4651 lines
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Entry
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- *603089 - BRCA1-ASSOCIATED PROTEIN 1; BAP1
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- OMIM
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<p>
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<span class="h4">*603089</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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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="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603089">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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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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=ENSG00000163930;t=ENST00000460680" 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=8314" 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=603089" 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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<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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<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=ENSG00000163930;t=ENST00000460680" 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_001410772,NM_004656,XM_011534149,XM_011534150,XM_011534151,XM_011534152,XM_047449044" 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_004656" 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=603089" 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=04366&isoform_id=04366_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/BAP1" 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/2854121,4757836,12804391,13874429,13874441,32492935,68565074,119585624,119585625,158258653,193787396,194379994,767924383,767924385,767924387,767924389,929653928,1466117760,1634087231,2217346393,2286439527,2462593011,2462593013,2462593015,2462593017,2462593019" 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/Q92560" 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 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=8314" 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=ENSG00000163930;t=ENST00000460680" 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=BAP1" 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=BAP1" 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+8314" 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/BAP1" 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:8314" 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/8314" 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=chr3&hgg_gene=ENST00000460680.6&hgg_start=52401008&hgg_end=52410008&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:950" 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:950" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/bap1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603089[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=603089[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/BAP1/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/ENSG00000163930" 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.gwascentral.org/search?q=BAP1" 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=BAP1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=BAP1&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/PA25254" 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:950" 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/FBgn0262166.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:1206586" 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/BAP1#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:1206586" 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/8314/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=8314" 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-050208-492" 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:8314" 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=BAP1&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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603089
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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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BRCA1-ASSOCIATED PROTEIN 1; BAP1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=BAP1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BAP1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/3/374?start=-3&limit=10&highlight=374">3p21.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:52401008-52410008&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'})">3:52,401,008-52,410,008</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=606661,619762,614327" 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>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
|
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<span class="mim-font">
|
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<a href="/geneMap/3/374?start=-3&limit=10&highlight=374">
|
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3p21.1
|
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Uveal melanoma, susceptibility to, 2}
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/606661"> 606661 </a>
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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Kury-Isidor syndrome
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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/619762"> 619762 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
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Tumor predisposition syndrome 1
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
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<a href="/entry/614327"> 614327 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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<p>BAP1 encodes a nuclear ubiquitin carboxy-terminal hydrolase (UCH), one of several classes of deubiquitinating enzymes. BAP1 contains binding domains for BRCA1 (<a href="/entry/113705">113705</a>) and BARD1 (<a href="/entry/601593">601593</a>), which form a tumor suppressor heterodimeric complex, and HCFC1 (<a href="/entry/300019">300019</a>), which interacts with histone-modifying complexes during cell division. BAP1 also interacts with ASXL1 (<a href="/entry/612990">612990</a>) to form the Polycomb group repressive deubiquitinase complex (PR-DUB), which is involved in stem cell pluripotency and other developmental processes (summary by <a href="#7" class="mim-tip-reference" title="Harbour, J. W., Onken, M. D., Roberson, E. D. O., Duan, S., Cao, L., Worley, L. A., Council, M. L., Matatall, K. A., Helms, C., Bowcock, A. M. <strong>Frequent mutation of BAP1 in metastasizing uveal melanomas.</strong> Science 330: 1410-1413, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21051595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21051595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21051595[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/10.1126/science.1194472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21051595">Harbour et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21051595" 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="#12" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong> DNA Res. 3: 321-329, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>] [<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039502">Nagase et al. (1996)</a> isolated a BAP1 cDNA, designated KIAA0272. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Jensen, D. E., Proctor, M., Marquis, S. T., Gardner, H. P., Ha, S. I., Chodosh, L. A., Ishov, A. M., Tommerup, N., Vissing, H., Sekido, Y., Minna, J., Borodovsky, A., Schultz, D. C., Wilkinson, K. D., Maul, G. G., Barlev, N., Berger, S. L., Prendergast, G. C., Rauscher, F. J., III. <strong>BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.</strong> Oncogene 16: 1097-1112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9528852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9528852</a>] [<a href="https://doi.org/10.1038/sj.onc.1201861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9528852">Jensen et al. (1998)</a> carried out a yeast 2-hybrid screen to identify proteins that interact with the RING finger domain of BRCA1 (<a href="/entry/113705">113705</a>). They recovered mouse embryo and human adult B-cell cDNAs encoding a protein that they designated 'BRCA1-associated protein-1,' or BAP1. The N-terminal 240 amino acids of the predicted 729-amino acid human protein show homology to ubiquitin C-terminal hydrolases (UCHs; see UCHL3, <a href="/entry/603090">603090</a>), thiol proteases that catalyze proteolytic processing of ubiquitin. In addition, BAP1 contains an acidic region, a highly charged C-terminal region, and 2 putative nuclear localization signals. Recombinant BAP1 had UCH activity in vitro. By coimmunoprecipitation and immunofluorescence studies, <a href="#9" class="mim-tip-reference" title="Jensen, D. E., Proctor, M., Marquis, S. T., Gardner, H. P., Ha, S. I., Chodosh, L. A., Ishov, A. M., Tommerup, N., Vissing, H., Sekido, Y., Minna, J., Borodovsky, A., Schultz, D. C., Wilkinson, K. D., Maul, G. G., Barlev, N., Berger, S. L., Prendergast, G. C., Rauscher, F. J., III. <strong>BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.</strong> Oncogene 16: 1097-1112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9528852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9528852</a>] [<a href="https://doi.org/10.1038/sj.onc.1201861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9528852">Jensen et al. (1998)</a> demonstrated that BAP1 and BRCA1 associate in vivo and have overlapping subnuclear localization patterns. However, BAP1 failed to bind to BRCA1 proteins with germline mutations of the RING finger domain found in breast cancer kindreds. BAP1 enhances BRCA1-mediated inhibition of breast cancer cell growth. Northern blot analysis indicated that BAP1 is expressed as a 4-kb mRNA in all human tissues. An additional 4.8-kb transcript is present in testis. Northern blot analysis and in situ hybridization revealed that BAP1 and BRCA1 are temporally and spatially coexpressed during murine breast development and remodeling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9528852" 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="#12" class="mim-tip-reference" title="Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. <strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong> DNA Res. 3: 321-329, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>] [<a href="https://doi.org/10.1093/dnares/3.5.321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9039502">Nagase et al. (1996)</a> mapped the BAP1 gene to chromosome 3 by analysis of radiation hybrids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039502" 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 fluorescence in situ hybridization, <a href="#9" class="mim-tip-reference" title="Jensen, D. E., Proctor, M., Marquis, S. T., Gardner, H. P., Ha, S. I., Chodosh, L. A., Ishov, A. M., Tommerup, N., Vissing, H., Sekido, Y., Minna, J., Borodovsky, A., Schultz, D. C., Wilkinson, K. D., Maul, G. G., Barlev, N., Berger, S. L., Prendergast, G. C., Rauscher, F. J., III. <strong>BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.</strong> Oncogene 16: 1097-1112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9528852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9528852</a>] [<a href="https://doi.org/10.1038/sj.onc.1201861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9528852">Jensen et al. (1998)</a> mapped the BAP1 gene to 3p21.3, a region of loss of heterozygosity for breast cancer as well as a region frequently deleted in lung carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9528852" 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="#9" class="mim-tip-reference" title="Jensen, D. E., Proctor, M., Marquis, S. T., Gardner, H. P., Ha, S. I., Chodosh, L. A., Ishov, A. M., Tommerup, N., Vissing, H., Sekido, Y., Minna, J., Borodovsky, A., Schultz, D. C., Wilkinson, K. D., Maul, G. G., Barlev, N., Berger, S. L., Prendergast, G. C., Rauscher, F. J., III. <strong>BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.</strong> Oncogene 16: 1097-1112, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9528852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9528852</a>] [<a href="https://doi.org/10.1038/sj.onc.1201861" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9528852">Jensen et al. (1998)</a> found intragenic homozygous rearrangements and deletions of BAP1 in lung carcinoma cell lines. They proposed that BAP1 is a tumor suppressor gene that functions in the BRCA1 growth control pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9528852" 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="Dey, A., Seshasayee, D., Noubade, R., French, D. M., Liu, J., Chaurushiya, M. S., Kirkpatrick, D. S., Pham. V. C., Lill, J. R., Bakalarski, C. E., Wu, J., Phu, L., and 15 others. <strong>Loss of the tumor suppressor BAP1 causes myeloid transformation.</strong> Science 337: 1541-1546, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22878500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22878500</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22878500[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/10.1126/science.1221711" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22878500">Dey et al. (2012)</a> showed that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (<a href="/entry/614286">614286</a>). Analysis of knockin mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with host cell factor-1 (HCF1; <a href="/entry/300019">300019</a>), O-linked N-acetylglucosamine transferase (OGT; <a href="/entry/300255">300255</a>), and the polycomb group proteins ASXL1 and ASXL2 (<a href="/entry/612991">612991</a>) in vivo. OGT and HCF1 levels were decreased by BAP1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML; <a href="/entry/607785">607785</a>), so an ASXL/BAP1 complex may suppress CMML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22878500" 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="Bononi, A., Giorgi, C., Patergnani, S., Larson, D., Verbruggen, K., Tanji, M., Pellegrini, L., Signorato, V., Olivetto, F., Pastorino, S., Nasu, M., Napolitano, A., and 13 others. <strong>BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation.</strong> Nature 546: 549-553, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28614305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28614305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28614305[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/nature22798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28614305">Bononi et al. (2017)</a> discovered that BAP1 localizes at the endoplasmic reticulum. There, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3; <a href="/entry/147267">147267</a>), modulating calcium release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1 +/- carriers cause reduction both of IP3R3 levels and of Ca(2+) flux, preventing BAP1 +/- cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. <a href="#2" class="mim-tip-reference" title="Bononi, A., Giorgi, C., Patergnani, S., Larson, D., Verbruggen, K., Tanji, M., Pellegrini, L., Signorato, V., Olivetto, F., Pastorino, S., Nasu, M., Napolitano, A., and 13 others. <strong>BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation.</strong> Nature 546: 549-553, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28614305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28614305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28614305[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/nature22798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28614305">Bononi et al. (2017)</a> proposed that the high incidence of cancers in BAP1 +/- carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. <a href="#2" class="mim-tip-reference" title="Bononi, A., Giorgi, C., Patergnani, S., Larson, D., Verbruggen, K., Tanji, M., Pellegrini, L., Signorato, V., Olivetto, F., Pastorino, S., Nasu, M., Napolitano, A., and 13 others. <strong>BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation.</strong> Nature 546: 549-553, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28614305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28614305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28614305[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/nature22798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28614305">Bononi et al. (2017)</a> concluded that their data provided a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28614305" 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="#8" class="mim-tip-reference" title="He, M., Chaurushiya, M. S., Webster, J. D., Kummerfeld, S., Reja, R., Chaudhuri, S., Chen, Y.-J., Modrusan, Z., Haley, B., Dugger, D. L., Eastham-Anderson, J., Lau, S., Dey, A., Caothien, R., Roose-Girma, M., Newton, K., Dixit, V. M. <strong>Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1.</strong> Science 364: 283-285, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31000662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31000662</a>] [<a href="https://doi.org/10.1126/science.aav4902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31000662">He et al. (2019)</a> showed that Bap1 inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver, and pancreatic tissue but not in melanocytes and mesothelial cells. Ubiquitin ligase Rnf2 (<a href="/entry/608985">608985</a>), which silences genes by monoubiquitinating histone H2a (see <a href="/entry/613499">613499</a>), promoted apoptosis in Bap1-deficient cells by suppressing expression of the prosurvival genes Bcl2 (<a href="/entry/151430">151430</a>) and Mcl1 (<a href="/entry/159552">159552</a>). In contrast, Bap1 loss in melanocytes had little impact on expression of prosurvival genes, instead inducing Mitf (<a href="/entry/156845">156845</a>). Thus, <a href="#8" class="mim-tip-reference" title="He, M., Chaurushiya, M. S., Webster, J. D., Kummerfeld, S., Reja, R., Chaudhuri, S., Chen, Y.-J., Modrusan, Z., Haley, B., Dugger, D. L., Eastham-Anderson, J., Lau, S., Dey, A., Caothien, R., Roose-Girma, M., Newton, K., Dixit, V. M. <strong>Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1.</strong> Science 364: 283-285, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31000662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31000662</a>] [<a href="https://doi.org/10.1126/science.aav4902" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31000662">He et al. (2019)</a> concluded that BAP1 appears to modulate gene expression by countering H2A ubiquitination, but its loss promotes tumorigenesis only in cells that do not engage an RNF2-dependent apoptotic program. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31000662" 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="#17" class="mim-tip-reference" title="Xiong, Z., Xia, P., Zhu, X., Geng, J., Wang, S., Ye, B., Qin, X., Qu, Y., He, L., Fan, D., Du, Y., Tian, Y., Fan, Z. <strong>Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis.</strong> J. Exp. Med. 217: e20190974, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31699823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31699823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31699823[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20190974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31699823">Xiong et al. (2020)</a> found that Bap1 facilitated expression of Hoxa1 (<a href="/entry/142955">142955</a>), which was required for self-renewal of mouse hematopoietic stem cells (HSCs). Ttll5 (<a href="/entry/612268">612268</a>) and Ttll7 (<a href="/entry/618813">618813</a>) glutamylated Bap1 at glu651 in HSCs, whereas Ccp3 (<a href="/entry/617346">617346</a>) removed Bap1 glutamylation. Bap1 glutamylation promoted its interaction with Ube2o (<a href="/entry/617649">617649</a>) and accelerated lys48-linked ubiquitination of Bap1 for its degradation. Degradation of Bap1 suppressed Hoxa1 expression, thereby enhancing HSC self-renewal and hematopoiesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31699823" 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>Somatic BAP1 Mutations</em></strong></p><p>
