeva, A., Lopes, A. M., Punab, A. M., Aston, K. I., Carvalho, F., Laasik, E., Smith, L. B., GEMINI Consortium, Conrad, D. F., Laan, M. <strong>Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia.</strong> Am. J. Hum. Genet. 103: 200-212, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30075111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30075111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30075111[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.07.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30075111">Kasak et al. (2018)</a> observed localization of FANCM to the cytoplasm of Sertoli cells and spermatogenic cells in the seminiferous tubules. Staining intensity was related to stage of maturation, with faint staining of spermatogonia, increased staining in primary spermatocytes to spermatids, and reduced staining in tubules with mature spermatozoa. FANCM expression was also present in the interstitial Leydig cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30075111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Fouquet, B., Pawlikowska, P., Caburet, S., Guigon, C., Makinen, M., Tanner, L., Hietala, M., Urbanska, K., Bellutti, L., Legois, B., Bessieres, B., Gougeon, A., Benachi, A., Livera, G., Rosselli, F., Veitia, R. A., Misrahi, M. <strong>A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency.</strong> eLIFE 6: e30490, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29231814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29231814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29231814[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/10.7554/eLife.30490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29231814">Fouquet et al. (2017)</a> performed qRT-PCR in germ cells from human fetal ovaries and observed expression throughout ovarian development, with highest expression in ovaries at stages containing the highest proportion of germ cells progressing into meiotic prophase I. Cell-sorting experiments revealed that FANCM transcripts were predominant in oogonial cells compared to somatic cells. Immunohistochemical analysis of human fetal ovaries showed that FANCM protein was present in the nuclei of oogonia, with strongest staining in pachytene stage oocytes. In addition, staining localized along the chromosomes in pachytene cells undergoing meiotic recombination. FANCM was also observed in oocytes arrested at the diplotene stage of prophase I during the last trimester of pregnancy and in adults. Costaining with SYCP3 (<a href="/entry/604759">604759</a>) and DDX4 (<a href="/entry/605281">605281</a>) confirmed the meiotic and germinal nature, respectively, of the FANCM-positive cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29231814" 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="#18" class="mim-tip-reference" title="Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong> DNA Res. 7: 273-281, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10997877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10997877</a>] [<a href="https://doi.org/10.1093/dnares/7.4.271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10997877">Nagase et al. (2000)</a> mapped the KIAA1596 cDNA, corresponding to the FANCM gene, to chromosome 14. <a href="#16" class="mim-tip-reference" title="Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W. <strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong> Nature Genet. 37: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[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/ng1626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116422">Meetei et al. (2005)</a> stated that 2 tightly linked flanking markers are D14S259 and D14S1027. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16116422+10997877" 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="#16" class="mim-tip-reference" title="Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W. <strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong> Nature Genet. 37: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[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/ng1626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116422">Meetei et al. (2005)</a> found that FANCM could dissociate DNA triplex, possibly owing to its ability to translocate on duplex DNA. FANCM was essential for monoubiquitination of FANCD2 and became hyperphosphorylated in response to DNA damage. The data of <a href="#16" class="mim-tip-reference" title="Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W. <strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong> Nature Genet. 37: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[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/ng1626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116422">Meetei et al. (2005)</a> suggested an evolutionary link between Fanconi anemia-associated proteins and DNA repair. They suggested that FANCM may act as an engine that translocates the Fanconi anemia core complex along DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16116422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Ciccia, A., Ling, C., Coulthard, R., Yan, Z., Xue, Y., Meetei, A. R., Laghmani, E. H., Joenje, H., McDonald, N., de Winter, J. P., Wang, W., West, S. C. <strong>Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM.</strong> Molec. Cell 25: 331-343, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17289582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17289582</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.01.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17289582">Ciccia et al. (2007)</a> found that FAAP24 (<a href="/entry/610884">610884</a>) interacted specifically with the C-terminal region of FANCM in several assays. In fractionated HeLa cells, the FAAP24/FANCM heterodimer associated with other FA core proteins in an 800-kD complex. Downregulation of FAAP24 by small interfering RNA resulted in reduced levels of monoubiquitylated FANCD2 after exposure to DNA crosslinking reagents. FAAP24 bound single-stranded DNA. <a href="#3" class="mim-tip-reference" title="Ciccia, A., Ling, C., Coulthard, R., Yan, Z., Xue, Y., Meetei, A. R., Laghmani, E. H., Joenje, H., McDonald, N., de Winter, J. P., Wang, W., West, S. C. <strong>Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM.</strong> Molec. Cell 25: 331-343, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17289582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17289582</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.01.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17289582">Ciccia et al. (2007)</a> suggested that FAAP24 promotes targeting of FANCM/FAAP24 dimers, and possibly other components of the FA core complex, to forked DNA intermediates generated after DNA damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17289582" 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>FANCM displays DNA-dependent ATPase activity and promotes dissociation of DNA triplexes. <a href="#7" class="mim-tip-reference" title="Gari, K., Decaillet, C., Stasiak, A. Z., Stasiak, A., Constantinou, A. <strong>The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks.</strong> Molec. Cell 29: 141-148, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18206976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18206976</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.11.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18206976">Gari et al. (2008)</a> found that recombinant human FANCM bound Holliday junctions and replication forks with high specificity and promoted migration of their junction point in an ATPase-dependent manner. FANCM dissociated large recombination intermediates via branch migration of Holliday junctions through 2.6 kb of DNA. <a href="#7" class="mim-tip-reference" title="Gari, K., Decaillet, C., Stasiak, A. Z., Stasiak, A., Constantinou, A. <strong>The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks.</strong> Molec. Cell 29: 141-148, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18206976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18206976</a>] [<a href="https://doi.org/10.1016/j.molcel.2007.11.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18206976">Gari et al. (2008)</a> concluded that FANCM has a direct role in DNA processing, consistent with the view that FA proteins coordinate DNA repair at stalled replication forks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18206976" 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>By copurification of epitope-tagged proteins, <a href="#4" class="mim-tip-reference" title="Collis, S. J., Ciccia, A., Deans, A. J., Horejsi, Z., Martin, J. S., Maslen, S. L., Skehel, J. M., Elledge, S. J., West, S. C., Boulton, S. J. <strong>FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex.</strong> Molec. Cell 32: 313-324, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18995830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18995830</a>] [<a href="https://doi.org/10.1016/j.molcel.2008.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18995830">Collis et al. (2008)</a> found that the checkpoint protein HCLK2 (TELO2; <a href="/entry/611140">611140</a>) interacted strongly with the N-terminal region of FANCM and weakly with the C-terminal region. The interaction required the HEAT repeat structure of HCLK2. Immunoprecipitation analysis of human cell lines showed that endogenous FANCM and FAAP24 formed a stable complex with HCLK2 in the absence of other FA core complex components. Knockdown of either FANCM, FAAP24, or HCLK2 via small interfering RNA compromised ATR (<a href="/entry/601215">601215</a>)/CHK1 (<a href="/entry/603078">603078</a>)-mediated checkpoint signaling, leading to increased endogenous DNA damage and failure to efficiently invoke cell cycle checkpoint responses. Moreover, the DNA translocase activity of FANCM, which is dispensable for FA pathway activation, was required for its role in ATR/CHK1 signaling. <a href="#4" class="mim-tip-reference" title="Collis, S. J., Ciccia, A., Deans, A. J., Horejsi, Z., Martin, J. S., Maslen, S. L., Skehel, J. M., Elledge, S. J., West, S. C., Boulton, S. J. <strong>FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex.</strong> Molec. Cell 32: 313-324, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18995830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18995830</a>] [<a href="https://doi.org/10.1016/j.molcel.2008.10.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18995830">Collis et al. (2008)</a> concluded that FANCM and FAAP24 couple checkpoint signaling with DNA repair via their interactions with HCLK2 and FA core complex components. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18995830" 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>Fanconi anemia and Bloom syndrome (BS; <a href="/entry/210900">210900</a>) share overlapping phenotypes, including aberrant DNA repair and cancer predisposition. Treatment of cells with DNA crosslinking agents results in association of the BS complex with the FA core complex in a supercomplex called BRAFT. <a href="#5" class="mim-tip-reference" title="Deans, A. J., West, S. C. <strong>FANCM connects the genome instability disorders Bloom's syndrome and Fanconi anemia.</strong> Molec. Cell 36: 943-953, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20064461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20064461</a>] [<a href="https://doi.org/10.1016/j.molcel.2009.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20064461">Deans and West (2009)</a> found that FANCM functioned as the bridge in the FA/BS supercomplex by binding specific FA and BS components via its highly conserved MM1 and MM2 motifs, respectively. MM1 specifically bound FANCF (<a href="/entry/603467">603467</a>) of the FA core complex. MM2 specifically bound the BS complex components RMI1 (<a href="/entry/610404">610404</a>) and topoisomerase III-alpha (TOP3A; <a href="/entry/601243">601243</a>), but not the helicase BLM (RECQL3; <a href="/entry/604610">604610</a>). Knockdown of FANCM using small interfering RNA eliminated FA/BS association. Alanine substitution of phe1232 and phe1236 within MM2 resulted in a FANCM protein unable to interact with the BS complex. Interaction of FANCM with RMI1 and TOP3A was required for targeting of BLM to nuclear foci after treatment with replication stalling agents, but not ionizing radiation. <a href="#5" class="mim-tip-reference" title="Deans, A. J., West, S. C. <strong>FANCM connects the genome instability disorders Bloom's syndrome and Fanconi anemia.</strong> Molec. Cell 36: 943-953, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20064461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20064461</a>] [<a href="https://doi.org/10.1016/j.molcel.2009.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20064461">Deans and West (2009)</a> concluded that the FA and BS complexes interact via FANCM in a subset of DNA repair reactions, including those at replication forks stalled at sites of DNA damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20064461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Blackford, A. N., Schwab, R. A., Nieminuszczy, J., Deans, A. J., West, S. C., Niedzwiedz, W. <strong>The DNA translocase activity of FANCM protects stalled replication forks.</strong> Hum. Molec. Genet. 21: 2005-2016, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22279085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22279085</a>] [<a href="https://doi.org/10.1093/hmg/dds013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22279085">Blackford et al. (2012)</a> found that cells expressing translocase-defective FANCM showed altered global replication due to increased accumulation of stalled replication forks, which subsequently degenerated into DNA double-strand breaks, leading to ATM activation, CTIP-dependent end resection, and homologous recombination repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22279085" 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>Spermatogenic Failure 28</em></strong></p><p>