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BAP1 exhibits tumor suppressor activity in cancer cells, and BAP1 mutations have been reported in a small number of breast and lung cancer samples. <a href="#7" class="mim-tip-reference" title="Harbour, J. W., Onken, M. D., Roberson, E. D. O., Duan, S., Cao, L., Worley, L. A., Council, M. L., Matatall, K. A., Helms, C., Bowcock, A. M. <strong>Frequent mutation of BAP1 in metastasizing uveal melanomas.</strong> Science 330: 1410-1413, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21051595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21051595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21051595[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/10.1126/science.1194472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21051595">Harbour et al. (2010)</a> used exome capture coupled with massively parallel sequencing to search for metastasis-related mutations in highly metastatic uveal melanomas (see UVM2, <a href="/entry/606661">606661</a>). Inactivating somatic mutations were identified in the BAP1 gene on chromosome 3p21.1 in 26 of 31 (84%) metastasizing tumors, including 15 mutations causing premature protein termination and 5 affecting its ubiquitin C-terminal hydrolase domain. One tumor harbored a frameshift mutation that was germline in origin, thus representing a susceptibility allele. <a href="#7" class="mim-tip-reference" title="Harbour, J. W., Onken, M. D., Roberson, E. D. O., Duan, S., Cao, L., Worley, L. A., Council, M. L., Matatall, K. A., Helms, C., Bowcock, A. M. <strong>Frequent mutation of BAP1 in metastasizing uveal melanomas.</strong> Science 330: 1410-1413, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21051595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21051595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21051595[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/10.1126/science.1194472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21051595">Harbour et al. (2010)</a> concluded that their findings implicated loss of BAP1 in uveal melanoma metastasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21051595" 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 studying copy number alterations followed by candidate gene sequencing of 53 primary malignant pleural mesothelioma (<a href="/entry/156240">156240</a>) samples, <a href="#3" class="mim-tip-reference" title="Bott, M., Brevet, M., Taylor, B. S., Shimizu, S., Ito, T., Wang, L., Creaney, J., Lake, R. A., Zakowski, M. F., Reva, B., Sander, C., Delsite, R., Powell, S., Zhou, Q., Shen, R., Olshen, A., Rusch, V., Ladanyi, M. <strong>The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.</strong> Nature Genet. 43: 668-672, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21642991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21642991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21642991[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/ng.855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21642991">Bott et al. (2011)</a> identified the BAP1 gene on chromosome 3p21.1 as a commonly somatically inactivated gene. Twelve (23%) of 53 tumors had nonsynonymous mutations, and 16 (30%) had at least single copy genomic loss of the BAP1 locus. Tumors with mutations showed loss of nuclear staining for BAP1. BAP1 losses were confirmed in an independent collection of MPM tumors. The somatic nature of the mutations was confirmed in all tumors that had matched normal tissue available. Knockdown of BAP1 in mesothelioma cell lines expressing wildtype BAP1 resulted in proliferation defects with an accumulation of cells in S phase and also downregulated E2F (see, e.g., <a href="/entry/189971">189971</a>)-responsive genes. Given the known role of BAP1 in regulatory ubiquitination of histones, the findings suggested transcriptional deregulation as a pathogenic mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21642991" 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 sequencing of the BAP1 gene in 156 tumors from patients with sporadic melanocytic neoplasms, <a href="#16" class="mim-tip-reference" title="Wiesner, T., Obenauf, A. C., Murali, R., Fried, I., Griewank, K. G., Ulz, P., Windpassinger, C., Wackernagel, W., Loy, S., Wolf, I., Viale, A., Lash, A. E., and 12 others. <strong>Germline mutations in BAP1 predispose to melanocytic tumors. (Letter)</strong> Nature Genet. 43: 1018-1021, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21874003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21874003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21874003[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/ng.910" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21874003">Wiesner et al. (2011)</a> found somatic mutations in 13 (40%) uveal melanomas, 2 (11%) atypical Spitz tumors, and 3 (5%) cutaneous melanomas (<a href="/entry/155600">155600</a>). Two of 5 sporadic cutaneous melanomas that arose in nevi harbored BAP1 mutations, and in both cases, the BAP1 mutations were absent in the nevus portion, suggesting that loss of function of BAP1 may have a role in progression from nevus to melanoma in some cases. The 2 atypical Spitz tumors lacked BAP1 expression and harbored a BRAF mutation (V600E; <a href="/entry/164757#0001">164757.0001</a>), suggesting that biallelic inactivation of BAP1 is associated with a distinct type of melanocytic neoplasm. Finally, all the uveal melanomas with BAP1 mutations also carried mutations at codon 209 in either GNAQ (<a href="/entry/600998">600998</a>) or GNA11 (<a href="/entry/139313">139313</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21874003" 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="Pena-Llopis, S., Vega-Rubin-de-Celis, S., Liao, A., Leng, N., Pavia-Jimenez, A., Wang, S., Yamasaki, T., Zhrebker, L., Sivanand, S., Spence, P., Kinch, L., Hambuch, T., and 15 others. <strong>BAP1 loss defines a new class of renal cell carcinoma.</strong> Nature Genet. 44: 751-759, 2012. Note: Erratum: Nature Genet. 44: 1072 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22683710[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/ng.2323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22683710">Pena-Llopis et al. (2012)</a> provided evidence that BAP1 can act as a tumor suppressor gene in clear cell renal cell carcinoma (ccRCC; see <a href="/entry/144700">144700</a>). The authors used whole-genome and exome sequencing of ccRCC as well as analyses of mutant allele ratios of a murine tumorgraft to identify putative 2-hit tumor suppressor genes. BAP1 was found to be somatically mutated in 24 (14%) of 176 tumors, and most mutations were predicted to truncate the protein. In a cell line with a missense BAP1 mutation, expression of wildtype BAP1 repressed cell proliferation without causing apoptosis. In this cell line, the majority of BAP1 cofractionated with and bound to HCFC1. Mutations disrupting the HCFC1 binding motif impaired BAP1-mediated suppression of cell proliferation, but not its deubiquitination of monoubiquitinated histone 2A. BAP1 loss sensitized RCC cells in vitro to genotoxic stress. Although mutations in BAP1 and PBRM1 (<a href="/entry/606083">606083</a>) anticorrelated in renal cell tumors, the few tumors that had combined loss of BAP1 and PBRM1 were associated with rhabdoid features. Moreover, BAP1 loss was associated with high tumor grade. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22683710" 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="Dey, A., Seshasayee, D., Noubade, R., French, D. M., Liu, J., Chaurushiya, M. S., Kirkpatrick, D. S., Pham. V. C., Lill, J. R., Bakalarski, C. E., Wu, J., Phu, L., and 15 others. <strong>Loss of the tumor suppressor BAP1 causes myeloid transformation.</strong> Science 337: 1541-1546, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22878500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22878500</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22878500[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/10.1126/science.1221711" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22878500">Dey et al. (2012)</a> identified a patient with a somatic frameshift mutation that causes premature termination within the UCH catalytic domain of BAP1. The patient with the somatic BAP1 mutation presented with refractory cytopenias and multilineage dysplasia, similar to the multilineage dysplasia and cytopenias seen in their murine model. No other mutations in known MDS genes were identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22878500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Jiao, Y., Pawlik, T. M., Anders, R. A., Selaru, F. M., Streppel, M. M., Lucas, D. J., Niknafs, N., Guthrie, V. B., Maitra, A., Argani, P., Offerhaus, G. J. A., Roa, J. C., and 24 others. <strong>Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.</strong> Nature Genet. 45: 1470-1473, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24185509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24185509</a>] [<a href="https://doi.org/10.1038/ng.2813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24185509">Jiao et al. (2013)</a> detected somatic BAP1 mutations in 8 of 32 (25%) intrahepatic cholangiocarcinomas (<a href="/entry/615619">615619</a>) in a discovery screen and in 5 of 32 (16%) independent intrahepatic cholangiocarcinomas in the prevalence screen. <a href="#5" class="mim-tip-reference" title="Chan-on, W., Nairismagi, M.-L., Ong, C. K., Lim, W. K., Dima, S., Pairojkul, C., Lim, K. H., McPherson, J. R., Cutcutache, I., Heng, H. L., Ooi, L., Chung, A., and 27 others. <strong>Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers.</strong> Nature Genet. 45: 1474-1478, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24185513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24185513</a>] [<a href="https://doi.org/10.1038/ng.2806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24185513">Chan-on et al. (2013)</a> identified somatic BAP1 mutations in 9 of 86 (10.5%) non-O.viverrini cholangiocarcinomas and in 3 of 108 (2.8%) O. viverrini-related cholangiocarcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24185509+24185513" 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>Tumor Predisposition Syndrome 1</em></strong></p><p>
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Using array-based comparative genomic hybridization, <a href="#16" class="mim-tip-reference" title="Wiesner, T., Obenauf, A. C., Murali, R., Fried, I., Griewank, K. G., Ulz, P., Windpassinger, C., Wackernagel, W., Loy, S., Wolf, I., Viale, A., Lash, A. E., and 12 others. <strong>Germline mutations in BAP1 predispose to melanocytic tumors. (Letter)</strong> Nature Genet. 43: 1018-1021, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21874003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21874003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21874003[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/ng.910" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21874003">Wiesner et al. (2011)</a> found loss of chromosome 3p in 50% of skin tumors from 3 affected individuals in a family with tumor predisposition syndrome-1 (TPDS1; <a href="/entry/614327">614327</a>), suggesting that this was a second hit resulting in the elimination of the remaining wildtype allele of a mutated tumor suppressor gene in this chromosomal region. Haplotype analysis showed segregation of the maternal allele in affected family members of 2 generations, and sequence analysis of this region identified a heterozygous germline mutation in the BAP1 gene (<a href="#0001">603089.0001</a>) that segregated with the phenotype. Reexamination of tumor tissue confirmed loss of BAP1 in 29 skin tumors and in a uveal melanoma. Tumors that did not show loss of 3p21 showed loss of BAP1 through additional somatic mechanisms, such as point mutation. Immunohistochemical studies showed loss of BAP1 nuclear expression in the melanocytic neoplasms. Molecular analysis of a second family with a similar phenotype identified a different heterozygous germline mutation in the BAP1 gene (<a href="#0002">603089.0002</a>). Somatic inactivation of the remaining allele, as determined by loss of heterozygosity (LOH), was found in 9 of 13 skin tumors, in a uveal melanoma, and in a cutaneous melanoma from 1 patient. In addition, 37 (88%) of 42 tumors in both families showed a somatic V600E mutation in the BRAF gene (<a href="/entry/164757#0001">164757.0001</a>). Notably, the families had a low number of melanomas compared to the number of papular melanocytic tumors, suggesting that the risk of malignant progression in individual tumors from patients with this disorder is low. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21874003" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated families with a tumor predisposition syndrome characterized mainly by the development of asbestos-related malignant mesothelioma, <a href="#15" class="mim-tip-reference" title="Testa, J. R., Cheung, M., Pei, J., Below, J. E., Tan, Y., Sementino, E., Cox, N. J., Dogan, A. U., Pass, H. I., Trusa, S., Hesdorffer, M., Nasu, M., Powers, A., Rivera, Z., Comertpay, S., Tanji, M., Gaudino, G., Yang, H., Carbone, M. <strong>Germline BAP1 mutations predispose to malignant mesothelioma. (Letter)</strong> Nature Genet. 43: 1022-1025, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21874000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21874000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21874000[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/ng.912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21874000">Testa et al. (2011)</a> identified 2 different heterozygous mutations in the BAP1 gene (<a href="#0003">603089.0003</a> and <a href="#0004">603089.0004</a>, respectively) that segregated with the phenotype. Array-comparative genomic hybridization had found loss of BAP1 at 3p21 in 2 malignant mesothelioma tumors from these families, and subsequent linkage analysis identified an inherited susceptibility locus on chromosome 3p21. Tumor tissue showed loss of BAP1 nuclear expression by immunohistochemistry. The findings were consistent with somatic loss of the second BAP1 allele in tumor tissue. Further analysis of 26 germline DNA samples from patients with sporadic mesothelioma found that 2 carried heterozygous BAP1 deletions (<a href="#0005">603089.0005</a> and <a href="#0006">603089.0006</a>, respectively). Each of these patients also had a history of uveal melanoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21874000" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Abdel-Rahman, M. H., Pilarski, R., Cebulla, C. M., Massengill, J. B., Christopher, B. N., Boru, G., Hovland, P., Davidorf, F. H. <strong>Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.</strong> J. Med. Genet. 48: 856-859, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21941004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21941004</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21941004[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21941004">Abdel-Rahman et al. (2011)</a> identified a heterozygous germline mutation in the BAP1 gene (<a href="#0007">603089.0007</a>) in 1 of 53 probands with uveal melanoma and evidence of a familial cancer syndrome who were screened specifically for BAP1 mutations. In this family, the mutation segregated with various types of cancer, including lung adenocarcinoma, cutaneous melanoma, and meningioma. Tumor tissue showed LOH for the BAP1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21941004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a large family with a tumor predisposition syndrome characterized mainly by renal cell carcinoma (RCC), <a href="#14" class="mim-tip-reference" title="Popova, T., Hebert, L., Jacquemin, V., Gad, S., Caux-Moncoutier, V., Dubois-d'Enghien, C., Richaudeau, B., Renaudin, X., Sellers, J., Nicolas, A., Sastre-Garau, X., Desjardins, L., and 22 others. <strong>Germline BAP1 mutations predispose to renal cell carcinomas.</strong> Am. J. Hum. Genet. 92: 974-980, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23684012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23684012</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23684012[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.2013.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23684012">Popova et al. (2013)</a> identified a heterozygous germline mutation in the BAP1 gene (<a href="#0008">603089.0008</a>). The mutation was identified using a combination of whole-exome sequencing and tumor profiling, and was confirmed by Sanger sequencing. Three renal cell carcinomas from this family showed loss of heterozygosity for BAP1, consistent with the 2-hit hypothesis of cancer development. Subsequently, sequence analysis identified heterozygous truncating mutations in the BAP1 gene (see, e.g., <a href="#0009">603089.0009</a> and <a href="#0010">603089.0010</a>) in 11 (18%) of 60 unrelated families with either uveal melanoma, cutaneous melanoma, or mesothelioma. A total of 33 individuals were diagnosed with these 3 cancers in diverse associations; 14 individuals had other cancers, including renal, lung, breast, prostatic, thyroid, and bladder carcinomas. Nine RCCs were reported in 6 of the 11 families with BAP1 mutations, indicating that RCC should be added to the tumor spectrum of this syndrome. However, no BAP1 mutations were detected in a separate series of 32 French families with renal cell carcinoma, suggesting that germline BAP1 mutations rarely explain families affected only with RCC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23684012" 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 6 affected members of a large multigenerational kindred (K4) of European origin with TPDS1, <a href="#4" class="mim-tip-reference" title="Carbone, M., Flores, E. G., Emi, M., Johnson, T. A., Tsunoda, T., Behner, D., Hoffman, H., Hesdorffer, M., Nasu, M., Napolitano, A., Powers, A., Minaai, M., and 10 others. <strong>Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s.</strong> PLoS Genet. 11: e1005633, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26683624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26683624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26683624[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.1005633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26683624">Carbone et al. (2015)</a> identified a heterozygous germline frameshift mutation in the BAP1 gene (c.1717delC; <a href="#0015">603089.0015</a>). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family in those who were genotyped. The mutant protein was predicted to lack the nuclear localization signal, and immunohistochemical studies of mesothelioma tissue showed lack of nuclear BAP1 staining with only cytoplasmic localization. Somatic loss of heterozygosity of the BAP1 gene was confirmed in available tumor tissue. These findings were consistent with BAP1 being a tumor suppressor gene. <a href="#4" class="mim-tip-reference" title="Carbone, M., Flores, E. G., Emi, M., Johnson, T. A., Tsunoda, T., Behner, D., Hoffman, H., Hesdorffer, M., Nasu, M., Napolitano, A., Powers, A., Minaai, M., and 10 others. <strong>Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s.</strong> PLoS Genet. 11: e1005633, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26683624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26683624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26683624[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.1005633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26683624">Carbone et al. (2015)</a> emphasized the importance of identifying mutation carriers in this family who can then be monitored for malignant mesothelioma or other cancers because early detection and diagnosis can lead to effective treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26683624" 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>Melanoma, Uveal, Susceptibility to, 2</em></strong></p><p>
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In 2 unrelated Caucasian men with bilateral uveal melanoma-2 (UVM2; <a href="/entry/606661">606661</a>), <a href="#18" class="mim-tip-reference" title="Yu, M. D., Masoomian, B., Shields, J. A., Shields, C. L. <strong>BAP1 germline mutation associated with bilateral primary uveal melanoma.</strong> Ocul. Oncol. Path. 6: 10-14, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32002398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32002398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32002398[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/10.1159/000499570" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32002398">Yu et al. (2020)</a> identified germline heterozygous frameshift mutations in the BAP1 gene (<a href="#0015">603089.0015</a> and <a href="#0016">603089.0016</a>). Functional studies of the variants were not performed. Cytogenetic profile of tumor tissue showed somatic changes affecting chromosomes 3, 6, and 8. Family history in patient 1 was significant for cancer, although familial genetic segregation studies were not conducted in either proband. The patients did not have other tumors or systemic metastasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32002398" 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>Kury-Isidor Syndrome</em></strong></p><p>