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In 2 Estonian brothers with nonobstructive azoospermia and Sertoli cell-only syndrome (SPGF28; <a href="/entry/618086">618086</a>), <a href="#10" class="mim-tip-reference" title="Kasak, L., Punab, M., Nagirmaja, L., Grigorova, M., Minajeva, A., Lopes, A. M., Punab, A. M., Aston, K. I., Carvalho, F., Laasik, E., Smith, L. B., GEMINI Consortium, Conrad, D. F., Laan, M. <strong>Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia.</strong> Am. J. Hum. Genet. 103: 200-212, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30075111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30075111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30075111[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.07.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30075111">Kasak et al. (2018)</a> identified compound heterozygosity for a 1-bp duplication (<a href="#0003">609644.0003</a>) and a splice site mutation (<a href="#0004">609644.0004</a>) in the FANCM gene. The authors also reported homozygosity for nonsense mutations in the FANCM gene in 2 additional men with nonobstructive azoospermia: an unrelated Estonian man (Q1701X; <a href="#0005">609644.0005</a>) and a Portuguese man (R1931X; <a href="#0006">609644.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30075111" 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 3 Pakistani brothers with infertility due to oligoasthenospermia or azoospermia, <a href="#20" class="mim-tip-reference" title="Yin, H., Ma, H., Hussain, S., Zhang, H., Xie, X., Jiang, L., Jiang, X., Iqbal, F., Bukhari, I., Jiang, H., Ali, A., Zhong, L. and 17 others. <strong>A homozygous FANCM frameshift pathogenic variant causes male infertility.</strong> Genet. Med. 21: 62, 2019. Note: Electronic Article. Erratum: Genet. Med. 21: 266, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29895858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29895858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29895858[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/s41436-018-0015-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29895858">Yin et al. (2019)</a> identified homozygosity for a 13-bp deletion in the FANCM gene (<a href="#0007">609644.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29895858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Premature Ovarian Failure 15</em></strong></p><p>
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In 2 Finnish sisters with premature ovarian failure-15 (POF15; <a href="/entry/618096">618096</a>), <a href="#6" class="mim-tip-reference" title="Fouquet, B., Pawlikowska, P., Caburet, S., Guigon, C., Makinen, M., Tanner, L., Hietala, M., Urbanska, K., Bellutti, L., Legois, B., Bessieres, B., Gougeon, A., Benachi, A., Livera, G., Rosselli, F., Veitia, R. A., Misrahi, M. <strong>A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency.</strong> eLIFE 6: e30490, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29231814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29231814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29231814[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/10.7554/eLife.30490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29231814">Fouquet et al. (2017)</a> identified homozygosity for the Q1701X mutation (<a href="#0005">609644.0005</a>) in the FANCM gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29231814" 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>By whole-exome sequencing in a cohort of 10 women with POF, <a href="#9" class="mim-tip-reference" title="Jaillard, S., Bell, K., Akloul, L., Walton, K., McElreavy, K., Stocker, W. A., Beaumont, M., Harrisson, C., Jaaskelainen, T., Palvimo, J. J., Robevska, G., Launay, E., and 16 others. <strong>New insights into the genetic basis of premature ovarian insufficiency: novel causative variants and candidate genes revealed by genomic sequencing.</strong> Maturitas 141: 9-19, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33036707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33036707</a>] [<a href="https://doi.org/10.1016/j.maturitas.2020.06.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33036707">Jaillard et al. (2020)</a> identified 1 proband who was compound heterozygous for nonsense mutations in the FANCM gene: the previously reported R1931X mutation (<a href="#0006">609644.0006</a>) and an R1030X mutation (<a href="#0008">609644.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33036707" 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>By targeted or whole-exome sequencing in an international cohort of 375 women with POF from 70 families, <a href="#8" class="mim-tip-reference" title="Heddar, A., Ogur, C., Da Costa, S., Braham, I., Billaud-Rist, L., Findikli, N., Beneteau, C., Reynaud, R., Mahmoud, K., Legrand, S., Marchand, M., Cedrin-Durnerin, I., and 46 others. <strong>Genetic landscape of a large cohort of primary ovarian insufficiency: new genes and pathways and implications for personalized medicine.</strong> EBioMedicine 84: 104246, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36099812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36099812</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36099812[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ebiom.2022.104246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36099812">Heddar et al. (2022)</a> identified 3 Finnish women and 2 European women with mutations in the FANCM gene: all carried the previously reported nonsense mutation Q1701X, for which the 3 Finnish women were homozygous. In patients 167 and 326, the second variant was a missense mutation, G510S (<a href="#0009">609644.0009</a>) or Q192L (<a href="#0010">609644.0010</a>), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36099812" 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>Associations Pending Confirmation</em></strong></p><p>
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<a href="#11" class="mim-tip-reference" title="Kiiski, J. I., Pelttari, L. M., Khan, S., Freysteinsdottir, E. S., Reynisdottir, I., Hart, S. N., Shimelis, H., Vilske, S., Kallioniemi, A., Schleutker, J., Leminen, A., Butzow, R., Blomqvist, C., Barkardottir, R. B., Couch, F. J., Aittomaki, K., Nevanlinna, H. <strong>Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer.</strong> Proc. Nat. Acad. Sci. 111: 15172-15177, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25288723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25288723</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25288723[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.1407909111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25288723">Kiiski et al. (2014)</a> performed whole-exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. A nonsense mutation in FANCM, c.5101C-T (Q1701X, <a href="#0005">609644.0005</a>; <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs147021911;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs147021911</a>) was significantly more frequent among breast cancer patients than among controls (odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; p = 0.0018), with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, p = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. <a href="#11" class="mim-tip-reference" title="Kiiski, J. I., Pelttari, L. M., Khan, S., Freysteinsdottir, E. S., Reynisdottir, I., Hart, S. N., Shimelis, H., Vilske, S., Kallioniemi, A., Schleutker, J., Leminen, A., Butzow, R., Blomqvist, C., Barkardottir, R. B., Couch, F. J., Aittomaki, K., Nevanlinna, H. <strong>Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer.</strong> Proc. Nat. Acad. Sci. 111: 15172-15177, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25288723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25288723</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25288723[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.1407909111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25288723">Kiiski et al. (2014)</a> concluded that their findings identified FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25288723" 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>Exclusion Studies</em></strong></p><p>
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In a large population-based exome-sequencing study of 3,000 Finnish individuals, <a href="#12" class="mim-tip-reference" title="Lim, E. T., Wurtz, P., Havulinna, A. S., Palta, P., Tukiainen, T., Rehnstrom, K., Esko, T., Magi, R., Inouye, M., Lappalainen, T., Chan, Y., Salem, R. M., and 48 others. <strong>Distribution and medical impact of loss-of-function variants in the Finnish founder population.</strong> PLoS Genet. 10: e1004494, 2014. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25078778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25078778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25078778[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/10.1371/journal.pgen.1004494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25078778">Lim et al. (2014)</a> did not find a deficit of individuals homozygous for predicted loss-of-function variants in the FANCM gene (5 expected, 7 observed). Examination of hospital records for homozygous carriers did not provide any evidence for blood diseases, increased cancer events, or other chronic diseases in these individuals compared to those without these variants. The findings did not support the hypothesis that FANCM is a gene associated with Fanconi anemia (see, e.g., FANCA, <a href="/entry/227650">227650</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25078778" 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="#1" class="mim-tip-reference" title="Bakker, S. T., van de Vrugt, H. J., Rooimans, M. A., Oostra, A. B., Steltenpool, J., Delzenne-Goette, E., van der Wal, A., van der Valk, M., Joenje, H., Riele H., de Winter, J. P. <strong>Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M.</strong> Hum. Molec. Genet. 18: 3484-3495, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19561169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19561169</a>] [<a href="https://doi.org/10.1093/hmg/ddp297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19561169">Bakker et al. (2009)</a> generated Fancm-deficient mice by deleting exon 2. Fancm deficiency caused hypogonadism in mice and hypersensitivity to crosslinking agents in mouse embryonic fibroblasts (MEFs), similar to other FA mouse models. Fancm -/- mice also showed unique features atypical for FA mice, including underrepresentation of female Fancm -/- mice and decreased overall and tumor-free survival. This increased cancer incidence may be correlated to the role of FANCM in the suppression of spontaneous sister chromatid exchanges as observed in MEFs. In addition, Fancm appeared to have a stimulatory rather than essential role in Fancd2 (<a href="/entry/227646">227646</a>) monoubiquitination. <a href="#1" class="mim-tip-reference" title="Bakker, S. T., van de Vrugt, H. J., Rooimans, M. A., Oostra, A. B., Steltenpool, J., Delzenne-Goette, E., van der Wal, A., van der Valk, M., Joenje, H., Riele H., de Winter, J. P. <strong>Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M.</strong> Hum. Molec. Genet. 18: 3484-3495, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19561169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19561169</a>] [<a href="https://doi.org/10.1093/hmg/ddp297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19561169">Bakker et al. (2009)</a> suggested that FANCM functions both inside and outside the FA core complex to maintain genome stability and to prevent tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19561169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="McNairn, A. J., Chuang, C.-H., Bloom, J. C., Wallace, M. D., Schimenti, J. C. <strong>Female-biased embryonic death from inflammation induced by genomic instability.</strong> Nature 567: 105-108, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30787433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30787433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30787433[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/s41586-019-0936-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30787433">McNairn et al. (2019)</a> found that mutations in the heterohexameric minichromosome maintenance (MCM; see <a href="/entry/116945">116945</a>) complex that cause genomic instability render female mouse embryos markedly more susceptible than males to embryonic lethality. XX embryos could be rescued by transgene-mediated sex reversal or testosterone administration. The ability of exogenous or endogenous testosterone to protect embryos was related to its antiinflammatory properties. Ibuprofen, a nonsteroidal antiinflammatory drug, rescued female embryos that contained mutations in not only the Mcm genes but also the Fancm gene; similar to Mcm mutants, Fancm mutant embryos have increased levels of genomic instability (measured as the number of cells with micronuclei) from compromised replication fork repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30787433" 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>This variant, formerly titled FANCONI ANEMIA, COMPLEMENTATION GROUP M based on the report of <a href="#16" class="mim-tip-reference" title="Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W. <strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong> Nature Genet. 37: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[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/ng1626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116422">Meetei et al. (2005)</a>, has been reclassified based on the findings of <a href="#19" class="mim-tip-reference" title="Singh, T. R., Bakker, S. T., Agarwal, S., Jansen, M., Grassman, E., Godthelp, B. C., Ali, A. M., Du, C., Rooimans, M. A., Fan, Q., Wahengbam, K., Steltenpool, J., Andreassen, P. R., Williams, D. A., Joenje, H., de Winter, J. P., Meetei, A. R. <strong>Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.</strong> Blood 114: 174-180, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19423727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19423727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19423727[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/10.1182/blood-2009-02-207811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19423727">Singh et al. (2009)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16116422+19423727" 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 cell line derived from a patient (EUFA867) with Fanconi anemia, <a href="#16" class="mim-tip-reference" title="Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W. <strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong> Nature Genet. 