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In 8 unrelated patients (patients 1-4 and 7-10) with Kury-Isidor syndrome (KURIS; <a href="/entry/619762">619762</a>), <a href="#11" class="mim-tip-reference" title="Kury, S., Ebstein, F., Molle, A., Besnard, T., Lee, M.-K., Vignard, V., Hery, T., Nizon, M., Mancini, G. M. S., Giltay, J. C., Cogne, B., McWalter, K., and 47 others. <strong>Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.</strong> Am. J. Hum. Genet. 109: 361-372, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35051358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35051358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35051358[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.2021.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35051358">Kury et al. (2022)</a> identified de novo heterozygous missense mutations in the BAP1 gene (see, e.g., <a href="/entry/602089#0011">602089.0011</a>-<a href="/entry/601089#0014">601089.0014</a>). The patients were ascertained through collaborative efforts such as the GeneMatcher Program, and the phenotype was compiled after the variants were identified by exome sequencing. All the mutations occurred at conserved residues in the catalytic ubiquitin C-terminal hydrolase domain; none were present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that some of the variants tested (P12T, <a href="#0011">603089.0011</a>; C91R, <a href="#0013">603089.0013</a>; and H169R, <a href="#0014">603089.0014</a>) were unable to rescue BAP1 activity, as measured by increased BAP1 H2AK119ub substrate levels. Rescue with another variant (P12A; <a href="#0012">603089.0012</a>) was similar to controls for that particular substrate. All variants, including P12A, were unable to rescue the expression of BAP1 target genes TMSB4X (<a href="/entry/300159">300159</a>) and S100A11 (<a href="/entry/603114">603114</a>) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data suggested that the BAP1 mutations were unable to compensate H2A deubiquitination of substrates in BAP1-null cells, consistent with a loss-of-function effect. Of note, all the BAP1 variants localized properly to the nucleus in transfected cells. T cells derived from 2 patients carrying the P12T and C91S mutations showed that steady-state levels of ubiquitinated H2A were substantially increased compared to controls, again consistent with a loss-of-function effect for BAP1. CHIP-seq analysis indicated that the variants induced genomewide chromatin state alterations in the 2 patient cell lines; there was also some evidence of proteosome perturbation. <a href="#11" class="mim-tip-reference" title="Kury, S., Ebstein, F., Molle, A., Besnard, T., Lee, M.-K., Vignard, V., Hery, T., Nizon, M., Mancini, G. M. S., Giltay, J. C., Cogne, B., McWalter, K., and 47 others. <strong>Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.</strong> Am. J. Hum. Genet. 109: 361-372, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35051358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35051358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35051358[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.2021.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35051358">Kury et al. (2022)</a> concluded that BAP1 missense variants alter chromatin remodeling through abnormal histone ubiquitination, leading to transcriptional dysregulation of developmental genes. None of the patients developed tumors. The authors noted that BAP1 mutations that predispose to tumor syndrome are truncating or splice-site mutations; the missense mutations identified in patients with KURIS are loss-of-function and may disrupt the deubiquitinase activity without altering other protein-protein interactions. Some of the patients, including 3 additional patients (patients 5, 6, and 11) with variable developmental abnormalities associated with de novo missense BAP1 variants identified in the study, had additional genetic variants of uncertain significance that may have contributed to the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35051358" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603089[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776877 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776877;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=rs587776877" 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=rs587776877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 4 affected members of a family with tumor predisposition syndrome-1 (TPDS1; <a href="/entry/614327">614327</a>) characterized mainly by the development of melanocytic skin tumors, <a href="#16" class="mim-tip-reference" title="Wiesner, T., Obenauf, A. C., Murali, R., Fried, I., Griewank, K. G., Ulz, P., Windpassinger, C., Wackernagel, W., Loy, S., Wolf, I., Viale, A., Lash, A. E., and 12 others. <strong>Germline mutations in BAP1 predispose to melanocytic tumors. (Letter)</strong> Nature Genet. 43: 1018-1021, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21874003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21874003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21874003[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/ng.910" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21874003">Wiesner et al. (2011)</a> identified a germline heterozygous 1-bp deletion (1305delG) in exon 13 of the BAP1 gene, resulting in a frameshift. The mutation was found after tumor analysis showed loss of chromosome 3p in 50% of tumors and haplotype analysis showed segregation of a maternal allele in the 3p21 region in affected family members of 2 generations. All 4 had multiple melanocytic tumors, and 1 had a uveal melanoma. Reexamination of tumor tissue confirmed loss of BAP1 in 29 skin tumors and the uveal melanoma. Tumors that did not show loss of 3p21 showed loss of BAP1 through additional somatic mechanisms, such as point mutation. The findings were consistent with germline predisposition to development of the disorder with a second somatic hit in a tumor suppressor gene resulting in tumor development. Immunohistochemical studies showed loss of BAP1 nuclear expression in all the melanocytic neoplasms. Most of the tumors also carried a somatic V600E mutation in the BRAF gene (<a href="/entry/164757#0001">164757.0001</a>). Notably, none of the patients in this family developed cutaneous melanoma despite the large number of papular melanocytic tumors, suggesting that the risk of malignant progression in individual tumors from patients with this disorder is low. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21874003" 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">rs587776878 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776878;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=rs587776878" 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=rs587776878" 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=RCV000023235 OR RCV003162259" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023235, RCV003162259" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023235...</a>
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<p>In affected members of a family with tumor predisposition syndrome-1 (TPDS1; <a href="/entry/614327">614327</a>) characterized mainly by the development of melanocytic skin tumors, <a href="#16" class="mim-tip-reference" title="Wiesner, T., Obenauf, A. C., Murali, R., Fried, I., Griewank, K. G., Ulz, P., Windpassinger, C., Wackernagel, W., Loy, S., Wolf, I., Viale, A., Lash, A. E., and 12 others. <strong>Germline mutations in BAP1 predispose to melanocytic tumors. (Letter)</strong> Nature Genet. 43: 1018-1021, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21874003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21874003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21874003[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/ng.910" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21874003">Wiesner et al. (2011)</a> identified a heterozygous A-to-G transition removing the acceptor splice site of the last exon (2057-2A-G). Analysis of cDNA showed that the last intron was not removed by splicing. One mutation carrier developed a uveal melanoma, and 3 developed cutaneous melanoma. Somatic inactivation of the remaining BAP1 allele, as determined by loss of heterozygosity (LOH), was found in 9 of 13 skin tumors, in the 1 uveal melanoma, and in a cutaneous melanoma from 1 patient. A metastatic melanoma from another family member did not show LOH for BAP1, but no additional tissue was available to investigate alternative mechanisms of BAP1 inactivation. In contrast, microscopic examination of common acquired flat nevi showed small uniform melanocytes and strong nuclear expression of BAP1. Most of the tumors also carried a somatic V600E mutation in the BRAF gene (<a href="/entry/164757#0001">164757.0001</a>). Notably, only 3 patients in this family developed cutaneous melanoma, compared to the number of papular melanocytic tumors, suggesting that the risk of malignant progression in individual tumors from patients with this disorder is low. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21874003" 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> rs587776879 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776879;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/rs587776879?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=rs587776879" 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=rs587776879" 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=RCV000023236 OR RCV002326682 OR RCV003320548" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023236, RCV002326682, RCV003320548" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023236...</a>
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<p>In affected members of a 3-generation Wisconsin family with tumor predisposition syndrome-1 (TPDS1; <a href="/entry/614327">614327</a>) characterized mainly by the development of malignant mesothelioma, <a href="#15" class="mim-tip-reference" title="Testa, J. R., Cheung, M., Pei, J., Below, J. E., Tan, Y., Sementino, E., Cox, N. J., Dogan, A. U., Pass, H. I., Trusa, S., Hesdorffer, M., Nasu, M., Powers, A., Rivera, Z., Comertpay, S., Tanji, M., Gaudino, G., Yang, H., Carbone, M. <strong>Germline BAP1 mutations predispose to malignant mesothelioma. (Letter)</strong> Nature Genet. 43: 1022-1025, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21874000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21874000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21874000[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/ng.912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21874000">Testa et al. (2011)</a> identified a heterozygous germline A-to-G transition in the splice acceptor site of intron 6 of the BAP1 gene. Transfection of mammalian cells with this mutation resulted in an aberrant splice product lacking exon 8 and a frameshift predicted to result in a premature stop codon and nonsense-mediated decay. Tumor tissue from 3 patients showed complete loss of BAP1, consistent with somatic loss of the wildtype allele, and immunohistochemistry of tumor tissue showed lack of BAP1 nuclear expression. Five mutation carriers developed mesothelioma after household exposure. Among other mutation carriers in the family, 1 each had breast, ovarian, and renal cancer. The mutation was identified after tumor tissue showed loss of BAP1 at 3p21 with subsequent performance of linkage analysis in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21874000" 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> rs387906848 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906848;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/rs387906848?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=rs387906848" 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=rs387906848" 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=RCV000023237 OR RCV000487149 OR RCV001014205" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023237, RCV000487149, RCV001014205" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023237...</a>
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<p>In affected members of a 2-generation family from Louisiana with tumor predisposition syndrome-1 (TPDS1; <a href="/entry/614327">614327</a>) characterized mainly by the development of malignant mesothelioma, <a href="#15" class="mim-tip-reference" title="Testa, J. R., Cheung, M., Pei, J., Below, J. E., Tan, Y., Sementino, E., Cox, N. J., Dogan, A. U., Pass, H. I., Trusa, S., Hesdorffer, M., Nasu, M., Powers, A., Rivera, Z., Comertpay, S., Tanji, M., Gaudino, G., Yang, H., Carbone, M. <strong>Germline BAP1 mutations predispose to malignant mesothelioma. (Letter)</strong> Nature Genet. 43: 1022-1025, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21874000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21874000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21874000[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/ng.912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21874000">Testa et al. (2011)</a> identified a heterozygous germline C-to-T transition in exon 16 of the BAP1 gene, resulting in a gln684-to-ter (Q684X) substitution. Immunohistochemistry of tumor tissue showed lack of BAP1 nuclear expression. Six mutation carriers developed mesothelioma after household exposure. Among other mutation carriers in the family, 2 developed skin cancer (squamous cell and basal cell, respectively), and 1 developed pancreatic cancer. Two family members with prostate cancer did not carry the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21874000" 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">rs869025212 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025212;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=rs869025212" 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=rs869025212" 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=RCV000207031 OR RCV000464745 OR RCV000567996 OR RCV001795342 OR RCV002273820" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000207031, RCV000464745, RCV000567996, RCV001795342, RCV002273820" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000207031...</a>
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<p>In a patient with tumor predisposition syndrome-1 (TPDS1; <a href="/entry/614327">614327</a>) who developed malignant mesothelioma and a uveal melanoma, <a href="#15" class="mim-tip-reference" title="Testa, J. R., Cheung, M., Pei, J., Below, J. E., Tan, Y., Sementino, E., Cox, N. J., Dogan, A. U., Pass, H. I., Trusa, S., Hesdorffer, M., Nasu, M., Powers, A., Rivera, Z., Comertpay, S., Tanji, M., Gaudino, G., Yang, H., Carbone, M. <strong>Germline BAP1 mutations predispose to malignant mesothelioma. (Letter)</strong> Nature Genet. 43: 1022-1025, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21874000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21874000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21874000[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/ng.912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21874000">Testa et al. (2011)</a> identified a heterozygous germline 1-bp deletion (1832delC) in exon 13 of the BAP1 gene, resulting in a frameshift and truncation upstream of the BAP1 nuclear localization signal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21874000" 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">rs1559585778 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1559585778;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=rs1559585778" 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=rs1559585778" 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=RCV000772520 OR RCV001312026 OR RCV001850964" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000772520, RCV001312026, RCV001850964" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000772520...</a>
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<p>In a patient with tumor predisposition syndrome-1 (TPDS1; <a href="/entry/614327">614327</a>) who developed malignant mesothelioma and uveal melanoma, <a href="#15" class="mim-tip-reference" title="Testa, J. R., Cheung, M., Pei, J., Below, J. E., Tan, Y., Sementino, E., Cox, N. J., Dogan, A. U., Pass, H. I., Trusa, S., Hesdorffer, M., Nasu, M., Powers, A., Rivera, Z., Comertpay, S., Tanji, M., Gaudino, G., Yang, H., Carbone, M. <strong>Germline BAP1 mutations predispose to malignant mesothelioma. (Letter)</strong> Nature Genet. 43: 1022-1025, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21874000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21874000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21874000[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/ng.912" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21874000">Testa et al. (2011)</a> identified a heterozygous germline 4-bp deletion (2008delTCAC) in exon 14 of the BAP1 gene, resulting in a frameshift and truncation upstream of the BAP1 nuclear localization signal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21874000" 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">rs387906849 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906849;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=rs387906849" 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=rs387906849" 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=RCV000023240 OR RCV001027030" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023240, RCV001027030" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023240...</a>
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<p>In affected members of a family with tumor predisposition syndrome-1 (TPDS1; <a href="/entry/614327">614327</a>), <a href="#1" class="mim-tip-reference" title="Abdel-Rahman, M. H., Pilarski, R., Cebulla, C. M., Massengill, J. B., Christopher, B. N., Boru, G., Hovland, P., Davidorf, F. H. <strong>Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.</strong> J. Med. Genet. 48: 856-859, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21941004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21941004</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21941004[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21941004">Abdel-Rahman et al. (2011)</a> identified a heterozygous 799C-T transition in the BAP1 gene, resulting in a gln267-to-ter (Q267X) substitution proximal to the nuclear localization region. The mutation was not found in 1,000 genomes. The proband was ascertained due to the onset of uveal melanoma at age 52 years, and she also had lung adenocarcinoma. Three additional living family members with cancer also carried the mutation: 1 had cutaneous melanoma, 1 had meningioma, and 1 had uveal melanoma and neuroendocrine carcinoma. There were 2 deceased obligate carriers, who had a history of abdominal adenocarcinoma, likely ovarian, and mesothelioma, respectively. One additional mutation carrier was cancer-free at age 55 years. Tumor tissue from lung adenocarcinoma, meningioma, and uveal melanoma of 3 patients all showed somatic loss of heterozygosity for the BAP1 gene, and all had decreased BAP1 nuclear expression using immunohistochemical studies. The findings were consistent with biallelic inactivation of the BAP1 gene. <a href="#1" class="mim-tip-reference" title="Abdel-Rahman, M. H., Pilarski, R., Cebulla, C. M., Massengill, J. B., Christopher, B. N., Boru, G., Hovland, P., Davidorf, F. H. <strong>Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.</strong> J. Med. Genet. 48: 856-859, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21941004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21941004</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21941004[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21941004">Abdel-Rahman et al. (2011)</a> concluded that this family had a hereditary cancer predisposition syndrome that increases the risk of several different types of tumors. The proband in this family was the only 1 of 53 unrelated patients with uveal melanoma and evidence of a familial cancer syndrome screened for BAP1 mutations who was found to carry a mutation, suggesting that is it a rare cause of hereditary uveal melanoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21941004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 TUMOR PREDISPOSITION SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs375129361 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs375129361;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/rs375129361?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=rs375129361" 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=rs375129361" 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=RCV000049290 OR RCV002433548" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049290, RCV002433548" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049290...</a>