37: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[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/ng1626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116422">Meetei et al. (2005)</a> identified compound heterozygous variants in the FANCM gene: a c.2171C-A transversion in exon 13 resulting in a ser724-to-ter (S724X) substitution, and a 2,554-bp deletion (<a href="#0002">609644.0002</a>), spanning part of intron 14 and almost all of exon 15, resulting in absence of the sequence encoded by exon 15. A sib with Fanconi anemia was reported to carry the same 2 mutations. The nonsense mutation was inherited from the healthy mother; the deletion was not detected in the father but he was thought to be gonadal mosaic for it. Immunoblotting of patient cells showed absence of the FANCM protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16116422" 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 cell lines derived from the 2 sibs originally reported by <a href="#16" class="mim-tip-reference" title="Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W. <strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong> Nature Genet. 37: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[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/ng1626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116422">Meetei et al. (2005)</a>, <a href="#19" class="mim-tip-reference" title="Singh, T. R., Bakker, S. T., Agarwal, S., Jansen, M., Grassman, E., Godthelp, B. C., Ali, A. M., Du, C., Rooimans, M. A., Fan, Q., Wahengbam, K., Steltenpool, J., Andreassen, P. R., Williams, D. A., Joenje, H., de Winter, J. P., Meetei, A. R. <strong>Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.</strong> Blood 114: 174-180, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19423727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19423727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19423727[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/10.1182/blood-2009-02-207811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19423727">Singh et al. (2009)</a> identified biallelic mutations in the FANCA gene (<a href="/entry/607139#0011">607139.0011</a> and <a href="/entry/607139#0012">607139.0012</a>). In addition, <a href="#19" class="mim-tip-reference" title="Singh, T. R., Bakker, S. T., Agarwal, S., Jansen, M., Grassman, E., Godthelp, B. C., Ali, A. M., Du, C., Rooimans, M. A., Fan, Q., Wahengbam, K., Steltenpool, J., Andreassen, P. R., Williams, D. A., Joenje, H., de Winter, J. P., Meetei, A. R. <strong>Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.</strong> Blood 114: 174-180, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19423727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19423727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19423727[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/10.1182/blood-2009-02-207811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19423727">Singh et al. (2009)</a> noted that only 1 of the sibs had clinical features of the disorder and that the clinically affected sib carried only 1 of the FANCM variants. The clinically unaffected sib (EUFA867) carried both biallelic FANCA mutations and biallelic FANCM variants. <a href="#19" class="mim-tip-reference" title="Singh, T. R., Bakker, S. T., Agarwal, S., Jansen, M., Grassman, E., Godthelp, B. C., Ali, A. M., Du, C., Rooimans, M. A., Fan, Q., Wahengbam, K., Steltenpool, J., Andreassen, P. R., Williams, D. A., Joenje, H., de Winter, J. P., Meetei, A. R. <strong>Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.</strong> Blood 114: 174-180, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19423727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19423727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19423727[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/10.1182/blood-2009-02-207811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19423727">Singh et al. (2009)</a> reclassified the affected sib as having FANCA, and suggested that FANCM deficiency in the unaffected sib may have overruled the FANCA defect and changed the clinical outcome, possibly even attenuating the phenotype. Cellular studies of EUFA867 by <a href="#19" class="mim-tip-reference" title="Singh, T. R., Bakker, S. T., Agarwal, S., Jansen, M., Grassman, E., Godthelp, B. C., Ali, A. M., Du, C., Rooimans, M. A., Fan, Q., Wahengbam, K., Steltenpool, J., Andreassen, P. R., Williams, D. A., Joenje, H., de Winter, J. P., Meetei, A. R. <strong>Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.</strong> Blood 114: 174-180, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19423727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19423727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19423727[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/10.1182/blood-2009-02-207811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19423727">Singh et al. (2009)</a> showed that expression of FANCA could rescue the FANCD2 (<a href="/entry/613984">613984</a>) monoubiquitination defect. After correction of the FANCA defect, the FANCM-deficient cells remained hypersensitive to the cross-linking agent mitomycin C; they were also sensitive to the topoisomerase inhibitor camptothecin and to UV light. FANCM-null cells had some residual monoubiquitinating FANCD2. The findings suggested that FANCM is involved in different steps of the DNA damage response, including efficient FANCD2 monoubiquitination and DNA repair steps later in the Fanconi anemia pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16116422+19423727" 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>This variant, formerly titled FANCONI ANEMIA, COMPLEMENTATION GROUP M based on the report of <a href="#16" class="mim-tip-reference" title="Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W. <strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong> Nature Genet. 37: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[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/ng1626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116422">Meetei et al. (2005)</a>, has been reclassified based on the findings of <a href="#19" class="mim-tip-reference" title="Singh, T. R., Bakker, S. T., Agarwal, S., Jansen, M., Grassman, E., Godthelp, B. C., Ali, A. M., Du, C., Rooimans, M. A., Fan, Q., Wahengbam, K., Steltenpool, J., Andreassen, P. R., Williams, D. A., Joenje, H., de Winter, J. P., Meetei, A. R. <strong>Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.</strong> Blood 114: 174-180, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19423727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19423727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19423727[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/10.1182/blood-2009-02-207811" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19423727">Singh et al. (2009)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16116422+19423727" 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>For discussion of the 2,554-bp deletion identified by <a href="#16" class="mim-tip-reference" title="Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W. <strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong> Nature Genet. 37: 958-963, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[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/ng1626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16116422">Meetei et al. (2005)</a>, see <a href="#0001">609644.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16116422" 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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FANCM, 1-BP DUP, 1491A (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs761250416;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs761250416</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs797045116 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797045116;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=rs797045116" 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=rs797045116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 Estonian brothers with nonobstructive azoospermia and Sertoli cell-only syndrome (SPGF28; <a href="/entry/618086">618086</a>), <a href="#10" class="mim-tip-reference" title="Kasak, L., Punab, M., Nagirmaja, L., Grigorova, M., Minajeva, A., Lopes, A. M., Punab, A. M., Aston, K. I., Carvalho, F., Laasik, E., Smith, L. B., GEMINI Consortium, Conrad, D. F., Laan, M. <strong>Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia.</strong> Am. J. Hum. Genet. 103: 200-212, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30075111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30075111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30075111[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.07.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30075111">Kasak et al. (2018)</a> identified compound heterozygosity for a 1-bp duplication (c.1491dupA; chr14.45,159,189dupA, NCBI36) in exon 9 of the FANCM gene, causing a frameshift predicted to result in a premature termination codon (Gln498ThrfsTer7) within the conserved helicase domain, and a splice site mutation (c.4387-10A-G; <a href="#0004">609644.0004</a>) in intron 16, predicted to activate an intronic cryptic acceptor site and extend exon 17 by 9 base pairs, resulting in a premature termination codon (Arg1436_Ser1437insLeuLeuTer). The duplication was inherited from their mother, and the splice site mutation from their father. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The duplication was present at low frequency in the gnomAD database (minor allele frequency, 7.22 x 10(-5); no homozygotes). Immunohistochemistry revealed absent or only faint staining for FANCM in patient seminiferous tubules compared to control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30075111" 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">rs1555365959 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555365959;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=rs1555365959" 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=rs1555365959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the splice site mutation (c.4387-10A-G) in intron 16 of the FANCM gene, predicted to activate an intronic cryptic acceptor site and extend exon 17 by 9 basepairs, resulting in a premature termination codon (Arg1436_Ser1437insLeuLeuTer), that was found in compound heterozygous state in 2 Estonian brothers with spermatogenic failure-28 (SPGF28; <a href="/entry/618086">618086</a>) by <a href="#10" class="mim-tip-reference" title="Kasak, L., Punab, M., Nagirmaja, L., Grigorova, M., Minajeva, A., Lopes, A. M., Punab, A. M., Aston, K. I., Carvalho, F., Laasik, E., Smith, L. B., GEMINI Consortium, Conrad, D. F., Laan, M. <strong>Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia.</strong> Am. J. Hum. Genet. 103: 200-212, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30075111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30075111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30075111[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.07.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30075111">Kasak et al. (2018)</a>, see <a href="#0003">609644.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30075111" 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> rs147021911 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs147021911;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/rs147021911?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=rs147021911" 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=rs147021911" 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=RCV000456962 OR RCV000585292 OR RCV000677276 OR RCV000678209 OR RCV000989212 OR RCV001250424 OR RCV003991578 OR RCV004737537 OR RCV005010382" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000456962, RCV000585292, RCV000677276, RCV000678209, RCV000989212, RCV001250424, RCV003991578, RCV004737537, RCV005010382" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000456962...</a>
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<p><strong><em>Spermatogenic Failure 28</em></strong></p><p>
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In a 52-year-old Estonian man with small testes, nonobstructive azoospermia, elevated gonadotropic hormones, and low testosterone (SPGF28; <a href="/entry/618086">618086</a>), <a href="#10" class="mim-tip-reference" title="Kasak, L., Punab, M., Nagirmaja, L., Grigorova, M., Minajeva, A., Lopes, A. M., Punab, A. M., Aston, K. I., Carvalho, F., Laasik, E., Smith, L. B., GEMINI Consortium, Conrad, D. F., Laan, M. <strong>Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia.</strong> Am. J. Hum. Genet. 103: 200-212, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30075111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30075111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30075111[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.07.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30075111">Kasak et al. (2018)</a> identified homozygosity for a c.5101C-T transition (chr14.45,189,123C-T, NCBI36) in exon 20 of the FANCM gene, resulting in a gln1701-to-ter (Q1701X) substitution. The variant was present at low frequency in the gnomAD database (minor allele frequency, 1.34 x 10(-3); 1 homozygote). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30075111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Premature Ovarian Failure 15</em></strong></p><p>