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<p>In affected members of a family with tumor predisposition syndrome-1 (TPDS1; <a href="/entry/614327">614327</a>) characterized mainly by the development of renal cell carcinoma, <a href="#14" class="mim-tip-reference" title="Popova, T., Hebert, L., Jacquemin, V., Gad, S., Caux-Moncoutier, V., Dubois-d'Enghien, C., Richaudeau, B., Renaudin, X., Sellers, J., Nicolas, A., Sastre-Garau, X., Desjardins, L., and 22 others. <strong>Germline BAP1 mutations predispose to renal cell carcinomas.</strong> Am. J. Hum. Genet. 92: 974-980, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23684012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23684012</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23684012[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.2013.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23684012">Popova et al. (2013)</a> identified a heterozygous c.277A-G transition in the BAP1 gene, predicted to result in a thr93-to-ala (T93A) substitution at a conserved residue close to the active site of the ubiquitin domain. The mutation also created a new splice acceptor site within exon 5, and patient cells showed 2 transcripts: c.256_277del, resulting in premature termination (Ile87MetfsTer4) (80% of transcripts) and the missense mutation T93A (20% of transcripts). Three renal cell carcinomas from this family showed loss of heterozygosity for BAP1, consistent with the 2-hit hypothesis of cancer development. The mutation was identified using a combination of whole-exome sequencing and tumor profiling, and was confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23684012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 TUMOR PREDISPOSITION SYNDROME 1</strong>
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BAP1, 1-BP DEL, 1654G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397509414 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509414;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=rs397509414" 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=rs397509414" 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=RCV000049291" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049291" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049291</a>
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<p>In 2 affected members of a family with tumor predisposition syndrome-1 (TPDS; <a href="/entry/614327">614327</a>) characterized mainly by uveal melanoma and mesothelioma, <a href="#14" class="mim-tip-reference" title="Popova, T., Hebert, L., Jacquemin, V., Gad, S., Caux-Moncoutier, V., Dubois-d'Enghien, C., Richaudeau, B., Renaudin, X., Sellers, J., Nicolas, A., Sastre-Garau, X., Desjardins, L., and 22 others. <strong>Germline BAP1 mutations predispose to renal cell carcinomas.</strong> Am. J. Hum. Genet. 92: 974-980, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23684012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23684012</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23684012[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.2013.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23684012">Popova et al. (2013)</a> identified a heterozygous 1-bp deletion (c.1654delG) in the BAP1 gene, resulting in a frameshift and premature termination (Asp552IlefsTer19). One obligate mutation carrier had a renal cell carcinoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23684012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<strong>.0010 TUMOR PREDISPOSITION SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397509413 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509413;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=rs397509413" 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=rs397509413" 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=RCV000049289" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000049289" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000049289</a>
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<p>In 2 sibs with tumor predisposition syndrome-1 (TPDS1; <a href="/entry/614327">614327</a>) characterized by renal cell carcinoma, mesothelioma, lung cancer, and cutaneous melanoma, <a href="#14" class="mim-tip-reference" title="Popova, T., Hebert, L., Jacquemin, V., Gad, S., Caux-Moncoutier, V., Dubois-d'Enghien, C., Richaudeau, B., Renaudin, X., Sellers, J., Nicolas, A., Sastre-Garau, X., Desjardins, L., and 22 others. <strong>Germline BAP1 mutations predispose to renal cell carcinomas.</strong> Am. J. Hum. Genet. 92: 974-980, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23684012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23684012</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23684012[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.2013.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23684012">Popova et al. (2013)</a> identified a heterozygous 2-bp deletion (c.78_79delGG) in the BAP1 gene, resulting in a frameshift and premature termination (Val27AlafsTer41). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23684012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<strong>.0011 KURY-ISIDOR SYNDROME</strong>
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BAP1, PRO12THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2153228682 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2153228682;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=rs2153228682" 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=rs2153228682" 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=RCV001374940 OR RCV001839042" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001374940, RCV001839042" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001374940...</a>
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<p>In a 10-year-old girl (patient 1) with Kury-Isidor syndrome (KURIS; <a href="/entry/619762">619762</a>), <a href="#11" class="mim-tip-reference" title="Kury, S., Ebstein, F., Molle, A., Besnard, T., Lee, M.-K., Vignard, V., Hery, T., Nizon, M., Mancini, G. M. S., Giltay, J. C., Cogne, B., McWalter, K., and 47 others. <strong>Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.</strong> Am. J. Hum. Genet. 109: 361-372, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35051358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35051358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35051358[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.2021.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35051358">Kury et al. (2022)</a> identified a de novo heterozygous c.34C-A transversion (c.34C-A, NM_004656.3) in the BAP1 gene, resulting in a pro12-to-thr (P12T) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the P12T variant was unable to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. The mutation was also unable to rescue the expression of BAP1 target genes TMSB4X (<a href="/entry/300159">300159</a>) and S100A11 (<a href="/entry/603114">603114</a>) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect. T cells derived from the patient carrying the P12T mutation showed that steady-state levels of ubiquitinated H2A were substantially increased compared to controls, again consistent with a loss-of-function effect on BAP1 deubiquitination activity. The patient walked at 18 months of age and had early speech delay, but later had good conversation. She had 3 febrile seizures as an infant; brain imaging was normal. She also had behavioral abnormalities and was noted to be emotional, sensitive, and have poor attention. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35051358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 KURY-ISIDOR SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2153228682 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2153228682;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=rs2153228682" 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=rs2153228682" 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=RCV001776248 OR RCV001797183 OR RCV001839045" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001776248, RCV001797183, RCV001839045" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001776248...</a>
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<p>In a 3-year-old boy (patient 2) with Kury-Isidor syndrome (KURIS; <a href="/entry/619762">619762</a>), <a href="#11" class="mim-tip-reference" title="Kury, S., Ebstein, F., Molle, A., Besnard, T., Lee, M.-K., Vignard, V., Hery, T., Nizon, M., Mancini, G. M. S., Giltay, J. C., Cogne, B., McWalter, K., and 47 others. <strong>Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.</strong> Am. J. Hum. Genet. 109: 361-372, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35051358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35051358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35051358[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.2021.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35051358">Kury et al. (2022)</a> identified a de novo heterozygous c.34C-G transversion (c.34C-G, NM_004656.3) in the BAP1 gene, resulting in a pro12-to-ala (P12A) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the P12A variant was able to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. However, the mutation was unable to rescue the expression of BAP1 target genes TMSB4X (<a href="/entry/300159">300159</a>) and S100A11 (<a href="/entry/603114">603114</a>) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect on BAP1 deubiquitination activity. The patient had delayed walking at age 19 months, speech delay, and autistic features. Other features included frontal bossing, finger syndactyly, astigmatism, bicuspid aortic valve, and recurrent ear infections. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35051358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 KURY-ISIDOR SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1705222655 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1705222655;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=rs1705222655" 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=rs1705222655" 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=RCV001269477 OR RCV001797164 OR RCV001836979 OR RCV001839038 OR RCV002480883 OR RCV003985491" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001269477, RCV001797164, RCV001836979, RCV001839038, RCV002480883, RCV003985491" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001269477...</a>
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<p>In 2 unrelated children (patients 7 and 8) with Kury-Isidor syndrome (KURIS; <a href="/entry/619762">619762</a>), <a href="#11" class="mim-tip-reference" title="Kury, S., Ebstein, F., Molle, A., Besnard, T., Lee, M.-K., Vignard, V., Hery, T., Nizon, M., Mancini, G. M. S., Giltay, J. C., Cogne, B., McWalter, K., and 47 others. <strong>Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.</strong> Am. J. Hum. Genet. 109: 361-372, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35051358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35051358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35051358[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.2021.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35051358">Kury et al. (2022)</a> identified a de novo heterozygous c.271T-C transition (c.271T-C, NM_004656.3) in the BAP1 gene, resulting in a cys91-to-arg (C91R) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the variant was unable to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. The mutation was also unable to rescue the expression of BAP1 target genes TMSB4X (<a href="/entry/300159">300159</a>) and S100A11 (<a href="/entry/603114">603114</a>) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect on BAP1 deubiquitination activity. Patient 7 was a 2-year-old boy with walking at age 17 months and mild speech delay. The pregnancy was complicated by polyhydramnios and cystic hygroma. He had coarse facial features with mild dysmorphism. Patient 8 was a 4-year-old girl with delayed walking, poor speech, hypotonia, behavioral problems, and dysmorphic facies. She also had ocular abnormalities, including exudative vitreoretinopathy and high myopia. In addition to the BAP1 variant, patient 8 carried a truncating R731X variant in the CTNNA1 gene (<a href="/entry/116805">116805</a>) that was maternally inherited. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35051358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 KURY-ISIDOR SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2153227828 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2153227828;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=rs2153227828" 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=rs2153227828" 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=RCV001776249 OR RCV001797189 OR RCV001839046 OR RCV003642960" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001776249, RCV001797189, RCV001839046, RCV003642960" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001776249...</a>
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<p>In 2 unrelated patients (patients 9 and 10) with Kury-Isidor syndrome (KURIS; <a href="/entry/619762">619762</a>), <a href="#11" class="mim-tip-reference" title="Kury, S., Ebstein, F., Molle, A., Besnard, T., Lee, M.-K., Vignard, V., Hery, T., Nizon, M., Mancini, G. M. S., Giltay, J. C., Cogne, B., McWalter, K., and 47 others. <strong>Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.</strong> Am. J. Hum. Genet. 109: 361-372, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35051358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35051358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35051358[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.2021.12.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35051358">Kury et al. (2022)</a> identified a de novo heterozygous c.506A-G transition (c.506A-G, NM_004656.3) in the BAP1 gene, resulting in a his169-to-arg (H169R) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the variant was unable to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. The mutation was also unable to rescue the expression of BAP1 target genes TMSB4X (<a href="/entry/300159">300159</a>) and S100A11 (<a href="/entry/603114">603114</a>) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect on BAP1 deubiquitination activity. Patient 9 was a 16-year-old boy with mild developmental delay, behavioral problems noted as sensitivity, seizures, distal skeletal anomalies, and patchy alopecia. He also carried biallelic variants in the NCSTN gene (<a href="/entry/605254">605254</a>). Patient 10 was an 8-year-old girl with mild global developmental delay, poor speech, a history of seizures, behavioral abnormalities, and mild dysmorphic features. She carried a mitochondrial variant of uncertain significance that showed low (2%) heteroplasmy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35051358" 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>Tumor Predisposition Syndrome 1</em></strong></p><p>
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In 6 affected members of a large kindred (K4) of European origin with tumor predisposition syndrome-1 (TPDS1; <a href="/entry/614327">614327</a>), <a href="#4" class="mim-tip-reference" title="Carbone, M., Flores, E. G., Emi, M., Johnson, T. A., Tsunoda, T., Behner, D., Hoffman, H., Hesdorffer, M., Nasu, M., Napolitano, A., Powers, A., Minaai, M., and 10 others. <strong>Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s.</strong> PLoS Genet. 11: e1005633, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26683624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26683624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26683624[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.1005633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26683624">Carbone et al. (2015)</a> identified a heterozygous germline 1-bp deletion (c.1717delC) in exon 13 of the BAP1 gene, resulting in a frameshift and premature termination (Leu573fsTer3). The mutation, which was found by exome sequencing and confirmed, segregated with the disorder in the family in those who were genotyped. The mutant protein was predicted to lack the nuclear localization signal, and immunohistochemical studies of mesothelioma tissue showed lack of nuclear BAP1 staining with only cytoplasmic localization. Somatic loss of heterozygosity of the BAP1 gene was confirmed in available tumor tissue. These findings were consistent with BAP1 being a tumor suppressor gene. Multiple family members spanning at least 6 generations showed various types of cancer, including malignant mesothelioma, uveal melanoma, basal cell carcinoma, leiomyosarcoma, renal cell carcinoma, and cutaneous melanoma. One mutation carrier had breast cancer. There was high penetrance of cancer manifestation by age 55 years. <a href="#4" class="mim-tip-reference" title="Carbone, M., Flores, E. G., Emi, M., Johnson, T. A., Tsunoda, T., Behner, D., Hoffman, H., Hesdorffer, M., Nasu, M., Napolitano, A., Powers, A., Minaai, M., and 10 others. <strong>Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s.</strong> PLoS Genet. 11: e1005633, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26683624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26683624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26683624[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.1005633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26683624">Carbone et al. (2015)</a> emphasized the importance of identifying mutation carriers in this family who can then be monitored for malignant mesothelioma or other cancers, because early detection and diagnosis can lead to effective treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26683624" 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>Melanoma, Uveal, Susceptibility to, 2</em></strong></p><p>
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In a 48-year-old Caucasian man (patient 1) with bilateral uveal melanoma-2 (UVM2; <a href="/entry/606661">606661</a>), <a href="#18" class="mim-tip-reference" title="Yu, M. D., Masoomian, B., Shields, J. A., Shields, C. L. <strong>BAP1 germline mutation associated with bilateral primary uveal melanoma.</strong> Ocul. Oncol. Path. 6: 10-14, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32002398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32002398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32002398[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/10.1159/000499570" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32002398">Yu et al. (2020)</a> identified a germline heterozygous c.1717delC mutation in the BAP1 gene. Functional studies of the variant were not performed. Cytogenetic profile of tumor tissue showed somatic disomy of chromosomes 3, 6, and 8. Family history was significant for ovarian and bladder cancer in his mother and pancreatic cancer in his maternal great-grandfather, although familial genetic segregation studies were not conducted. The patient did not have other tumors or systemic metastasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32002398" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 MELANOMA, UVEAL, SUSCEPTIBILITY TO, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397509413 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397509413;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=rs397509413" 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=rs397509413" 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=RCV001216166 OR RCV002273840 OR RCV002418740 OR RCV004697073" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001216166, RCV002273840, RCV002418740, RCV004697073" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001216166...</a>
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<p>In a 54-year-old Caucasian man (patient 2) with uveal melanoma-2 (UVM2; <a href="/entry/606661">606661</a>), <a href="#18" class="mim-tip-reference" title="Yu, M. D., Masoomian, B., Shields, J. A., Shields, C. L. <strong>BAP1 germline mutation associated with bilateral primary uveal melanoma.</strong> Ocul. Oncol. Path. 6: 10-14, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32002398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32002398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32002398[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/10.1159/000499570" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32002398">Yu et al. (2020)</a> identified a germline heterozygous 1-bp deletion (c.79delG) in exon 3 of the BAP1 gene, predicted to result in a frameshift and premature termination. Functional studies of the variant and familial segregation studies were not performed. The patient had enucleation of 1 eye due to uveal melanoma and later was found to have a melanoma in the ciliary body of the other eye. There was no evidence of systemic metastasis. Cytogenetic profile of the tumor tissue showed somatic chromosome 3 monosomy, chromosome 6 disomy, and chromosome 8q amplification. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32002398" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Abdel-Rahman2011" class="mim-anchor"></a>
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Abdel-Rahman, M. H., Pilarski, R., Cebulla, C. M., Massengill, J. B., Christopher, B. N., Boru, G., Hovland, P., Davidorf, F. H.
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<strong>Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.</strong>
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J. Med. Genet. 48: 856-859, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21941004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21941004</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21941004[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=21941004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2011-100156" target="_blank">Full Text</a>]
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Bononi, A., Giorgi, C., Patergnani, S., Larson, D., Verbruggen, K., Tanji, M., Pellegrini, L., Signorato, V., Olivetto, F., Pastorino, S., Nasu, M., Napolitano, A., and 13 others.
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<strong>BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation.</strong>
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Nature 546: 549-553, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28614305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28614305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28614305[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=28614305" 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/nature22798" target="_blank">Full Text</a>]
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Bott, M., Brevet, M., Taylor, B. S., Shimizu, S., Ito, T., Wang, L., Creaney, J., Lake, R. A., Zakowski, M. F., Reva, B., Sander, C., Delsite, R., Powell, S., Zhou, Q., Shen, R., Olshen, A., Rusch, V., Ladanyi, M.
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<strong>The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.</strong>
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Nature Genet. 43: 668-672, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21642991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21642991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21642991[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=21642991" 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/ng.855" target="_blank">Full Text</a>]
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Carbone, M., Flores, E. G., Emi, M., Johnson, T. A., Tsunoda, T., Behner, D., Hoffman, H., Hesdorffer, M., Nasu, M., Napolitano, A., Powers, A., Minaai, M., and 10 others.
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<strong>Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s.</strong>
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PLoS Genet. 11: e1005633, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26683624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26683624</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26683624[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=26683624" 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.1005633" target="_blank">Full Text</a>]
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Chan-on, W., Nairismagi, M.-L., Ong, C. K., Lim, W. K., Dima, S., Pairojkul, C., Lim, K. H., McPherson, J. R., Cutcutache, I., Heng, H. L., Ooi, L., Chung, A., and 27 others.
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<strong>Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers.</strong>
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Nature Genet. 45: 1474-1478, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24185513/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24185513</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24185513" 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/ng.2806" target="_blank">Full Text</a>]
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<a id="Dey2012" class="mim-anchor"></a>
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Dey, A., Seshasayee, D., Noubade, R., French, D. M., Liu, J., Chaurushiya, M. S., Kirkpatrick, D. S., Pham. V. C., Lill, J. R., Bakalarski, C. E., Wu, J., Phu, L., and 15 others.
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<strong>Loss of the tumor suppressor BAP1 causes myeloid transformation.</strong>
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Science 337: 1541-1546, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22878500/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22878500</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22878500[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=22878500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1221711" target="_blank">Full Text</a>]
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Harbour, J. W., Onken, M. D., Roberson, E. D. O., Duan, S., Cao, L., Worley, L. A., Council, M. L., Matatall, K. A., Helms, C., Bowcock, A. M.
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<strong>Frequent mutation of BAP1 in metastasizing uveal melanomas.</strong>
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Science 330: 1410-1413, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21051595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21051595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21051595[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=21051595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1194472" target="_blank">Full Text</a>]
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<a id="He2019" class="mim-anchor"></a>
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He, M., Chaurushiya, M. S., Webster, J. D., Kummerfeld, S., Reja, R., Chaudhuri, S., Chen, Y.-J., Modrusan, Z., Haley, B., Dugger, D. L., Eastham-Anderson, J., Lau, S., Dey, A., Caothien, R., Roose-Girma, M., Newton, K., Dixit, V. M.
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<strong>Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1.</strong>
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Science 364: 283-285, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31000662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31000662</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31000662" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aav4902" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Jensen1998" class="mim-anchor"></a>
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<div class="">
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Jensen, D. E., Proctor, M., Marquis, S. T., Gardner, H. P., Ha, S. I., Chodosh, L. A., Ishov, A. M., Tommerup, N., Vissing, H., Sekido, Y., Minna, J., Borodovsky, A., Schultz, D. C., Wilkinson, K. D., Maul, G. G., Barlev, N., Berger, S. L., Prendergast, G. C., Rauscher, F. J., III.
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<strong>BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.</strong>
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Oncogene 16: 1097-1112, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9528852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9528852</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9528852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.onc.1201861" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Jiao2013" class="mim-anchor"></a>
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<div class="">
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Jiao, Y., Pawlik, T. M., Anders, R. A., Selaru, F. M., Streppel, M. M., Lucas, D. J., Niknafs, N., Guthrie, V. B., Maitra, A., Argani, P., Offerhaus, G. J. A., Roa, J. C., and 24 others.
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<strong>Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.</strong>
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Nature Genet. 45: 1470-1473, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24185509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24185509</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24185509" 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/ng.2813" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Kury2022" class="mim-anchor"></a>
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<div class="">
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Kury, S., Ebstein, F., Molle, A., Besnard, T., Lee, M.-K., Vignard, V., Hery, T., Nizon, M., Mancini, G. M. S., Giltay, J. C., Cogne, B., McWalter, K., and 47 others.
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<strong>Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.</strong>
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Am. J. Hum. Genet. 109: 361-372, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35051358/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35051358</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35051358[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=35051358" 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.2021.12.011" target="_blank">Full Text</a>]
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<a id="Nagase1996" class="mim-anchor"></a>
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Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N.
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<strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong>
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DNA Res. 3: 321-329, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9039502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9039502</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9039502" 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/3.5.321" target="_blank">Full Text</a>]
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<a id="Pena-Llopis2012" class="mim-anchor"></a>
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<div class="">
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Pena-Llopis, S., Vega-Rubin-de-Celis, S., Liao, A., Leng, N., Pavia-Jimenez, A., Wang, S., Yamasaki, T., Zhrebker, L., Sivanand, S., Spence, P., Kinch, L., Hambuch, T., and 15 others.
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<strong>BAP1 loss defines a new class of renal cell carcinoma.</strong>
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Nature Genet. 44: 751-759, 2012. Note: Erratum: Nature Genet. 44: 1072 only, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22683710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22683710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22683710[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=22683710" 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/ng.2323" target="_blank">Full Text</a>]
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<a id="Popova2013" class="mim-anchor"></a>
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Popova, T., Hebert, L., Jacquemin, V., Gad, S., Caux-Moncoutier, V., Dubois-d'Enghien, C., Richaudeau, B., Renaudin, X., Sellers, J., Nicolas, A., Sastre-Garau, X., Desjardins, L., and 22 others.
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<strong>Germline BAP1 mutations predispose to renal cell carcinomas.</strong>
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Am. J. Hum. Genet. 92: 974-980, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23684012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23684012</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23684012[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=23684012" 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.2013.04.012" target="_blank">Full Text</a>]
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<a id="15" class="mim-anchor"></a>
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<a id="Testa2011" class="mim-anchor"></a>
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Testa, J. R., Cheung, M., Pei, J., Below, J. E., Tan, Y., Sementino, E., Cox, N. J., Dogan, A. U., Pass, H. I., Trusa, S., Hesdorffer, M., Nasu, M., Powers, A., Rivera, Z., Comertpay, S., Tanji, M., Gaudino, G., Yang, H., Carbone, M.
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<strong>Germline BAP1 mutations predispose to malignant mesothelioma. (Letter)</strong>
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Nature Genet. 43: 1022-1025, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21874000/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21874000</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21874000[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=21874000" 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/ng.912" target="_blank">Full Text</a>]
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<a id="16" class="mim-anchor"></a>
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<a id="Wiesner2011" class="mim-anchor"></a>
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Wiesner, T., Obenauf, A. C., Murali, R., Fried, I., Griewank, K. G., Ulz, P., Windpassinger, C., Wackernagel, W., Loy, S., Wolf, I., Viale, A., Lash, A. E., and 12 others.
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<strong>Germline mutations in BAP1 predispose to melanocytic tumors. (Letter)</strong>
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Nature Genet. 43: 1018-1021, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21874003/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21874003</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21874003[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=21874003" 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/ng.910" target="_blank">Full Text</a>]
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<a id="Xiong2020" class="mim-anchor"></a>
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Xiong, Z., Xia, P., Zhu, X., Geng, J., Wang, S., Ye, B., Qin, X., Qu, Y., He, L., Fan, D., Du, Y., Tian, Y., Fan, Z.
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<strong>Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis.</strong>
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J. Exp. Med. 217: e20190974, 2020. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31699823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31699823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31699823[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=31699823" 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/10.1084/jem.20190974" target="_blank">Full Text</a>]
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<a id="Yu2020" class="mim-anchor"></a>
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Yu, M. D., Masoomian, B., Shields, J. A., Shields, C. L.