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In 2 Finnish sisters with premature ovarian failure-15 (POF15; <a href="/entry/618096">618096</a>), <a href="#6" class="mim-tip-reference" title="Fouquet, B., Pawlikowska, P., Caburet, S., Guigon, C., Makinen, M., Tanner, L., Hietala, M., Urbanska, K., Bellutti, L., Legois, B., Bessieres, B., Gougeon, A., Benachi, A., Livera, G., Rosselli, F., Veitia, R. A., Misrahi, M. <strong>A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency.</strong> eLIFE 6: e30490, 2017. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29231814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29231814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29231814[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/10.7554/eLife.30490" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29231814">Fouquet et al. (2017)</a> identified homozygosity for the Q1701X mutation in the FANCM gene. Their unaffected parents and brother were heterozygous for the mutation, which was present in the ExAC database at minor allele frequencies of 0.0013 in the general population and 0.0089 in the Finnish population, including 1 homozygote. Immunoblot analysis of patient cells confirmed expression of a truncated FANCM protein, which the authors noted would lack the C-terminal endonuclease and FAAP24 (<a href="/entry/610884">610884</a>)-interaction domain. In cells from the heterozygous mother, the mutant protein was present at significantly reduced levels compared to wildtype, consistent with nonsense-mediated decay. Analysis of patient lymphocytes exposed to mitomycin C (MMC) showed higher occurrence of chromosome breakages and rearrangements in patient cells than in those of their mother. MMC-treated patient lymphocytes also showed reduced monoubiquitination of FANCD2 (<a href="/entry/613984">613984</a>); however, the cells maintained detectable monoubiquitination capability in response to the replication-inhibiting agents hydroxyurea and aphidicolin. Patient lymphoblasts transiently complemented with wildtype FANCM recovered significant resistance to MMC and showed improved monoubiquitination of FANCD2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29231814" 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 3 Finnish women with POF (patients 192, 305, and 306), <a href="#8" class="mim-tip-reference" title="Heddar, A., Ogur, C., Da Costa, S., Braham, I., Billaud-Rist, L., Findikli, N., Beneteau, C., Reynaud, R., Mahmoud, K., Legrand, S., Marchand, M., Cedrin-Durnerin, I., and 46 others. <strong>Genetic landscape of a large cohort of primary ovarian insufficiency: new genes and pathways and implications for personalized medicine.</strong> EBioMedicine 84: 104246, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36099812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36099812</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36099812[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ebiom.2022.104246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36099812">Heddar et al. (2022)</a> identified homozygosity for the Q1701X mutation in the FANCM gene. In 2 European women with POF (patients 167 and 326), the authors identified compound heterozygosity for the Q1701X mutation and a missense substitution: patient 167 had a c.1528G-A transition, resulting in a gly510-to-ser (G510S; <a href="#0009">609644.0009</a>) substitution, and patient 326 had a c.575A-T transversion, resulting in a gln192-to-leu (Q192L; <a href="#0010">609644.0010</a>) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36099812" 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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FANCM, ARG1931TER (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144567652;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs144567652</a>)
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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> rs144567652 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144567652;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/rs144567652?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=rs144567652" 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=rs144567652" 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=RCV000630904 OR RCV000677277 OR RCV000722040 OR RCV001250442 OR RCV001531186 OR RCV001797115 OR RCV001821777 OR RCV002245059 OR RCV004595521 OR RCV005010605" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000630904, RCV000677277, RCV000722040, RCV001250442, RCV001531186, RCV001797115, RCV001821777, RCV002245059, RCV004595521, RCV005010605" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000630904...</a>
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<p><strong><em>Spermatogenic Failure 28</em></strong></p><p>
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In a Portuguese man with nonobstructive azoospermia (SPGF28; <a href="/entry/618086">618086</a>), <a href="#10" class="mim-tip-reference" title="Kasak, L., Punab, M., Nagirmaja, L., Grigorova, M., Minajeva, A., Lopes, A. M., Punab, A. M., Aston, K. I., Carvalho, F., Laasik, E., Smith, L. B., GEMINI Consortium, Conrad, D. F., Laan, M. <strong>Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia.</strong> Am. J. Hum. Genet. 103: 200-212, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30075111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30075111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30075111[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.07.005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30075111">Kasak et al. (2018)</a> identified homozygosity for a c.5791C-T transition (chr14.45,198,718C-T, NCBI36) in exon 22 of the FANCM gene, resulting in an arg1931-to-ter (R1931X) substitution. The variant was present at low frequency in the gnomAD database (minor allele frequency, 1.03 x 10(-3); no homozygotes). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30075111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Premature Ovarian Failure 15</em></strong></p><p>
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In a woman (patient 5) who experienced secondary amenorrhea at age 25 years (POF15; <a href="/entry/618096">618096</a>), <a href="#9" class="mim-tip-reference" title="Jaillard, S., Bell, K., Akloul, L., Walton, K., McElreavy, K., Stocker, W. A., Beaumont, M., Harrisson, C., Jaaskelainen, T., Palvimo, J. J., Robevska, G., Launay, E., and 16 others. <strong>New insights into the genetic basis of premature ovarian insufficiency: novel causative variants and candidate genes revealed by genomic sequencing.</strong> Maturitas 141: 9-19, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33036707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33036707</a>] [<a href="https://doi.org/10.1016/j.maturitas.2020.06.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33036707">Jaillard et al. (2020)</a> identified compound heterozygosity for nonsense mutations in the FANCM gene: the first was the previously reported R1931X substitution, and the second was a c.3088C-T transition, resulting in an arg1030-to-ter (R1030X; <a href="#0008">609644.0008</a>) substitution. Both nonsense variants were present in the gnomAD database at low minor allele frequency (0.000003996 and 0.001012, respectively), only in heterozygosity. Cytogenetic analysis after mitomycin C induction revealed increased rates of chromosome breakages and rearrangements in the proband compared to a control. The proband had an older sister who also experienced secondary amenorrhea, at age 30; mutation status of the sister was not reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33036707" 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 3 Pakistani brothers with infertility due to oligoasthenospermia or azoospermia (SPGF28; <a href="/entry/618086">618086</a>), <a href="#20" class="mim-tip-reference" title="Yin, H., Ma, H., Hussain, S., Zhang, H., Xie, X., Jiang, L., Jiang, X., Iqbal, F., Bukhari, I., Jiang, H., Ali, A., Zhong, L. and 17 others. <strong>A homozygous FANCM frameshift pathogenic variant causes male infertility.</strong> Genet. Med. 21: 62, 2019. Note: Electronic Article. Erratum: Genet. Med. 21: 266, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29895858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29895858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29895858[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/s41436-018-0015-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29895858">Yin et al. (2019)</a> identified homozygosity for a 13-bp deletion (c.1946_1958del) in exon 11 of the FANCM gene, causing a frameshift predicted to result in a premature termination codon (Pro648LeufsTer16). Their unaffected first-cousin parents were each heterozygous for the mutation. Western blot analysis confirmed absence of full-length FANCM protein from blood samples of all 3 infertile brothers. Patient lymphocytes treated with mitomycin C displayed a dose-dependent increase in chromosomal breaks per cell, which averaged 3 to 17 times the number observed in similarly treated lymphocytes from the unaffected father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29895858" 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=RCV002937698 OR RCV004595677 OR RCV004721092 OR RCV004725418" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002937698, RCV004595677, RCV004721092, RCV004725418" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002937698...</a>
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<p>For discussion of the c.3088C-T transition (c.3088C-T, NM_020937.3) in the FANCM gene, resulting in an arg1030-to-ter (R1030X) substitution, that was found in compound heterozygous state in a woman (patient 5) with premature ovarian failure (POF15; <a href="/entry/618096">618096</a>) by <a href="#9" class="mim-tip-reference" title="Jaillard, S., Bell, K., Akloul, L., Walton, K., McElreavy, K., Stocker, W. A., Beaumont, M., Harrisson, C., Jaaskelainen, T., Palvimo, J. J., Robevska, G., Launay, E., and 16 others. <strong>New insights into the genetic basis of premature ovarian insufficiency: novel causative variants and candidate genes revealed by genomic sequencing.</strong> Maturitas 141: 9-19, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33036707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33036707</a>] [<a href="https://doi.org/10.1016/j.maturitas.2020.06.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33036707">Jaillard et al. (2020)</a>, see <a href="#0006">609644.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33036707" 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> rs146291619 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs146291619;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/rs146291619?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=rs146291619" 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=rs146291619" 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=RCV001758475 OR RCV001868499 OR RCV002477964 OR RCV004595629" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001758475, RCV001868499, RCV002477964, RCV004595629" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001758475...</a>
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<p>For discussion of the c.1528G-A transition (c.1528G-A, NM_020937.4) in the FANCM gene, resulting in a gly510-to-ser (G510S) substitution, that was found in compound heterozygous state in a European woman (patient 167) with premature ovarian failure (POF15; <a href="/entry/618096">618096</a>) by <a href="#8" class="mim-tip-reference" title="Heddar, A., Ogur, C., Da Costa, S., Braham, I., Billaud-Rist, L., Findikli, N., Beneteau, C., Reynaud, R., Mahmoud, K., Legrand, S., Marchand, M., Cedrin-Durnerin, I., and 46 others. <strong>Genetic landscape of a large cohort of primary ovarian insufficiency: new genes and pathways and implications for personalized medicine.</strong> EBioMedicine 84: 104246, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36099812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36099812</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36099812[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ebiom.2022.104246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36099812">Heddar et al. (2022)</a>, see <a href="#0005">609644.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36099812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 PREMATURE OVARIAN FAILURE 15</strong>
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FANCM, GLN192LEU
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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> rs768031730 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs768031730;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/rs768031730?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=rs768031730" 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=rs768031730" 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=RCV001338061 OR RCV001568753 OR RCV004595595" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001338061, RCV001568753, RCV004595595" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001338061...</a>
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<p>For discussion of the c.575A-T transversion (c.575A-T, NM_020937.4) in the FANCM gene, resulting in a gln192-to-leu (Q192L) substitution, that was found in compound heterozygous state in a European woman (patient 326) with premature ovarian failure (POF15; <a href="/entry/618096">618096</a>) by <a href="#8" class="mim-tip-reference" title="Heddar, A., Ogur, C., Da Costa, S., Braham, I., Billaud-Rist, L., Findikli, N., Beneteau, C., Reynaud, R., Mahmoud, K., Legrand, S., Marchand, M., Cedrin-Durnerin, I., and 46 others. <strong>Genetic landscape of a large cohort of primary ovarian insufficiency: new genes and pathways and implications for personalized medicine.</strong> EBioMedicine 84: 104246, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36099812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36099812</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36099812[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ebiom.2022.104246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36099812">Heddar et al. (2022)</a>, see <a href="#0005">609644.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36099812" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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<a id="Bakker2009" class="mim-anchor"></a>
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Bakker, S. T., van de Vrugt, H. J., Rooimans, M. A., Oostra, A. B., Steltenpool, J., Delzenne-Goette, E., van der Wal, A., van der Valk, M., Joenje, H., Riele H., de Winter, J. P.