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<strong>BAP1 germline mutation associated with bilateral primary uveal melanoma.</strong>
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Ocul. Oncol. Path. 6: 10-14, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32002398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32002398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32002398[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=32002398" 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/10.1159/000499570" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 07/29/2022
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Cassandra L. Kniffin - updated : 02/23/2022<br>Bao Lige - updated : 03/16/2020<br>Ada Hamosh - updated : 10/09/2019<br>Ada Hamosh - updated : 04/04/2018<br>Ada Hamosh - updated : 01/28/2014<br>Cassandra L. Kniffin - updated : 7/9/2013<br>Ada Hamosh - updated : 11/1/2012<br>Cassandra L. Kniffin - updated : 7/25/2012<br>Cassandra L. Kniffin - updated : 11/3/2011<br>Cassandra L. Kniffin - updated : 8/8/2011<br>Ada Hamosh - updated : 12/28/2010
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Rebekah S. Rasooly : 10/5/1998
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carol : 08/04/2022<br>ckniffin : 07/29/2022<br>alopez : 02/24/2022<br>ckniffin : 02/23/2022<br>mgross : 03/16/2020<br>carol : 10/10/2019<br>alopez : 10/09/2019<br>alopez : 04/04/2018<br>alopez : 01/28/2014<br>carol : 9/13/2013<br>tpirozzi : 7/11/2013<br>tpirozzi : 7/10/2013<br>ckniffin : 7/9/2013<br>alopez : 11/2/2012<br>terry : 11/1/2012<br>carol : 9/14/2012<br>carol : 7/25/2012<br>ckniffin : 7/25/2012<br>terry : 7/5/2012<br>carol : 11/9/2011<br>ckniffin : 11/8/2011<br>ckniffin : 11/3/2011<br>wwang : 8/12/2011<br>ckniffin : 8/8/2011<br>alopez : 1/5/2011<br>alopez : 1/3/2011<br>terry : 12/28/2010<br>carol : 12/26/2000<br>alopez : 10/5/1998
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BRCA1-ASSOCIATED PROTEIN 1; BAP1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: BAP1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 3p21.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:52,401,008-52,410,008 </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="3">
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<span class="mim-font">
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3p21.1
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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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{Uveal melanoma, susceptibility to, 2}
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</span>
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</td>
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<td>
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<span class="mim-font">
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606661
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Kury-Isidor syndrome
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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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619762
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Tumor predisposition syndrome 1
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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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614327
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</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>BAP1 encodes a nuclear ubiquitin carboxy-terminal hydrolase (UCH), one of several classes of deubiquitinating enzymes. BAP1 contains binding domains for BRCA1 (113705) and BARD1 (601593), which form a tumor suppressor heterodimeric complex, and HCFC1 (300019), which interacts with histone-modifying complexes during cell division. BAP1 also interacts with ASXL1 (612990) to form the Polycomb group repressive deubiquitinase complex (PR-DUB), which is involved in stem cell pluripotency and other developmental processes (summary by Harbour et al., 2010). </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>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Nagase et al. (1996) isolated a BAP1 cDNA, designated KIAA0272. </p><p>Jensen et al. (1998) carried out a yeast 2-hybrid screen to identify proteins that interact with the RING finger domain of BRCA1 (113705). They recovered mouse embryo and human adult B-cell cDNAs encoding a protein that they designated 'BRCA1-associated protein-1,' or BAP1. The N-terminal 240 amino acids of the predicted 729-amino acid human protein show homology to ubiquitin C-terminal hydrolases (UCHs; see UCHL3, 603090), thiol proteases that catalyze proteolytic processing of ubiquitin. In addition, BAP1 contains an acidic region, a highly charged C-terminal region, and 2 putative nuclear localization signals. Recombinant BAP1 had UCH activity in vitro. By coimmunoprecipitation and immunofluorescence studies, Jensen et al. (1998) demonstrated that BAP1 and BRCA1 associate in vivo and have overlapping subnuclear localization patterns. However, BAP1 failed to bind to BRCA1 proteins with germline mutations of the RING finger domain found in breast cancer kindreds. BAP1 enhances BRCA1-mediated inhibition of breast cancer cell growth. Northern blot analysis indicated that BAP1 is expressed as a 4-kb mRNA in all human tissues. An additional 4.8-kb transcript is present in testis. Northern blot analysis and in situ hybridization revealed that BAP1 and BRCA1 are temporally and spatially coexpressed during murine breast development and remodeling. </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. (1996) mapped the BAP1 gene to chromosome 3 by analysis of radiation hybrids. </p><p>By fluorescence in situ hybridization, Jensen et al. (1998) mapped the BAP1 gene to 3p21.3, a region of loss of heterozygosity for breast cancer as well as a region frequently deleted in lung carcinomas. </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>Jensen et al. (1998) found intragenic homozygous rearrangements and deletions of BAP1 in lung carcinoma cell lines. They proposed that BAP1 is a tumor suppressor gene that functions in the BRCA1 growth control pathway. </p><p>Dey et al. (2012) showed that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (614286). Analysis of knockin mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with host cell factor-1 (HCF1; 300019), O-linked N-acetylglucosamine transferase (OGT; 300255), and the polycomb group proteins ASXL1 and ASXL2 (612991) in vivo. OGT and HCF1 levels were decreased by BAP1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML; 607785), so an ASXL/BAP1 complex may suppress CMML. </p><p>Bononi et al. (2017) discovered that BAP1 localizes at the endoplasmic reticulum. There, it binds, deubiquitylates, and stabilizes type 3 inositol-1,4,5-trisphosphate receptor (IP3R3; 147267), modulating calcium release from the endoplasmic reticulum into the cytosol and mitochondria, promoting apoptosis. Reduced levels of BAP1 in BAP1 +/- carriers cause reduction both of IP3R3 levels and of Ca(2+) flux, preventing BAP1 +/- cells that accumulate DNA damage from executing apoptosis. A higher fraction of cells exposed to either ionizing or ultraviolet radiation, or to asbestos, survive genotoxic stress, resulting in a higher rate of cellular transformation. Bononi et al. (2017) proposed that the high incidence of cancers in BAP1 +/- carriers results from the combined reduced nuclear and cytoplasmic activities of BAP1. Bononi et al. (2017) concluded that their data provided a mechanistic rationale for the powerful ability of BAP1 to regulate gene-environment interaction in human carcinogenesis. </p><p>He et al. (2019) showed that Bap1 inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver, and pancreatic tissue but not in melanocytes and mesothelial cells. Ubiquitin ligase Rnf2 (608985), which silences genes by monoubiquitinating histone H2a (see 613499), promoted apoptosis in Bap1-deficient cells by suppressing expression of the prosurvival genes Bcl2 (151430) and Mcl1 (159552). In contrast, Bap1 loss in melanocytes had little impact on expression of prosurvival genes, instead inducing Mitf (156845). Thus, He et al. (2019) concluded that BAP1 appears to modulate gene expression by countering H2A ubiquitination, but its loss promotes tumorigenesis only in cells that do not engage an RNF2-dependent apoptotic program. </p><p>Xiong et al. (2020) found that Bap1 facilitated expression of Hoxa1 (142955), which was required for self-renewal of mouse hematopoietic stem cells (HSCs). Ttll5 (612268) and Ttll7 (618813) glutamylated Bap1 at glu651 in HSCs, whereas Ccp3 (617346) removed Bap1 glutamylation. Bap1 glutamylation promoted its interaction with Ube2o (617649) and accelerated lys48-linked ubiquitination of Bap1 for its degradation. Degradation of Bap1 suppressed Hoxa1 expression, thereby enhancing HSC self-renewal and hematopoiesis. </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>Molecular Genetics</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><strong><em>Somatic BAP1 Mutations</em></strong></p><p>
|
|
BAP1 exhibits tumor suppressor activity in cancer cells, and BAP1 mutations have been reported in a small number of breast and lung cancer samples. Harbour et al. (2010) used exome capture coupled with massively parallel sequencing to search for metastasis-related mutations in highly metastatic uveal melanomas (see UVM2, 606661). Inactivating somatic mutations were identified in the BAP1 gene on chromosome 3p21.1 in 26 of 31 (84%) metastasizing tumors, including 15 mutations causing premature protein termination and 5 affecting its ubiquitin C-terminal hydrolase domain. One tumor harbored a frameshift mutation that was germline in origin, thus representing a susceptibility allele. Harbour et al. (2010) concluded that their findings implicated loss of BAP1 in uveal melanoma metastasis. </p><p>By studying copy number alterations followed by candidate gene sequencing of 53 primary malignant pleural mesothelioma (156240) samples, Bott et al. (2011) identified the BAP1 gene on chromosome 3p21.1 as a commonly somatically inactivated gene. Twelve (23%) of 53 tumors had nonsynonymous mutations, and 16 (30%) had at least single copy genomic loss of the BAP1 locus. Tumors with mutations showed loss of nuclear staining for BAP1. BAP1 losses were confirmed in an independent collection of MPM tumors. The somatic nature of the mutations was confirmed in all tumors that had matched normal tissue available. Knockdown of BAP1 in mesothelioma cell lines expressing wildtype BAP1 resulted in proliferation defects with an accumulation of cells in S phase and also downregulated E2F (see, e.g., 189971)-responsive genes. Given the known role of BAP1 in regulatory ubiquitination of histones, the findings suggested transcriptional deregulation as a pathogenic mechanism. </p><p>By sequencing of the BAP1 gene in 156 tumors from patients with sporadic melanocytic neoplasms, Wiesner et al. (2011) found somatic mutations in 13 (40%) uveal melanomas, 2 (11%) atypical Spitz tumors, and 3 (5%) cutaneous melanomas (155600). Two of 5 sporadic cutaneous melanomas that arose in nevi harbored BAP1 mutations, and in both cases, the BAP1 mutations were absent in the nevus portion, suggesting that loss of function of BAP1 may have a role in progression from nevus to melanoma in some cases. The 2 atypical Spitz tumors lacked BAP1 expression and harbored a BRAF mutation (V600E; 164757.0001), suggesting that biallelic inactivation of BAP1 is associated with a distinct type of melanocytic neoplasm. Finally, all the uveal melanomas with BAP1 mutations also carried mutations at codon 209 in either GNAQ (600998) or GNA11 (139313). </p><p>Pena-Llopis et al. (2012) provided evidence that BAP1 can act as a tumor suppressor gene in clear cell renal cell carcinoma (ccRCC; see 144700). The authors used whole-genome and exome sequencing of ccRCC as well as analyses of mutant allele ratios of a murine tumorgraft to identify putative 2-hit tumor suppressor genes. BAP1 was found to be somatically mutated in 24 (14%) of 176 tumors, and most mutations were predicted to truncate the protein. In a cell line with a missense BAP1 mutation, expression of wildtype BAP1 repressed cell proliferation without causing apoptosis. In this cell line, the majority of BAP1 cofractionated with and bound to HCFC1. Mutations disrupting the HCFC1 binding motif impaired BAP1-mediated suppression of cell proliferation, but not its deubiquitination of monoubiquitinated histone 2A. BAP1 loss sensitized RCC cells in vitro to genotoxic stress. Although mutations in BAP1 and PBRM1 (606083) anticorrelated in renal cell tumors, the few tumors that had combined loss of BAP1 and PBRM1 were associated with rhabdoid features. Moreover, BAP1 loss was associated with high tumor grade. </p><p>Dey et al. (2012) identified a patient with a somatic frameshift mutation that causes premature termination within the UCH catalytic domain of BAP1. The patient with the somatic BAP1 mutation presented with refractory cytopenias and multilineage dysplasia, similar to the multilineage dysplasia and cytopenias seen in their murine model. No other mutations in known MDS genes were identified. </p><p>Jiao et al. (2013) detected somatic BAP1 mutations in 8 of 32 (25%) intrahepatic cholangiocarcinomas (615619) in a discovery screen and in 5 of 32 (16%) independent intrahepatic cholangiocarcinomas in the prevalence screen. Chan-on et al. (2013) identified somatic BAP1 mutations in 9 of 86 (10.5%) non-O.viverrini cholangiocarcinomas and in 3 of 108 (2.8%) O. viverrini-related cholangiocarcinomas. </p><p><strong><em>Tumor Predisposition Syndrome 1</em></strong></p><p>
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Using array-based comparative genomic hybridization, Wiesner et al. (2011) found loss of chromosome 3p in 50% of skin tumors from 3 affected individuals in a family with tumor predisposition syndrome-1 (TPDS1; 614327), suggesting that this was a second hit resulting in the elimination of the remaining wildtype allele of a mutated tumor suppressor gene in this chromosomal region. Haplotype analysis showed segregation of the maternal allele in affected family members of 2 generations, and sequence analysis of this region identified a heterozygous germline mutation in the BAP1 gene (603089.0001) that segregated with the phenotype. Reexamination of tumor tissue confirmed loss of BAP1 in 29 skin tumors and in a uveal melanoma. Tumors that did not show loss of 3p21 showed loss of BAP1 through additional somatic mechanisms, such as point mutation. Immunohistochemical studies showed loss of BAP1 nuclear expression in the melanocytic neoplasms. Molecular analysis of a second family with a similar phenotype identified a different heterozygous germline mutation in the BAP1 gene (603089.0002). Somatic inactivation of the remaining allele, as determined by loss of heterozygosity (LOH), was found in 9 of 13 skin tumors, in a uveal melanoma, and in a cutaneous melanoma from 1 patient. In addition, 37 (88%) of 42 tumors in both families showed a somatic V600E mutation in the BRAF gene (164757.0001). Notably, the families had a low number of melanomas compared to the number of papular melanocytic tumors, suggesting that the risk of malignant progression in individual tumors from patients with this disorder is low. </p><p>In 2 unrelated families with a tumor predisposition syndrome characterized mainly by the development of asbestos-related malignant mesothelioma, Testa et al. (2011) identified 2 different heterozygous mutations in the BAP1 gene (603089.0003 and 603089.0004, respectively) that segregated with the phenotype. Array-comparative genomic hybridization had found loss of BAP1 at 3p21 in 2 malignant mesothelioma tumors from these families, and subsequent linkage analysis identified an inherited susceptibility locus on chromosome 3p21. Tumor tissue showed loss of BAP1 nuclear expression by immunohistochemistry. The findings were consistent with somatic loss of the second BAP1 allele in tumor tissue. Further analysis of 26 germline DNA samples from patients with sporadic mesothelioma found that 2 carried heterozygous BAP1 deletions (603089.0005 and 603089.0006, respectively). Each of these patients also had a history of uveal melanoma. </p><p>Abdel-Rahman et al. (2011) identified a heterozygous germline mutation in the BAP1 gene (603089.0007) in 1 of 53 probands with uveal melanoma and evidence of a familial cancer syndrome who were screened specifically for BAP1 mutations. In this family, the mutation segregated with various types of cancer, including lung adenocarcinoma, cutaneous melanoma, and meningioma. Tumor tissue showed LOH for the BAP1 gene. </p><p>In affected members of a large family with a tumor predisposition syndrome characterized mainly by renal cell carcinoma (RCC), Popova et al. (2013) identified a heterozygous germline mutation in the BAP1 gene (603089.0008). The mutation was identified using a combination of whole-exome sequencing and tumor profiling, and was confirmed by Sanger sequencing. Three renal cell carcinomas from this family showed loss of heterozygosity for BAP1, consistent with the 2-hit hypothesis of cancer development. Subsequently, sequence analysis identified heterozygous truncating mutations in the BAP1 gene (see, e.g., 603089.0009 and 603089.0010) in 11 (18%) of 60 unrelated families with either uveal melanoma, cutaneous melanoma, or mesothelioma. A total of 33 individuals were diagnosed with these 3 cancers in diverse associations; 14 individuals had other cancers, including renal, lung, breast, prostatic, thyroid, and bladder carcinomas. Nine RCCs were reported in 6 of the 11 families with BAP1 mutations, indicating that RCC should be added to the tumor spectrum of this syndrome. However, no BAP1 mutations were detected in a separate series of 32 French families with renal cell carcinoma, suggesting that germline BAP1 mutations rarely explain families affected only with RCC. </p><p>In 6 affected members of a large multigenerational kindred (K4) of European origin with TPDS1, Carbone et al. (2015) identified a heterozygous germline frameshift mutation in the BAP1 gene (c.1717delC; 603089.0015). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family in those who were genotyped. The mutant protein was predicted to lack the nuclear localization signal, and immunohistochemical studies of mesothelioma tissue showed lack of nuclear BAP1 staining with only cytoplasmic localization. Somatic loss of heterozygosity of the BAP1 gene was confirmed in available tumor tissue. These findings were consistent with BAP1 being a tumor suppressor gene. Carbone et al. (2015) emphasized the importance of identifying mutation carriers in this family who can then be monitored for malignant mesothelioma or other cancers because early detection and diagnosis can lead to effective treatment. </p><p><strong><em>Melanoma, Uveal, Susceptibility to, 2</em></strong></p><p>
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|
In 2 unrelated Caucasian men with bilateral uveal melanoma-2 (UVM2; 606661), Yu et al. (2020) identified germline heterozygous frameshift mutations in the BAP1 gene (603089.0015 and 603089.0016). Functional studies of the variants were not performed. Cytogenetic profile of tumor tissue showed somatic changes affecting chromosomes 3, 6, and 8. Family history in patient 1 was significant for cancer, although familial genetic segregation studies were not conducted in either proband. The patients did not have other tumors or systemic metastasis. </p><p><strong><em>Kury-Isidor Syndrome</em></strong></p><p>
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In 8 unrelated patients (patients 1-4 and 7-10) with Kury-Isidor syndrome (KURIS; 619762), Kury et al. (2022) identified de novo heterozygous missense mutations in the BAP1 gene (see, e.g., 602089.0011-601089.0014). The patients were ascertained through collaborative efforts such as the GeneMatcher Program, and the phenotype was compiled after the variants were identified by exome sequencing. All the mutations occurred at conserved residues in the catalytic ubiquitin C-terminal hydrolase domain; none were present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that some of the variants tested (P12T, 603089.0011; C91R, 603089.0013; and H169R, 603089.0014) were unable to rescue BAP1 activity, as measured by increased BAP1 H2AK119ub substrate levels. Rescue with another variant (P12A; 603089.0012) was similar to controls for that particular substrate. All variants, including P12A, were unable to rescue the expression of BAP1 target genes TMSB4X (300159) and S100A11 (603114) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data suggested that the BAP1 mutations were unable to compensate H2A deubiquitination of substrates in BAP1-null cells, consistent with a loss-of-function effect. Of note, all the BAP1 variants localized properly to the nucleus in transfected cells. T cells derived from 2 patients carrying the P12T and C91S mutations showed that steady-state levels of ubiquitinated H2A were substantially increased compared to controls, again consistent with a loss-of-function effect for BAP1. CHIP-seq analysis indicated that the variants induced genomewide chromatin state alterations in the 2 patient cell lines; there was also some evidence of proteosome perturbation. Kury et al. (2022) concluded that BAP1 missense variants alter chromatin remodeling through abnormal histone ubiquitination, leading to transcriptional dysregulation of developmental genes. None of the patients developed tumors. The authors noted that BAP1 mutations that predispose to tumor syndrome are truncating or splice-site mutations; the missense mutations identified in patients with KURIS are loss-of-function and may disrupt the deubiquitinase activity without altering other protein-protein interactions. Some of the patients, including 3 additional patients (patients 5, 6, and 11) with variable developmental abnormalities associated with de novo missense BAP1 variants identified in the study, had additional genetic variants of uncertain significance that may have contributed to the phenotype. </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">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>16 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">
|
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<strong>.0001 TUMOR PREDISPOSITION SYNDROME 1</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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BAP1, 1-BP DEL, 1305G
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<br />
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SNP: rs587776877,
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ClinVar: RCV000023234
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 affected members of a family with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of melanocytic skin tumors, Wiesner et al. (2011) identified a germline heterozygous 1-bp deletion (1305delG) in exon 13 of the BAP1 gene, resulting in a frameshift. The mutation was found after tumor analysis showed loss of chromosome 3p in 50% of tumors and haplotype analysis showed segregation of a maternal allele in the 3p21 region in affected family members of 2 generations. All 4 had multiple melanocytic tumors, and 1 had a uveal melanoma. Reexamination of tumor tissue confirmed loss of BAP1 in 29 skin tumors and the uveal melanoma. Tumors that did not show loss of 3p21 showed loss of BAP1 through additional somatic mechanisms, such as point mutation. The findings were consistent with germline predisposition to development of the disorder with a second somatic hit in a tumor suppressor gene resulting in tumor development. Immunohistochemical studies showed loss of BAP1 nuclear expression in all the melanocytic neoplasms. Most of the tumors also carried a somatic V600E mutation in the BRAF gene (164757.0001). Notably, none of the patients in this family developed cutaneous melanoma despite the large number of papular melanocytic tumors, suggesting that the risk of malignant progression in individual tumors from patients with this disorder is low. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0002 TUMOR PREDISPOSITION SYNDROME 1</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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BAP1, IVS16AS, -2, A-G
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<br />
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SNP: rs587776878,
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ClinVar: RCV000023235, RCV003162259
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of melanocytic skin tumors, Wiesner et al. (2011) identified a heterozygous A-to-G transition removing the acceptor splice site of the last exon (2057-2A-G). Analysis of cDNA showed that the last intron was not removed by splicing. One mutation carrier developed a uveal melanoma, and 3 developed cutaneous melanoma. Somatic inactivation of the remaining BAP1 allele, as determined by loss of heterozygosity (LOH), was found in 9 of 13 skin tumors, in the 1 uveal melanoma, and in a cutaneous melanoma from 1 patient. A metastatic melanoma from another family member did not show LOH for BAP1, but no additional tissue was available to investigate alternative mechanisms of BAP1 inactivation. In contrast, microscopic examination of common acquired flat nevi showed small uniform melanocytes and strong nuclear expression of BAP1. Most of the tumors also carried a somatic V600E mutation in the BRAF gene (164757.0001). Notably, only 3 patients in this family developed cutaneous melanoma, compared to the number of papular melanocytic tumors, suggesting that the risk of malignant progression in individual tumors from patients with this disorder is low. </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>.0003 TUMOR PREDISPOSITION SYNDROME 1</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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BAP1, IVS6AS, A-G, -2
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<br />
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SNP: rs587776879,
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gnomAD: rs587776879,
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ClinVar: RCV000023236, RCV002326682, RCV003320548
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a 3-generation Wisconsin family with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of malignant mesothelioma, Testa et al. (2011) identified a heterozygous germline A-to-G transition in the splice acceptor site of intron 6 of the BAP1 gene. Transfection of mammalian cells with this mutation resulted in an aberrant splice product lacking exon 8 and a frameshift predicted to result in a premature stop codon and nonsense-mediated decay. Tumor tissue from 3 patients showed complete loss of BAP1, consistent with somatic loss of the wildtype allele, and immunohistochemistry of tumor tissue showed lack of BAP1 nuclear expression. Five mutation carriers developed mesothelioma after household exposure. Among other mutation carriers in the family, 1 each had breast, ovarian, and renal cancer. The mutation was identified after tumor tissue showed loss of BAP1 at 3p21 with subsequent performance of linkage analysis in this family. </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>.0004 TUMOR PREDISPOSITION SYNDROME 1</strong>
|
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</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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BAP1, GLN684TER
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<br />
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SNP: rs387906848,
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|
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gnomAD: rs387906848,
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|
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ClinVar: RCV000023237, RCV000487149, RCV001014205
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a 2-generation family from Louisiana with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of malignant mesothelioma, Testa et al. (2011) identified a heterozygous germline C-to-T transition in exon 16 of the BAP1 gene, resulting in a gln684-to-ter (Q684X) substitution. Immunohistochemistry of tumor tissue showed lack of BAP1 nuclear expression. Six mutation carriers developed mesothelioma after household exposure. Among other mutation carriers in the family, 2 developed skin cancer (squamous cell and basal cell, respectively), and 1 developed pancreatic cancer. Two family members with prostate cancer did not carry the mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 TUMOR PREDISPOSITION SYNDROME 1</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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|
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BAP1, 1-BP DEL, 1832C
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<br />
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SNP: rs869025212,
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ClinVar: RCV000207031, RCV000464745, RCV000567996, RCV001795342, RCV002273820
|
|
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|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with tumor predisposition syndrome-1 (TPDS1; 614327) who developed malignant mesothelioma and a uveal melanoma, Testa et al. (2011) identified a heterozygous germline 1-bp deletion (1832delC) in exon 13 of the BAP1 gene, resulting in a frameshift and truncation upstream of the BAP1 nuclear localization signal. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 TUMOR PREDISPOSITION SYNDROME 1</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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BAP1, 4-BP DEL, 2008TCAC
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<br />
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SNP: rs1559585778,
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|
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|
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ClinVar: RCV000772520, RCV001312026, RCV001850964
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with tumor predisposition syndrome-1 (TPDS1; 614327) who developed malignant mesothelioma and uveal melanoma, Testa et al. (2011) identified a heterozygous germline 4-bp deletion (2008delTCAC) in exon 14 of the BAP1 gene, resulting in a frameshift and truncation upstream of the BAP1 nuclear localization signal. </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>.0007 TUMOR PREDISPOSITION SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BAP1, GLN267TER
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|
<br />
|
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|
|
SNP: rs387906849,
|
|
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|
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|
|
|
ClinVar: RCV000023240, RCV001027030
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with tumor predisposition syndrome-1 (TPDS1; 614327), Abdel-Rahman et al. (2011) identified a heterozygous 799C-T transition in the BAP1 gene, resulting in a gln267-to-ter (Q267X) substitution proximal to the nuclear localization region. The mutation was not found in 1,000 genomes. The proband was ascertained due to the onset of uveal melanoma at age 52 years, and she also had lung adenocarcinoma. Three additional living family members with cancer also carried the mutation: 1 had cutaneous melanoma, 1 had meningioma, and 1 had uveal melanoma and neuroendocrine carcinoma. There were 2 deceased obligate carriers, who had a history of abdominal adenocarcinoma, likely ovarian, and mesothelioma, respectively. One additional mutation carrier was cancer-free at age 55 years. Tumor tissue from lung adenocarcinoma, meningioma, and uveal melanoma of 3 patients all showed somatic loss of heterozygosity for the BAP1 gene, and all had decreased BAP1 nuclear expression using immunohistochemical studies. The findings were consistent with biallelic inactivation of the BAP1 gene. Abdel-Rahman et al. (2011) concluded that this family had a hereditary cancer predisposition syndrome that increases the risk of several different types of tumors. The proband in this family was the only 1 of 53 unrelated patients with uveal melanoma and evidence of a familial cancer syndrome screened for BAP1 mutations who was found to carry a mutation, suggesting that is it a rare cause of hereditary uveal melanoma. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 TUMOR PREDISPOSITION SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BAP1, THR93ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs375129361,
|
|
|
|
|
|
gnomAD: rs375129361,
|
|
|
|
|
|
ClinVar: RCV000049290, RCV002433548
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with tumor predisposition syndrome-1 (TPDS1; 614327) characterized mainly by the development of renal cell carcinoma, Popova et al. (2013) identified a heterozygous c.277A-G transition in the BAP1 gene, predicted to result in a thr93-to-ala (T93A) substitution at a conserved residue close to the active site of the ubiquitin domain. The mutation also created a new splice acceptor site within exon 5, and patient cells showed 2 transcripts: c.256_277del, resulting in premature termination (Ile87MetfsTer4) (80% of transcripts) and the missense mutation T93A (20% of transcripts). Three renal cell carcinomas from this family showed loss of heterozygosity for BAP1, consistent with the 2-hit hypothesis of cancer development. The mutation was identified using a combination of whole-exome sequencing and tumor profiling, and was confirmed by Sanger sequencing. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 TUMOR PREDISPOSITION SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BAP1, 1-BP DEL, 1654G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397509414,
|
|
|
|
|
|
|
|
ClinVar: RCV000049291
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 affected members of a family with tumor predisposition syndrome-1 (TPDS; 614327) characterized mainly by uveal melanoma and mesothelioma, Popova et al. (2013) identified a heterozygous 1-bp deletion (c.1654delG) in the BAP1 gene, resulting in a frameshift and premature termination (Asp552IlefsTer19). One obligate mutation carrier had a renal cell carcinoma. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 TUMOR PREDISPOSITION SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BAP1, 2-BP DEL, 78GG
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs397509413,
|
|
|
|
|
|
|
|
ClinVar: RCV000049289
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with tumor predisposition syndrome-1 (TPDS1; 614327) characterized by renal cell carcinoma, mesothelioma, lung cancer, and cutaneous melanoma, Popova et al. (2013) identified a heterozygous 2-bp deletion (c.78_79delGG) in the BAP1 gene, resulting in a frameshift and premature termination (Val27AlafsTer41). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 KURY-ISIDOR SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BAP1, PRO12THR
|
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|
|
<br />
|
|
|
|
SNP: rs2153228682,
|
|
|
|
|
|
|
|
ClinVar: RCV001374940, RCV001839042
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 10-year-old girl (patient 1) with Kury-Isidor syndrome (KURIS; 619762), Kury et al. (2022) identified a de novo heterozygous c.34C-A transversion (c.34C-A, NM_004656.3) in the BAP1 gene, resulting in a pro12-to-thr (P12T) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the P12T variant was unable to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. The mutation was also unable to rescue the expression of BAP1 target genes TMSB4X (300159) and S100A11 (603114) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect. T cells derived from the patient carrying the P12T mutation showed that steady-state levels of ubiquitinated H2A were substantially increased compared to controls, again consistent with a loss-of-function effect on BAP1 deubiquitination activity. The patient walked at 18 months of age and had early speech delay, but later had good conversation. She had 3 febrile seizures as an infant; brain imaging was normal. She also had behavioral abnormalities and was noted to be emotional, sensitive, and have poor attention. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<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>.0012 KURY-ISIDOR SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BAP1, PRO12ALA
|
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|
|
|
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<br />
|
|
|
|
SNP: rs2153228682,
|
|
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|
|
|
|
|
ClinVar: RCV001776248, RCV001797183, RCV001839045
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old boy (patient 2) with Kury-Isidor syndrome (KURIS; 619762), Kury et al. (2022) identified a de novo heterozygous c.34C-G transversion (c.34C-G, NM_004656.3) in the BAP1 gene, resulting in a pro12-to-ala (P12A) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the P12A variant was able to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. However, the mutation was unable to rescue the expression of BAP1 target genes TMSB4X (300159) and S100A11 (603114) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect on BAP1 deubiquitination activity. The patient had delayed walking at age 19 months, speech delay, and autistic features. Other features included frontal bossing, finger syndactyly, astigmatism, bicuspid aortic valve, and recurrent ear infections. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 KURY-ISIDOR SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BAP1, CYS91ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1705222655,
|
|
|
|
|
|
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ClinVar: RCV001269477, RCV001797164, RCV001836979, RCV001839038, RCV002480883, RCV003985491
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated children (patients 7 and 8) with Kury-Isidor syndrome (KURIS; 619762), Kury et al. (2022) identified a de novo heterozygous c.271T-C transition (c.271T-C, NM_004656.3) in the BAP1 gene, resulting in a cys91-to-arg (C91R) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the variant was unable to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. The mutation was also unable to rescue the expression of BAP1 target genes TMSB4X (300159) and S100A11 (603114) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect on BAP1 deubiquitination activity. Patient 7 was a 2-year-old boy with walking at age 17 months and mild speech delay. The pregnancy was complicated by polyhydramnios and cystic hygroma. He had coarse facial features with mild dysmorphism. Patient 8 was a 4-year-old girl with delayed walking, poor speech, hypotonia, behavioral problems, and dysmorphic facies. She also had ocular abnormalities, including exudative vitreoretinopathy and high myopia. In addition to the BAP1 variant, patient 8 carried a truncating R731X variant in the CTNNA1 gene (116805) that was maternally inherited. </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>.0014 KURY-ISIDOR SYNDROME</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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BAP1, HIS169ARG
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<br />
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SNP: rs2153227828,
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ClinVar: RCV001776249, RCV001797189, RCV001839046, RCV003642960
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated patients (patients 9 and 10) with Kury-Isidor syndrome (KURIS; 619762), Kury et al. (2022) identified a de novo heterozygous c.506A-G transition (c.506A-G, NM_004656.3) in the BAP1 gene, resulting in a his169-to-arg (H169R) substitution at a highly conserved residue in the catalytic ubiquitin C-terminal hydrolase domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. In vitro functional expression studies in BAP1-null HAP1 cells showed that the variant was unable to rescue BAP1 activity, as measured by increased levels of the BAP1 H2AK119ub substrate. The mutation was also unable to rescue the expression of BAP1 target genes TMSB4X (300159) and S100A11 (603114) in a BAP1-null cell line, whereas wildtype BAP1 was able to restore expression of these genes. These data were consistent with a loss-of-function effect on BAP1 deubiquitination activity. Patient 9 was a 16-year-old boy with mild developmental delay, behavioral problems noted as sensitivity, seizures, distal skeletal anomalies, and patchy alopecia. He also carried biallelic variants in the NCSTN gene (605254). Patient 10 was an 8-year-old girl with mild global developmental delay, poor speech, a history of seizures, behavioral abnormalities, and mild dysmorphic features. She carried a mitochondrial variant of uncertain significance that showed low (2%) heteroplasmy. </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>.0015 TUMOR PREDISPOSITION SYNDROME 1</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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MELANOMA, UVEAL, SUSCEPTIBILITY TO, 2, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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BAP1, 1-BP DEL, 1717C
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<br />
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ClinVar: RCV000207031, RCV000464745, RCV000567996, RCV001795342, RCV002273820
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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>Tumor Predisposition Syndrome 1</em></strong></p><p>
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In 6 affected members of a large kindred (K4) of European origin with tumor predisposition syndrome-1 (TPDS1; 614327), Carbone et al. (2015) identified a heterozygous germline 1-bp deletion (c.1717delC) in exon 13 of the BAP1 gene, resulting in a frameshift and premature termination (Leu573fsTer3). The mutation, which was found by exome sequencing and confirmed, segregated with the disorder in the family in those who were genotyped. The mutant protein was predicted to lack the nuclear localization signal, and immunohistochemical studies of mesothelioma tissue showed lack of nuclear BAP1 staining with only cytoplasmic localization. Somatic loss of heterozygosity of the BAP1 gene was confirmed in available tumor tissue. These findings were consistent with BAP1 being a tumor suppressor gene. Multiple family members spanning at least 6 generations showed various types of cancer, including malignant mesothelioma, uveal melanoma, basal cell carcinoma, leiomyosarcoma, renal cell carcinoma, and cutaneous melanoma. One mutation carrier had breast cancer. There was high penetrance of cancer manifestation by age 55 years. Carbone et al. (2015) emphasized the importance of identifying mutation carriers in this family who can then be monitored for malignant mesothelioma or other cancers, because early detection and diagnosis can lead to effective treatment. </p><p><strong><em>Melanoma, Uveal, Susceptibility to, 2</em></strong></p><p>
|
|
In a 48-year-old Caucasian man (patient 1) with bilateral uveal melanoma-2 (UVM2; 606661), Yu et al. (2020) identified a germline heterozygous c.1717delC mutation in the BAP1 gene. Functional studies of the variant were not performed. Cytogenetic profile of tumor tissue showed somatic disomy of chromosomes 3, 6, and 8. Family history was significant for ovarian and bladder cancer in his mother and pancreatic cancer in his maternal great-grandfather, although familial genetic segregation studies were not conducted. The patient did not have other tumors or systemic metastasis. </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>.0016 MELANOMA, UVEAL, SUSCEPTIBILITY TO, 2</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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BAP1, 1-BP DEL, 79G
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<br />
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SNP: rs397509413,
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ClinVar: RCV001216166, RCV002273840, RCV002418740, RCV004697073
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a 54-year-old Caucasian man (patient 2) with uveal melanoma-2 (UVM2; 606661), Yu et al. (2020) identified a germline heterozygous 1-bp deletion (c.79delG) in exon 3 of the BAP1 gene, predicted to result in a frameshift and premature termination. Functional studies of the variant and familial segregation studies were not performed. The patient had enucleation of 1 eye due to uveal melanoma and later was found to have a melanoma in the ciliary body of the other eye. There was no evidence of systemic metastasis. Cytogenetic profile of the tumor tissue showed somatic chromosome 3 monosomy, chromosome 6 disomy, and chromosome 8q amplification. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Abdel-Rahman, M. H., Pilarski, R., Cebulla, C. M., Massengill, J. B., Christopher, B. N., Boru, G., Hovland, P., Davidorf, F. H.