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<strong>Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M.</strong>
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Hum. Molec. Genet. 18: 3484-3495, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19561169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19561169</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19561169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp297" target="_blank">Full Text</a>]
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<a id="Blackford2012" class="mim-anchor"></a>
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Blackford, A. N., Schwab, R. A., Nieminuszczy, J., Deans, A. J., West, S. C., Niedzwiedz, W.
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<strong>The DNA translocase activity of FANCM protects stalled replication forks.</strong>
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Hum. Molec. Genet. 21: 2005-2016, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22279085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22279085</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22279085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/dds013" target="_blank">Full Text</a>]
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<a id="Ciccia2007" class="mim-anchor"></a>
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Ciccia, A., Ling, C., Coulthard, R., Yan, Z., Xue, Y., Meetei, A. R., Laghmani, E. H., Joenje, H., McDonald, N., de Winter, J. P., Wang, W., West, S. C.
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<strong>Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM.</strong>
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Molec. Cell 25: 331-343, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17289582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17289582</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17289582" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2007.01.003" target="_blank">Full Text</a>]
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<a id="Collis2008" class="mim-anchor"></a>
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<p class="mim-text-font">
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Collis, S. J., Ciccia, A., Deans, A. J., Horejsi, Z., Martin, J. S., Maslen, S. L., Skehel, J. M., Elledge, S. J., West, S. C., Boulton, S. J.
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<strong>FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex.</strong>
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Molec. Cell 32: 313-324, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18995830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18995830</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18995830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2008.10.014" target="_blank">Full Text</a>]
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<a id="Deans2009" class="mim-anchor"></a>
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Deans, A. J., West, S. C.
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<strong>FANCM connects the genome instability disorders Bloom's syndrome and Fanconi anemia.</strong>
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Molec. Cell 36: 943-953, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20064461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20064461</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20064461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2009.12.006" target="_blank">Full Text</a>]
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<a id="Fouquet2017" class="mim-anchor"></a>
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Fouquet, B., Pawlikowska, P., Caburet, S., Guigon, C., Makinen, M., Tanner, L., Hietala, M., Urbanska, K., Bellutti, L., Legois, B., Bessieres, B., Gougeon, A., Benachi, A., Livera, G., Rosselli, F., Veitia, R. A., Misrahi, M.
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<strong>A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency.</strong>
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eLIFE 6: e30490, 2017. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29231814/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29231814</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29231814[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=29231814" 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/10.7554/eLife.30490" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Gari2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gari, K., Decaillet, C., Stasiak, A. Z., Stasiak, A., Constantinou, A.
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<strong>The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks.</strong>
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Molec. Cell 29: 141-148, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18206976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18206976</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18206976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2007.11.032" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Heddar2022" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Heddar, A., Ogur, C., Da Costa, S., Braham, I., Billaud-Rist, L., Findikli, N., Beneteau, C., Reynaud, R., Mahmoud, K., Legrand, S., Marchand, M., Cedrin-Durnerin, I., and 46 others.
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<strong>Genetic landscape of a large cohort of primary ovarian insufficiency: new genes and pathways and implications for personalized medicine.</strong>
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EBioMedicine 84: 104246, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36099812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36099812</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36099812[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=36099812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ebiom.2022.104246" target="_blank">Full Text</a>]
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<a id="Jaillard2020" class="mim-anchor"></a>
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<div class="">
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Jaillard, S., Bell, K., Akloul, L., Walton, K., McElreavy, K., Stocker, W. A., Beaumont, M., Harrisson, C., Jaaskelainen, T., Palvimo, J. J., Robevska, G., Launay, E., and 16 others.
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<strong>New insights into the genetic basis of premature ovarian insufficiency: novel causative variants and candidate genes revealed by genomic sequencing.</strong>
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Maturitas 141: 9-19, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33036707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33036707</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33036707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.maturitas.2020.06.004" target="_blank">Full Text</a>]
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<a id="Kasak2018" class="mim-anchor"></a>
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Kasak, L., Punab, M., Nagirmaja, L., Grigorova, M., Minajeva, A., Lopes, A. M., Punab, A. M., Aston, K. I., Carvalho, F., Laasik, E., Smith, L. B., GEMINI Consortium, Conrad, D. F., Laan, M.
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<strong>Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia.</strong>
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Am. J. Hum. Genet. 103: 200-212, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30075111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30075111</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30075111[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=30075111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2018.07.005" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Kiiski2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Kiiski, J. I., Pelttari, L. M., Khan, S., Freysteinsdottir, E. S., Reynisdottir, I., Hart, S. N., Shimelis, H., Vilske, S., Kallioniemi, A., Schleutker, J., Leminen, A., Butzow, R., Blomqvist, C., Barkardottir, R. B., Couch, F. J., Aittomaki, K., Nevanlinna, H.
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<strong>Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer.</strong>
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Proc. Nat. Acad. Sci. 111: 15172-15177, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25288723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25288723</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25288723[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=25288723" 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/10.1073/pnas.1407909111" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
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<a id="Lim2014" class="mim-anchor"></a>
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<div class="">
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Lim, E. T., Wurtz, P., Havulinna, A. S., Palta, P., Tukiainen, T., Rehnstrom, K., Esko, T., Magi, R., Inouye, M., Lappalainen, T., Chan, Y., Salem, R. M., and 48 others.
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<strong>Distribution and medical impact of loss-of-function variants in the Finnish founder population.</strong>
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PLoS Genet. 10: e1004494, 2014. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25078778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25078778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25078778[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=25078778" 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/10.1371/journal.pgen.1004494" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="McNairn2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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McNairn, A. J., Chuang, C.-H., Bloom, J. C., Wallace, M. D., Schimenti, J. C.
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<strong>Female-biased embryonic death from inflammation induced by genomic instability.</strong>
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Nature 567: 105-108, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30787433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30787433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30787433[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=30787433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41586-019-0936-6" target="_blank">Full Text</a>]
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<a id="14" class="mim-anchor"></a>
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<a id="Meetei2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W.
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<strong>A novel ubiquitin ligase is deficient in Fanconi anemia.</strong>
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Nature Genet. 35: 165-170, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12973351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12973351</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12973351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1241" target="_blank">Full Text</a>]
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<a id="15" class="mim-anchor"></a>
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<a id="Meetei2004" class="mim-anchor"></a>
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<div class="">
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Meetei, A. R., Levitus, M., Xue, Y., Medhurst, A. L., Zwaan, M., Ling, C., Rooimans, M. A., Bier, P., Hoatlin, M., Pals, G., de Winter, J. P., Wang, W., Joenje, H.
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<strong>X-linked inheritance of Fanconi anemia complementation group B.</strong>
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Nature Genet. 36: 1219-1224, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15502827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15502827</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15502827" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1458" target="_blank">Full Text</a>]
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<a id="16" class="mim-anchor"></a>
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<a id="Meetei2005" class="mim-anchor"></a>
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<div class="">
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Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W.
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<strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong>
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Nature Genet. 37: 958-963, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16116422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16116422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16116422[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=16116422" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1626" target="_blank">Full Text</a>]
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<a id="17" class="mim-anchor"></a>
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<a id="Meetei2003" class="mim-anchor"></a>
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<div class="">
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Meetei, A. R., Sechi, S., Wallisch, M., Yang, D., Young, M. K., Joenje, H., Hoatlin, M. E., Wang, W.
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<strong>A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.</strong>
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Molec. Cell. Biol. 23: 3417-3426, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12724401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12724401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12724401[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=12724401" 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/10.1128/MCB.23.10.3417-3426.2003" target="_blank">Full Text</a>]
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<a id="18" class="mim-anchor"></a>
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<a id="Nagase2000" class="mim-anchor"></a>
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<p class="mim-text-font">
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Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O.
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<strong>Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong>
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DNA Res. 7: 273-281, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10997877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10997877</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10997877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/dnares/7.4.271" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
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<a id="Singh2009" class="mim-anchor"></a>
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Singh, T. R., Bakker, S. T., Agarwal, S., Jansen, M., Grassman, E., Godthelp, B. C., Ali, A. M., Du, C., Rooimans, M. A., Fan, Q., Wahengbam, K., Steltenpool, J., Andreassen, P. R., Williams, D. A., Joenje, H., de Winter, J. P., Meetei, A. R.
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<strong>Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.</strong>
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Blood 114: 174-180, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19423727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19423727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19423727[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=19423727" 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/10.1182/blood-2009-02-207811" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
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<a id="Yin2019" class="mim-anchor"></a>
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Yin, H., Ma, H., Hussain, S., Zhang, H., Xie, X., Jiang, L., Jiang, X., Iqbal, F., Bukhari, I., Jiang, H., Ali, A., Zhong, L. and 17 others.
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<strong>A homozygous FANCM frameshift pathogenic variant causes male infertility.</strong>
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Genet. Med. 21: 62, 2019. Note: Electronic Article. Erratum: Genet. Med. 21: 266, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29895858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29895858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29895858[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=29895858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41436-018-0015-7" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 07/23/2024
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<span class="mim-text-font">
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Ada Hamosh - updated : 10/07/2019<br>Marla J. F. O'Neill - updated : 08/27/2018<br>Marla J. F. O'Neill - updated : 08/13/2018<br>Ada Hamosh - updated : 03/09/2018<br>Cassandra L. Kniffin - updated : 6/17/2015<br>Patricia A. Hartz - updated : 7/29/2013<br>George E. Tiller - updated : 7/7/2010<br>Patricia A. Hartz - updated : 1/28/2010<br>Patricia A. Hartz - updated : 2/25/2009<br>Ada Hamosh - updated : 6/18/2008
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 10/11/2005
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alopez : 07/25/2024
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alopez : 07/23/2024<br>alopez : 10/07/2019<br>carol : 01/15/2019<br>carol : 08/27/2018<br>carol : 08/17/2018<br>carol : 08/14/2018<br>carol : 08/13/2018<br>alopez : 03/09/2018<br>carol : 06/22/2015<br>mcolton : 6/18/2015<br>ckniffin : 6/17/2015<br>mcolton : 6/12/2015<br>carol : 8/13/2013<br>tpirozzi : 7/29/2013<br>tpirozzi : 7/29/2013<br>tpirozzi : 7/29/2013<br>carol : 7/13/2011<br>alopez : 7/21/2010<br>terry : 7/7/2010<br>mgross : 1/29/2010<br>terry : 1/28/2010<br>mgross : 2/25/2009<br>mgross : 2/25/2009<br>terry : 2/25/2009<br>mgross : 6/19/2008<br>terry : 6/18/2008<br>alopez : 10/18/2005<br>alopez : 10/11/2005<br>alopez : 10/11/2005<br>alopez : 10/11/2005
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<strong>*</strong> 609644
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<h3>
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FANCM GENE; FANCM
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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FANCONI ANEMIA-ASSOCIATED POLYPEPTIDE, 250-KD; FAAP250<br />
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KIAA1596
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: FANCM</em></strong>
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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: 14q21.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 14:45,135,930-45,200,890 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<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">
|
|
14q21.2
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
|
Premature ovarian failure 15
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
618096
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|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Spermatogenic failure 28
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
618086
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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">
|
|
3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>TEXT</strong>
|
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</span>
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</h4>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned FANCM, which they designated KIAA1596. RT-PCR ELISA detected low to moderate FANCM expression in testis and ovary, lower levels in fetal liver and adult brain, skeletal muscle, kidney, and spleen, and little to no expression in fetal brain and adult spinal cord, heart, lung, liver, and pancreas. Within specific adult brain regions, low to moderate expression was detected in amygdala, with lower levels in all other brain regions examined. </p><p>Meetei et al. (2003, 2003, 2004) purified a Fanconi anemia core complex containing 7 Fanconi anemia-associated proteins each essential for monoubiquitination of FANCD2 (613984), a key reaction in the Fanconi anemia DNA damage-response pathway. Using mass spectrometry, Meetei et al. (2005) identified another component, FAAP250, as KIAA1596. Antibodies raised against KIAA1596 specifically recognized the 250-kD polypeptide of the Fanconi anemia core complex immunopurified using antibodies against FANCA (607139). FAAP250, or FANCM, has sequence similarity to DNA repair proteins, including archaeal Hef, yeast MPH1, and human ERCC4 (133520). The deduced 2,048-amino acid protein contains an N-terminal helicase domain homologous to those of DEAH box helicases (see 607570) or DNA-stimulated ATPases. It also has a C-terminal endonuclease domain homologous to that of ERCC4, but sequence degeneracy suggests that it is inactive. </p><p>By immunohistochemical analysis of human testicular tissue sections, Kasak et al. (2018) observed localization of FANCM to the cytoplasm of Sertoli cells and spermatogenic cells in the seminiferous tubules. Staining intensity was related to stage of maturation, with faint staining of spermatogonia, increased staining in primary spermatocytes to spermatids, and reduced staining in tubules with mature spermatozoa. FANCM expression was also present in the interstitial Leydig cells. </p><p>Fouquet et al. (2017) performed qRT-PCR in germ cells from human fetal ovaries and observed expression throughout ovarian development, with highest expression in ovaries at stages containing the highest proportion of germ cells progressing into meiotic prophase I. Cell-sorting experiments revealed that FANCM transcripts were predominant in oogonial cells compared to somatic cells. Immunohistochemical analysis of human fetal ovaries showed that FANCM protein was present in the nuclei of oogonia, with strongest staining in pachytene stage oocytes. In addition, staining localized along the chromosomes in pachytene cells undergoing meiotic recombination. FANCM was also observed in oocytes arrested at the diplotene stage of prophase I during the last trimester of pregnancy and in adults. Costaining with SYCP3 (604759) and DDX4 (605281) confirmed the meiotic and germinal nature, respectively, of the FANCM-positive cells. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Nagase et al. (2000) mapped the KIAA1596 cDNA, corresponding to the FANCM gene, to chromosome 14. Meetei et al. (2005) stated that 2 tightly linked flanking markers are D14S259 and D14S1027. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Meetei et al. (2005) found that FANCM could dissociate DNA triplex, possibly owing to its ability to translocate on duplex DNA. FANCM was essential for monoubiquitination of FANCD2 and became hyperphosphorylated in response to DNA damage. The data of Meetei et al. (2005) suggested an evolutionary link between Fanconi anemia-associated proteins and DNA repair. They suggested that FANCM may act as an engine that translocates the Fanconi anemia core complex along DNA. </p><p>Ciccia et al. (2007) found that FAAP24 (610884) interacted specifically with the C-terminal region of FANCM in several assays. In fractionated HeLa cells, the FAAP24/FANCM heterodimer associated with other FA core proteins in an 800-kD complex. Downregulation of FAAP24 by small interfering RNA resulted in reduced levels of monoubiquitylated FANCD2 after exposure to DNA crosslinking reagents. FAAP24 bound single-stranded DNA. Ciccia et al. (2007) suggested that FAAP24 promotes targeting of FANCM/FAAP24 dimers, and possibly other components of the FA core complex, to forked DNA intermediates generated after DNA damage. </p><p>FANCM displays DNA-dependent ATPase activity and promotes dissociation of DNA triplexes. Gari et al. (2008) found that recombinant human FANCM bound Holliday junctions and replication forks with high specificity and promoted migration of their junction point in an ATPase-dependent manner. FANCM dissociated large recombination intermediates via branch migration of Holliday junctions through 2.6 kb of DNA. Gari et al. (2008) concluded that FANCM has a direct role in DNA processing, consistent with the view that FA proteins coordinate DNA repair at stalled replication forks. </p><p>By copurification of epitope-tagged proteins, Collis et al. (2008) found that the checkpoint protein HCLK2 (TELO2; 611140) interacted strongly with the N-terminal region of FANCM and weakly with the C-terminal region. The interaction required the HEAT repeat structure of HCLK2. Immunoprecipitation analysis of human cell lines showed that endogenous FANCM and FAAP24 formed a stable complex with HCLK2 in the absence of other FA core complex components. Knockdown of either FANCM, FAAP24, or HCLK2 via small interfering RNA compromised ATR (601215)/CHK1 (603078)-mediated checkpoint signaling, leading to increased endogenous DNA damage and failure to efficiently invoke cell cycle checkpoint responses. Moreover, the DNA translocase activity of FANCM, which is dispensable for FA pathway activation, was required for its role in ATR/CHK1 signaling. Collis et al. (2008) concluded that FANCM and FAAP24 couple checkpoint signaling with DNA repair via their interactions with HCLK2 and FA core complex components. </p><p>Fanconi anemia and Bloom syndrome (BS; 210900) share overlapping phenotypes, including aberrant DNA repair and cancer predisposition. Treatment of cells with DNA crosslinking agents results in association of the BS complex with the FA core complex in a supercomplex called BRAFT. Deans and West (2009) found that FANCM functioned as the bridge in the FA/BS supercomplex by binding specific FA and BS components via its highly conserved MM1 and MM2 motifs, respectively. MM1 specifically bound FANCF (603467) of the FA core complex. MM2 specifically bound the BS complex components RMI1 (610404) and topoisomerase III-alpha (TOP3A; 601243), but not the helicase BLM (RECQL3; 604610). Knockdown of FANCM using small interfering RNA eliminated FA/BS association. Alanine substitution of phe1232 and phe1236 within MM2 resulted in a FANCM protein unable to interact with the BS complex. Interaction of FANCM with RMI1 and TOP3A was required for targeting of BLM to nuclear foci after treatment with replication stalling agents, but not ionizing radiation. Deans and West (2009) concluded that the FA and BS complexes interact via FANCM in a subset of DNA repair reactions, including those at replication forks stalled at sites of DNA damage. </p><p>Blackford et al. (2012) found that cells expressing translocase-defective FANCM showed altered global replication due to increased accumulation of stalled replication forks, which subsequently degenerated into DNA double-strand breaks, leading to ATM activation, CTIP-dependent end resection, and homologous recombination repair. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Spermatogenic Failure 28</em></strong></p><p>
|
|
In 2 Estonian brothers with nonobstructive azoospermia and Sertoli cell-only syndrome (SPGF28; 618086), Kasak et al. (2018) identified compound heterozygosity for a 1-bp duplication (609644.0003) and a splice site mutation (609644.0004) in the FANCM gene. The authors also reported homozygosity for nonsense mutations in the FANCM gene in 2 additional men with nonobstructive azoospermia: an unrelated Estonian man (Q1701X; 609644.0005) and a Portuguese man (R1931X; 609644.0006). </p><p>In 3 Pakistani brothers with infertility due to oligoasthenospermia or azoospermia, Yin et al. (2019) identified homozygosity for a 13-bp deletion in the FANCM gene (609644.0007). </p><p><strong><em>Premature Ovarian Failure 15</em></strong></p><p>
|
|
In 2 Finnish sisters with premature ovarian failure-15 (POF15; 618096), Fouquet et al. (2017) identified homozygosity for the Q1701X mutation (609644.0005) in the FANCM gene. </p><p>By whole-exome sequencing in a cohort of 10 women with POF, Jaillard et al. (2020) identified 1 proband who was compound heterozygous for nonsense mutations in the FANCM gene: the previously reported R1931X mutation (609644.0006) and an R1030X mutation (609644.0008). </p><p>By targeted or whole-exome sequencing in an international cohort of 375 women with POF from 70 families, Heddar et al. (2022) identified 3 Finnish women and 2 European women with mutations in the FANCM gene: all carried the previously reported nonsense mutation Q1701X, for which the 3 Finnish women were homozygous. In patients 167 and 326, the second variant was a missense mutation, G510S (609644.0009) or Q192L (609644.0010), respectively. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
|
|