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|
<strong>Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.</strong>
|
|
J. Med. Genet. 48: 856-859, 2011.
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[PubMed: 21941004]
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[Full Text: https://doi.org/10.1136/jmedgenet-2011-100156]
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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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Bononi, A., Giorgi, C., Patergnani, S., Larson, D., Verbruggen, K., Tanji, M., Pellegrini, L., Signorato, V., Olivetto, F., Pastorino, S., Nasu, M., Napolitano, A., and 13 others.
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|
<strong>BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation.</strong>
|
|
Nature 546: 549-553, 2017.
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[PubMed: 28614305]
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[Full Text: https://doi.org/10.1038/nature22798]
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</p>
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<li>
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<p class="mim-text-font">
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|
Bott, M., Brevet, M., Taylor, B. S., Shimizu, S., Ito, T., Wang, L., Creaney, J., Lake, R. A., Zakowski, M. F., Reva, B., Sander, C., Delsite, R., Powell, S., Zhou, Q., Shen, R., Olshen, A., Rusch, V., Ladanyi, M.
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|
<strong>The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.</strong>
|
|
Nature Genet. 43: 668-672, 2011.
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[PubMed: 21642991]
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[Full Text: https://doi.org/10.1038/ng.855]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Carbone, M., Flores, E. G., Emi, M., Johnson, T. A., Tsunoda, T., Behner, D., Hoffman, H., Hesdorffer, M., Nasu, M., Napolitano, A., Powers, A., Minaai, M., and 10 others.
|
|
<strong>Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred tracing back nine generations to a common ancestor from the 1700s.</strong>
|
|
PLoS Genet. 11: e1005633, 2015.
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[PubMed: 26683624]
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[Full Text: https://doi.org/10.1371/journal.pgen.1005633]
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</p>
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<li>
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<p class="mim-text-font">
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Chan-on, W., Nairismagi, M.-L., Ong, C. K., Lim, W. K., Dima, S., Pairojkul, C., Lim, K. H., McPherson, J. R., Cutcutache, I., Heng, H. L., Ooi, L., Chung, A., and 27 others.
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|
<strong>Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers.</strong>
|
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Nature Genet. 45: 1474-1478, 2013.
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[PubMed: 24185513]
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[Full Text: https://doi.org/10.1038/ng.2806]
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</p>
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<li>
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<p class="mim-text-font">
|
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Dey, A., Seshasayee, D., Noubade, R., French, D. M., Liu, J., Chaurushiya, M. S., Kirkpatrick, D. S., Pham. V. C., Lill, J. R., Bakalarski, C. E., Wu, J., Phu, L., and 15 others.
|
|
<strong>Loss of the tumor suppressor BAP1 causes myeloid transformation.</strong>
|
|
Science 337: 1541-1546, 2012.
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|
|
[PubMed: 22878500]
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[Full Text: https://doi.org/10.1126/science.1221711]
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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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Harbour, J. W., Onken, M. D., Roberson, E. D. O., Duan, S., Cao, L., Worley, L. A., Council, M. L., Matatall, K. A., Helms, C., Bowcock, A. M.
|
|
<strong>Frequent mutation of BAP1 in metastasizing uveal melanomas.</strong>
|
|
Science 330: 1410-1413, 2010.
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[PubMed: 21051595]
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[Full Text: https://doi.org/10.1126/science.1194472]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
He, M., Chaurushiya, M. S., Webster, J. D., Kummerfeld, S., Reja, R., Chaudhuri, S., Chen, Y.-J., Modrusan, Z., Haley, B., Dugger, D. L., Eastham-Anderson, J., Lau, S., Dey, A., Caothien, R., Roose-Girma, M., Newton, K., Dixit, V. M.
|
|
<strong>Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1.</strong>
|
|
Science 364: 283-285, 2019.
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|
[PubMed: 31000662]
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[Full Text: https://doi.org/10.1126/science.aav4902]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Jensen, D. E., Proctor, M., Marquis, S. T., Gardner, H. P., Ha, S. I., Chodosh, L. A., Ishov, A. M., Tommerup, N., Vissing, H., Sekido, Y., Minna, J., Borodovsky, A., Schultz, D. C., Wilkinson, K. D., Maul, G. G., Barlev, N., Berger, S. L., Prendergast, G. C., Rauscher, F. J., III.
|
|
<strong>BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.</strong>
|
|
Oncogene 16: 1097-1112, 1998.
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[PubMed: 9528852]
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[Full Text: https://doi.org/10.1038/sj.onc.1201861]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Jiao, Y., Pawlik, T. M., Anders, R. A., Selaru, F. M., Streppel, M. M., Lucas, D. J., Niknafs, N., Guthrie, V. B., Maitra, A., Argani, P., Offerhaus, G. J. A., Roa, J. C., and 24 others.
|
|
<strong>Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.</strong>
|
|
Nature Genet. 45: 1470-1473, 2013.
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[PubMed: 24185509]
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[Full Text: https://doi.org/10.1038/ng.2813]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kury, S., Ebstein, F., Molle, A., Besnard, T., Lee, M.-K., Vignard, V., Hery, T., Nizon, M., Mancini, G. M. S., Giltay, J. C., Cogne, B., McWalter, K., and 47 others.
|
|
<strong>Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder.</strong>
|
|
Am. J. Hum. Genet. 109: 361-372, 2022.
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|
[PubMed: 35051358]
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[Full Text: https://doi.org/10.1016/j.ajhg.2021.12.011]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N.
|
|
<strong>Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain.</strong>
|
|
DNA Res. 3: 321-329, 1996.
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|
[PubMed: 9039502]
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|
[Full Text: https://doi.org/10.1093/dnares/3.5.321]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Pena-Llopis, S., Vega-Rubin-de-Celis, S., Liao, A., Leng, N., Pavia-Jimenez, A., Wang, S., Yamasaki, T., Zhrebker, L., Sivanand, S., Spence, P., Kinch, L., Hambuch, T., and 15 others.
|
|
<strong>BAP1 loss defines a new class of renal cell carcinoma.</strong>
|
|
Nature Genet. 44: 751-759, 2012. Note: Erratum: Nature Genet. 44: 1072 only, 2012.
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|
|
[PubMed: 22683710]
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[Full Text: https://doi.org/10.1038/ng.2323]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Popova, T., Hebert, L., Jacquemin, V., Gad, S., Caux-Moncoutier, V., Dubois-d'Enghien, C., Richaudeau, B., Renaudin, X., Sellers, J., Nicolas, A., Sastre-Garau, X., Desjardins, L., and 22 others.
|
|
<strong>Germline BAP1 mutations predispose to renal cell carcinomas.</strong>
|
|
Am. J. Hum. Genet. 92: 974-980, 2013.
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|
|
[PubMed: 23684012]
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[Full Text: https://doi.org/10.1016/j.ajhg.2013.04.012]
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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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Testa, J. R., Cheung, M., Pei, J., Below, J. E., Tan, Y., Sementino, E., Cox, N. J., Dogan, A. U., Pass, H. I., Trusa, S., Hesdorffer, M., Nasu, M., Powers, A., Rivera, Z., Comertpay, S., Tanji, M., Gaudino, G., Yang, H., Carbone, M.
|
|
<strong>Germline BAP1 mutations predispose to malignant mesothelioma. (Letter)</strong>
|
|
Nature Genet. 43: 1022-1025, 2011.
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|
|
[PubMed: 21874000]
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[Full Text: https://doi.org/10.1038/ng.912]
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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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Wiesner, T., Obenauf, A. C., Murali, R., Fried, I., Griewank, K. G., Ulz, P., Windpassinger, C., Wackernagel, W., Loy, S., Wolf, I., Viale, A., Lash, A. E., and 12 others.
|
|
<strong>Germline mutations in BAP1 predispose to melanocytic tumors. (Letter)</strong>
|
|
Nature Genet. 43: 1018-1021, 2011.
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|
|
[PubMed: 21874003]
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[Full Text: https://doi.org/10.1038/ng.910]
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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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Xiong, Z., Xia, P., Zhu, X., Geng, J., Wang, S., Ye, B., Qin, X., Qu, Y., He, L., Fan, D., Du, Y., Tian, Y., Fan, Z.
|
|
<strong>Glutamylation of deubiquitinase BAP1 controls self-renewal of hematopoietic stem cells and hematopoiesis.</strong>
|
|
J. Exp. Med. 217: e20190974, 2020. Note: Electronic Article.
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[PubMed: 31699823]
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[Full Text: https://doi.org/10.1084/jem.20190974]
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Yu, M. D., Masoomian, B., Shields, J. A., Shields, C. L.
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<strong>BAP1 germline mutation associated with bilateral primary uveal melanoma.</strong>
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Ocul. Oncol. Path. 6: 10-14, 2020.
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[PubMed: 32002398]
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[Full Text: https://doi.org/10.1159/000499570]
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Cassandra L. Kniffin - updated : 07/29/2022<br>Cassandra L. Kniffin - updated : 02/23/2022<br>Bao Lige - updated : 03/16/2020<br>Ada Hamosh - updated : 10/09/2019<br>Ada Hamosh - updated : 04/04/2018<br>Ada Hamosh - updated : 01/28/2014<br>Cassandra L. Kniffin - updated : 7/9/2013<br>Ada Hamosh - updated : 11/1/2012<br>Cassandra L. Kniffin - updated : 7/25/2012<br>Cassandra L. Kniffin - updated : 11/3/2011<br>Cassandra L. Kniffin - updated : 8/8/2011<br>Ada Hamosh - updated : 12/28/2010
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Rebekah S. Rasooly : 10/5/1998
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carol : 08/05/2022<br>carol : 08/04/2022<br>ckniffin : 07/29/2022<br>alopez : 02/24/2022<br>ckniffin : 02/23/2022<br>mgross : 03/16/2020<br>carol : 10/10/2019<br>alopez : 10/09/2019<br>alopez : 04/04/2018<br>alopez : 01/28/2014<br>carol : 9/13/2013<br>tpirozzi : 7/11/2013<br>tpirozzi : 7/10/2013<br>ckniffin : 7/9/2013<br>alopez : 11/2/2012<br>terry : 11/1/2012<br>carol : 9/14/2012<br>carol : 7/25/2012<br>ckniffin : 7/25/2012<br>terry : 7/5/2012<br>carol : 11/9/2011<br>ckniffin : 11/8/2011<br>ckniffin : 11/3/2011<br>wwang : 8/12/2011<br>ckniffin : 8/8/2011<br>alopez : 1/5/2011<br>alopez : 1/3/2011<br>terry : 12/28/2010<br>carol : 12/26/2000<br>alopez : 10/5/1998
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