Kiiski et al. (2014) performed whole-exome sequencing of constitutional genomic DNA from 24 breast cancer patients from 11 Finnish breast cancer families. From all rare damaging variants, 22 variants in 21 DNA repair genes were genotyped in 3,166 breast cancer patients, 569 ovarian cancer patients, and 2,090 controls, all from the Helsinki or Tampere regions of Finland. A nonsense mutation in FANCM, c.5101C-T (Q1701X, 609644.0005; rs147021911) was significantly more frequent among breast cancer patients than among controls (odds ratio (OR) = 1.86, 95% CI = 1.26-2.75; p = 0.0018), with particular enrichment among patients with triple-negative breast cancer (TNBC; OR = 3.56, 95% CI = 1.81-6.98, p = 0.0002). In the Helsinki and Tampere regions, respectively, carrier frequencies of FANCM Q1701X were 2.9% and 4.0% of breast cancer patients, 5.6% and 6.6% of TNBC patients, 2.2% of ovarian cancer patients (from Helsinki), and 1.4% and 2.5% of controls. Kiiski et al. (2014) concluded that their findings identified FANCM as a breast cancer susceptibility gene, mutations in which confer a particularly strong predisposition for TNBC. </p><p><strong><em>Exclusion Studies</em></strong></p><p>
|
|
In a large population-based exome-sequencing study of 3,000 Finnish individuals, Lim et al. (2014) did not find a deficit of individuals homozygous for predicted loss-of-function variants in the FANCM gene (5 expected, 7 observed). Examination of hospital records for homozygous carriers did not provide any evidence for blood diseases, increased cancer events, or other chronic diseases in these individuals compared to those without these variants. The findings did not support the hypothesis that FANCM is a gene associated with Fanconi anemia (see, e.g., FANCA, 227650). </p>
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</span>
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<div>
|
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<br />
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p>Bakker et al. (2009) generated Fancm-deficient mice by deleting exon 2. Fancm deficiency caused hypogonadism in mice and hypersensitivity to crosslinking agents in mouse embryonic fibroblasts (MEFs), similar to other FA mouse models. Fancm -/- mice also showed unique features atypical for FA mice, including underrepresentation of female Fancm -/- mice and decreased overall and tumor-free survival. This increased cancer incidence may be correlated to the role of FANCM in the suppression of spontaneous sister chromatid exchanges as observed in MEFs. In addition, Fancm appeared to have a stimulatory rather than essential role in Fancd2 (227646) monoubiquitination. Bakker et al. (2009) suggested that FANCM functions both inside and outside the FA core complex to maintain genome stability and to prevent tumorigenesis. </p><p>McNairn et al. (2019) found that mutations in the heterohexameric minichromosome maintenance (MCM; see 116945) complex that cause genomic instability render female mouse embryos markedly more susceptible than males to embryonic lethality. XX embryos could be rescued by transgene-mediated sex reversal or testosterone administration. The ability of exogenous or endogenous testosterone to protect embryos was related to its antiinflammatory properties. Ibuprofen, a nonsteroidal antiinflammatory drug, rescued female embryos that contained mutations in not only the Mcm genes but also the Fancm gene; similar to Mcm mutants, Fancm mutant embryos have increased levels of genomic instability (measured as the number of cells with micronuclei) from compromised replication fork repair. </p>
|
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</span>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
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</span>
|
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<strong>10 Selected Examples):</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<p />
|
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0001 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
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</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FANCM, SER724TER
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<br />
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SNP: rs137852864,
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ClinVar: RCV000001665
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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>This variant, formerly titled FANCONI ANEMIA, COMPLEMENTATION GROUP M based on the report of Meetei et al. (2005), has been reclassified based on the findings of Singh et al. (2009). </p><p>In a cell line derived from a patient (EUFA867) with Fanconi anemia, Meetei et al. (2005) identified compound heterozygous variants in the FANCM gene: a c.2171C-A transversion in exon 13 resulting in a ser724-to-ter (S724X) substitution, and a 2,554-bp deletion (609644.0002), spanning part of intron 14 and almost all of exon 15, resulting in absence of the sequence encoded by exon 15. A sib with Fanconi anemia was reported to carry the same 2 mutations. The nonsense mutation was inherited from the healthy mother; the deletion was not detected in the father but he was thought to be gonadal mosaic for it. Immunoblotting of patient cells showed absence of the FANCM protein. </p><p>In cell lines derived from the 2 sibs originally reported by Meetei et al. (2005), Singh et al. (2009) identified biallelic mutations in the FANCA gene (607139.0011 and 607139.0012). In addition, Singh et al. (2009) noted that only 1 of the sibs had clinical features of the disorder and that the clinically affected sib carried only 1 of the FANCM variants. The clinically unaffected sib (EUFA867) carried both biallelic FANCA mutations and biallelic FANCM variants. Singh et al. (2009) reclassified the affected sib as having FANCA, and suggested that FANCM deficiency in the unaffected sib may have overruled the FANCA defect and changed the clinical outcome, possibly even attenuating the phenotype. Cellular studies of EUFA867 by Singh et al. (2009) showed that expression of FANCA could rescue the FANCD2 (613984) monoubiquitination defect. After correction of the FANCA defect, the FANCM-deficient cells remained hypersensitive to the cross-linking agent mitomycin C; they were also sensitive to the topoisomerase inhibitor camptothecin and to UV light. FANCM-null cells had some residual monoubiquitinating FANCD2. The findings suggested that FANCM is involved in different steps of the DNA damage response, including efficient FANCD2 monoubiquitination and DNA repair steps later in the Fanconi anemia pathway. </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>.0002 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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FANCM, 2,554-BP DEL
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<br />
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ClinVar: RCV000001666
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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>This variant, formerly titled FANCONI ANEMIA, COMPLEMENTATION GROUP M based on the report of Meetei et al. (2005), has been reclassified based on the findings of Singh et al. (2009). </p><p>For discussion of the 2,554-bp deletion identified by Meetei et al. (2005), see 609644.0001. </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>.0003 SPERMATOGENIC FAILURE 28</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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FANCM, 1-BP DUP, 1491A ({dbSNP rs761250416})
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<br />
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SNP: rs797045116,
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ClinVar: RCV000190644, RCV000677275, RCV001206024, RCV003991575
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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 2 Estonian brothers with nonobstructive azoospermia and Sertoli cell-only syndrome (SPGF28; 618086), Kasak et al. (2018) identified compound heterozygosity for a 1-bp duplication (c.1491dupA; chr14.45,159,189dupA, NCBI36) in exon 9 of the FANCM gene, causing a frameshift predicted to result in a premature termination codon (Gln498ThrfsTer7) within the conserved helicase domain, and a splice site mutation (c.4387-10A-G; 609644.0004) in intron 16, predicted to activate an intronic cryptic acceptor site and extend exon 17 by 9 base pairs, resulting in a premature termination codon (Arg1436_Ser1437insLeuLeuTer). The duplication was inherited from their mother, and the splice site mutation from their father. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The duplication was present at low frequency in the gnomAD database (minor allele frequency, 7.22 x 10(-5); no homozygotes). Immunohistochemistry revealed absent or only faint staining for FANCM in patient seminiferous tubules compared to control. </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>.0004 SPERMATOGENIC FAILURE 28</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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FANCM, IVS16AS, A-G, -10
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<br />
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SNP: rs1555365959,
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ClinVar: RCV000677274
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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>For discussion of the splice site mutation (c.4387-10A-G) in intron 16 of the FANCM gene, predicted to activate an intronic cryptic acceptor site and extend exon 17 by 9 basepairs, resulting in a premature termination codon (Arg1436_Ser1437insLeuLeuTer), that was found in compound heterozygous state in 2 Estonian brothers with spermatogenic failure-28 (SPGF28; 618086) by Kasak et al. (2018), see 609644.0003. </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 SPERMATOGENIC FAILURE 28</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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PREMATURE OVARIAN FAILURE 15, INCLUDED
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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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FANCM, GLN1701TER ({dbSNP rs147021911})
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<br />
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SNP: rs147021911,
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gnomAD: rs147021911,
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ClinVar: RCV000456962, RCV000585292, RCV000677276, RCV000678209, RCV000989212, RCV001250424, RCV003991578, RCV004737537, RCV005010382
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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 />
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<p><strong><em>Spermatogenic Failure 28</em></strong></p><p>
|
|
In a 52-year-old Estonian man with small testes, nonobstructive azoospermia, elevated gonadotropic hormones, and low testosterone (SPGF28; 618086), Kasak et al. (2018) identified homozygosity for a c.5101C-T transition (chr14.45,189,123C-T, NCBI36) in exon 20 of the FANCM gene, resulting in a gln1701-to-ter (Q1701X) substitution. The variant was present at low frequency in the gnomAD database (minor allele frequency, 1.34 x 10(-3); 1 homozygote). </p><p><strong><em>Premature Ovarian Failure 15</em></strong></p><p>
|
|
In 2 Finnish sisters with premature ovarian failure-15 (POF15; 618096), Fouquet et al. (2017) identified homozygosity for the Q1701X mutation in the FANCM gene. Their unaffected parents and brother were heterozygous for the mutation, which was present in the ExAC database at minor allele frequencies of 0.0013 in the general population and 0.0089 in the Finnish population, including 1 homozygote. Immunoblot analysis of patient cells confirmed expression of a truncated FANCM protein, which the authors noted would lack the C-terminal endonuclease and FAAP24 (610884)-interaction domain. In cells from the heterozygous mother, the mutant protein was present at significantly reduced levels compared to wildtype, consistent with nonsense-mediated decay. Analysis of patient lymphocytes exposed to mitomycin C (MMC) showed higher occurrence of chromosome breakages and rearrangements in patient cells than in those of their mother. MMC-treated patient lymphocytes also showed reduced monoubiquitination of FANCD2 (613984); however, the cells maintained detectable monoubiquitination capability in response to the replication-inhibiting agents hydroxyurea and aphidicolin. Patient lymphoblasts transiently complemented with wildtype FANCM recovered significant resistance to MMC and showed improved monoubiquitination of FANCD2. </p><p>In 3 Finnish women with POF (patients 192, 305, and 306), Heddar et al. (2022) identified homozygosity for the Q1701X mutation in the FANCM gene. In 2 European women with POF (patients 167 and 326), the authors identified compound heterozygosity for the Q1701X mutation and a missense substitution: patient 167 had a c.1528G-A transition, resulting in a gly510-to-ser (G510S; 609644.0009) substitution, and patient 326 had a c.575A-T transversion, resulting in a gln192-to-leu (Q192L; 609644.0010) substitution. </p>
|
|
</span>
|
|
</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 SPERMATOGENIC FAILURE 28</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
PREMATURE OVARIAN FAILURE 15, INCLUDED
|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
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|
FANCM, ARG1931TER ({dbSNP rs144567652})
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<br />
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|
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SNP: rs144567652,
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gnomAD: rs144567652,
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|
|
ClinVar: RCV000630904, RCV000677277, RCV000722040, RCV001250442, RCV001531186, RCV001797115, RCV001821777, RCV002245059, RCV004595521, RCV005010605
|
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p />
|
|
<p><strong><em>Spermatogenic Failure 28</em></strong></p><p>
|
|
In a Portuguese man with nonobstructive azoospermia (SPGF28; 618086), Kasak et al. (2018) identified homozygosity for a c.5791C-T transition (chr14.45,198,718C-T, NCBI36) in exon 22 of the FANCM gene, resulting in an arg1931-to-ter (R1931X) substitution. The variant was present at low frequency in the gnomAD database (minor allele frequency, 1.03 x 10(-3); no homozygotes). </p><p><strong><em>Premature Ovarian Failure 15</em></strong></p><p>
|
|
In a woman (patient 5) who experienced secondary amenorrhea at age 25 years (POF15; 618096), Jaillard et al. (2020) identified compound heterozygosity for nonsense mutations in the FANCM gene: the first was the previously reported R1931X substitution, and the second was a c.3088C-T transition, resulting in an arg1030-to-ter (R1030X; 609644.0008) substitution. Both nonsense variants were present in the gnomAD database at low minor allele frequency (0.000003996 and 0.001012, respectively), only in heterozygosity. Cytogenetic analysis after mitomycin C induction revealed increased rates of chromosome breakages and rearrangements in the proband compared to a control. The proband had an older sister who also experienced secondary amenorrhea, at age 30; mutation status of the sister was not reported. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 SPERMATOGENIC FAILURE 28</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FANCM, 13-BP DEL, NT1948
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|
|
<br />
|
|
|
|
SNP: rs1555363275,
|
|
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|
|
|
|
ClinVar: RCV000677278
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 Pakistani brothers with infertility due to oligoasthenospermia or azoospermia (SPGF28; 618086), Yin et al. (2019) identified homozygosity for a 13-bp deletion (c.1946_1958del) in exon 11 of the FANCM gene, causing a frameshift predicted to result in a premature termination codon (Pro648LeufsTer16). Their unaffected first-cousin parents were each heterozygous for the mutation. Western blot analysis confirmed absence of full-length FANCM protein from blood samples of all 3 infertile brothers. Patient lymphocytes treated with mitomycin C displayed a dose-dependent increase in chromosomal breaks per cell, which averaged 3 to 17 times the number observed in similarly treated lymphocytes from the unaffected father. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PREMATURE OVARIAN FAILURE 15</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FANCM, ARG1030TER ({dbSNP rs759378949})
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV002937698, RCV004595677, RCV004721092, RCV004725418
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.3088C-T transition (c.3088C-T, NM_020937.3) in the FANCM gene, resulting in an arg1030-to-ter (R1030X) substitution, that was found in compound heterozygous state in a woman (patient 5) with premature ovarian failure (POF15; 618096) by Jaillard et al. (2020), see 609644.0006. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PREMATURE OVARIAN FAILURE 15</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
FANCM, GLY510SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs146291619,
|
|
|
|
|
|
gnomAD: rs146291619,
|
|
|
|
|
|
ClinVar: RCV001758475, RCV001868499, RCV002477964, RCV004595629
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.1528G-A transition (c.1528G-A, NM_020937.4) in the FANCM gene, resulting in a gly510-to-ser (G510S) substitution, that was found in compound heterozygous state in a European woman (patient 167) with premature ovarian failure (POF15; 618096) by Heddar et al. (2022), see 609644.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PREMATURE OVARIAN FAILURE 15</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FANCM, GLN192LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs768031730,
|
|
|
|
|
|
gnomAD: rs768031730,
|
|
|
|
|
|
ClinVar: RCV001338061, RCV001568753, RCV004595595
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.575A-T transversion (c.575A-T, NM_020937.4) in the FANCM gene, resulting in a gln192-to-leu (Q192L) substitution, that was found in compound heterozygous state in a European woman (patient 326) with premature ovarian failure (POF15; 618096) by Heddar et al. (2022), see 609644.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
|
|
</div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bakker, S. T., van de Vrugt, H. J., Rooimans, M. A., Oostra, A. B., Steltenpool, J., Delzenne-Goette, E., van der Wal, A., van der Valk, M., Joenje, H., Riele H., de Winter, J. P.
|
|
<strong>Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M.</strong>
|
|
Hum. Molec. Genet. 18: 3484-3495, 2009.
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[PubMed: 19561169]
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[Full Text: https://doi.org/10.1093/hmg/ddp297]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Blackford, A. N., Schwab, R. A., Nieminuszczy, J., Deans, A. J., West, S. C., Niedzwiedz, W.
|
|
<strong>The DNA translocase activity of FANCM protects stalled replication forks.</strong>
|
|
Hum. Molec. Genet. 21: 2005-2016, 2012.
|
|
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|
|
[PubMed: 22279085]
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[Full Text: https://doi.org/10.1093/hmg/dds013]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Ciccia, A., Ling, C., Coulthard, R., Yan, Z., Xue, Y., Meetei, A. R., Laghmani, E. H., Joenje, H., McDonald, N., de Winter, J. P., Wang, W., West, S. C.
|
|
<strong>Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM.</strong>
|
|
Molec. Cell 25: 331-343, 2007.
|
|
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|
|
[PubMed: 17289582]
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|
[Full Text: https://doi.org/10.1016/j.molcel.2007.01.003]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Collis, S. J., Ciccia, A., Deans, A. J., Horejsi, Z., Martin, J. S., Maslen, S. L., Skehel, J. M., Elledge, S. J., West, S. C., Boulton, S. J.
|
|
<strong>FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex.</strong>
|
|
Molec. Cell 32: 313-324, 2008.
|
|
|
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|
|
[PubMed: 18995830]
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[Full Text: https://doi.org/10.1016/j.molcel.2008.10.014]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Deans, A. J., West, S. C.
|
|
<strong>FANCM connects the genome instability disorders Bloom's syndrome and Fanconi anemia.</strong>
|
|
Molec. Cell 36: 943-953, 2009.
|
|
|
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|
|
[PubMed: 20064461]
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[Full Text: https://doi.org/10.1016/j.molcel.2009.12.006]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Fouquet, B., Pawlikowska, P., Caburet, S., Guigon, C., Makinen, M., Tanner, L., Hietala, M., Urbanska, K., Bellutti, L., Legois, B., Bessieres, B., Gougeon, A., Benachi, A., Livera, G., Rosselli, F., Veitia, R. A., Misrahi, M.
|
|
<strong>A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency.</strong>
|
|
eLIFE 6: e30490, 2017. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 29231814]
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|
|
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|
|
[Full Text: https://doi.org/10.7554/eLife.30490]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Gari, K., Decaillet, C., Stasiak, A. Z., Stasiak, A., Constantinou, A.
|
|
<strong>The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks.</strong>
|
|
Molec. Cell 29: 141-148, 2008.
|
|
|
|
|
|
[PubMed: 18206976]
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|
|
[Full Text: https://doi.org/10.1016/j.molcel.2007.11.032]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Heddar, A., Ogur, C., Da Costa, S., Braham, I., Billaud-Rist, L., Findikli, N., Beneteau, C., Reynaud, R., Mahmoud, K., Legrand, S., Marchand, M., Cedrin-Durnerin, I., and 46 others.
|
|
<strong>Genetic landscape of a large cohort of primary ovarian insufficiency: new genes and pathways and implications for personalized medicine.</strong>
|
|
EBioMedicine 84: 104246, 2022.
|
|
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|
|
[PubMed: 36099812]
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[Full Text: https://doi.org/10.1016/j.ebiom.2022.104246]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Jaillard, S., Bell, K., Akloul, L., Walton, K., McElreavy, K., Stocker, W. A., Beaumont, M., Harrisson, C., Jaaskelainen, T., Palvimo, J. J., Robevska, G., Launay, E., and 16 others.
|
|
<strong>New insights into the genetic basis of premature ovarian insufficiency: novel causative variants and candidate genes revealed by genomic sequencing.</strong>
|
|
Maturitas 141: 9-19, 2020.
|
|
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|
|
[PubMed: 33036707]
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|
|
[Full Text: https://doi.org/10.1016/j.maturitas.2020.06.004]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Kasak, L., Punab, M., Nagirmaja, L., Grigorova, M., Minajeva, A., Lopes, A. M., Punab, A. M., Aston, K. I., Carvalho, F., Laasik, E., Smith, L. B., GEMINI Consortium, Conrad, D. F., Laan, M.
|
|
<strong>Bi-allelic recessive loss-of-function variants in FANCM cause non-obstructive azoospermia.</strong>
|
|
Am. J. Hum. Genet. 103: 200-212, 2018.
|
|
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|
|
[PubMed: 30075111]
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|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2018.07.005]
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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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Lim, E. T., Wurtz, P., Havulinna, A. S., Palta, P., Tukiainen, T., Rehnstrom, K., Esko, T., Magi, R., Inouye, M., Lappalainen, T., Chan, Y., Salem, R. M., and 48 others.
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<strong>Distribution and medical impact of loss-of-function variants in the Finnish founder population.</strong>
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Meetei, A. R., de Winter, J. P., Medhurst, A. L., Wallisch, M., Waisfisz, Q., van de Vrugt, H. J., Oostra, A. B., Yan, Z., Ling, C., Bishop, C. E., Hoatlin, M. E., Joenje, H., Wang, W.
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Meetei, A. R., Levitus, M., Xue, Y., Medhurst, A. L., Zwaan, M., Ling, C., Rooimans, M. A., Bier, P., Hoatlin, M., Pals, G., de Winter, J. P., Wang, W., Joenje, H.
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<strong>X-linked inheritance of Fanconi anemia complementation group B.</strong>
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Nature Genet. 36: 1219-1224, 2004.
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Meetei, A. R., Medhurst, A. L., Ling, C., Xue, Y., Singh, T. R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C. G., Hoatlin, M., Joenje, H., de Winter, J. P., Wang, W.
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<strong>A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M.</strong>
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Meetei, A. R., Sechi, S., Wallisch, M., Yang, D., Young, M. K., Joenje, H., Hoatlin, M. E., Wang, W.
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Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O.
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<strong>Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong>
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Singh, T. R., Bakker, S. T., Agarwal, S., Jansen, M., Grassman, E., Godthelp, B. C., Ali, A. M., Du, C., Rooimans, M. A., Fan, Q., Wahengbam, K., Steltenpool, J., Andreassen, P. R., Williams, D. A., Joenje, H., de Winter, J. P., Meetei, A. R.
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<strong>Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M.</strong>
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Blood 114: 174-180, 2009.
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Yin, H., Ma, H., Hussain, S., Zhang, H., Xie, X., Jiang, L., Jiang, X., Iqbal, F., Bukhari, I., Jiang, H., Ali, A., Zhong, L. and 17 others.
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<strong>A homozygous FANCM frameshift pathogenic variant causes male infertility.</strong>
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Genet. Med. 21: 62, 2019. Note: Electronic Article. Erratum: Genet. Med. 21: 266, 2019.
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[PubMed: 29895858]
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