{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T15:05:21Z","timestamp":1780067121477,"version":"3.54.0"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2019,4,10]],"date-time":"2019-04-10T00:00:00Z","timestamp":1554854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100015738","name":"Mary and Georg C. Ehrnrooth Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100015738","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010810","name":"Eye Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010810","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015736","name":"Folkh\u00e4lsan Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100015736","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100013510","name":"Eye and Tissue Bank Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100013510","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9lius Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010711","name":"Cancer Foundation Finland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Helsinki University Hospital Research Fund","award":["TYH2017218"],"award-info":[{"award-number":["TYH2017218"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Pathogenic germline variants in the BRCA1-associated protein 1 (BAP1) gene cause the BAP1 tumor predisposition syndrome (BAP1-TPDS) with increased risk of several cancers, the most frequent of which is uveal melanoma (UM). Pathogenicity of loss-of-function (LOF) BAP1 variants is clear, as opposed to that of missense and regulatory region variants. We sequenced the coding, promoter, untranslated region (UTR) and intronic regions of BAP1 and analyzed copy number variations (CNVs). In this nationwide study, the cohort comprised UM patients diagnosed between 2010 and 2017. These included 432 of 520 consecutive Finnish UM patients, 16 of whom were familial, and one additional patient from a Finnish\u2013Swedish family. Twenty-one different rare variants were found: seven exonic, seven intronic, four 3\u2032 UTR and three promoter. We considered five variants likely to be pathogenic by effect on splicing, nuclear localization or deubiquitination activity. Intron 2 (c.67+1G&gt;T) and exon 14 (c.1780_1781insT) LOF variants were presumed founder mutations, occurring in two and four families, respectively; both abolished nuclear localization in vitro. Intron 2, exons 5 (c.281A&gt;G) and 9 (c.680G&gt;A) missense variants markedly reduced deubiquitinating activity. A deep intronic 25 base pair deletion in intron 1 caused aberrant splicing in vitro. On the basis of functional studies and family cancer history, we classified four exon 13 missense variants as benign. No CNVs were found. The prevalence of pathogenic variants was 9\/433 (2%) and 4\/16 (25%) in Finnish UM families. Family cancer history and functional assays are indispensable when establishing the pathogenicity of BAP1 variants. Deep intronic variants can cause BAP1-TPDS.<\/jats:p>","DOI":"10.1093\/hmg\/ddz076","type":"journal-article","created":{"date-parts":[[2019,4,8]],"date-time":"2019-04-08T11:10:24Z","timestamp":1554721824000},"page":"2415-2426","source":"Crossref","is-referenced-by-count":24,"title":["Population-based analysis of BAP1 germline variations in patients with uveal melanoma"],"prefix":"10.1093","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9257-9376","authenticated-orcid":false,"given":"Pauliina","family":"Repo","sequence":"first","affiliation":[{"name":"Folkh\u00e4lsan Research Center, Biomedicum Helsinki, Haartmaninkatu, FI Helsinki, Finland"},{"name":"Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu C, FI Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reetta-Stiina","family":"J\u00e4rvinen","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Research Center, Biomedicum Helsinki, Haartmaninkatu, FI Helsinki, Finland"},{"name":"Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu C, FI Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes E","family":"J\u00e4ntti","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Research Center, Biomedicum Helsinki, Haartmaninkatu, FI Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salla","family":"Markkinen","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Research Center, Biomedicum Helsinki, Haartmaninkatu, FI Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"T\u00e4ll","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu C, FI Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virpi","family":"Raivio","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu C, FI Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joni A","family":"Turunen","sequence":"additional","affiliation":[{"name":"Folkh\u00e4lsan Research Center, Biomedicum Helsinki, Haartmaninkatu, FI Helsinki, Finland"},{"name":"Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu C, FI Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tero T","family":"Kivel\u00e4","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu C, FI Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,4,10]]},"reference":[{"key":"2019070301125877300_ref1","article-title":"BAP1 Tumor Predisposition Syndrome","volume-title":"GeneReviews","author":"Pilarski","year":"1993"},{"key":"2019070301125877300_ref2","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1111\/cge.12630","article-title":"Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases","volume":"89","author":"Rai","year":"2016","journal-title":"Clin. Genet."},{"key":"2019070301125877300_ref3","doi-asserted-by":"crossref","DOI":"10.1093\/jnci\/djy171","article-title":"Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide","author":"Walpole","year":"2018","journal-title":"J. Natl. Cancer Inst."},{"key":"2019070301125877300_ref4","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.ophtha.2016.01.008","article-title":"BAP1 germline mutations in Finnish patients with uveal melanoma","volume":"123","author":"Turunen","year":"2016","journal-title":"Ophthalmology"},{"key":"2019070301125877300_ref5","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1001\/jamaophthalmol.2015.1119","article-title":"Clinical characteristics of uveal melanoma in patients with germline BAP1 mutations","volume":"133","author":"Gupta","year":"2015","journal-title":"JAMA Ophthalmol."},{"key":"2019070301125877300_ref6","doi-asserted-by":"crossref","first-page":"7006","DOI":"10.1158\/0008-5472.CAN-08-0599","article-title":"The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families","volume":"68","author":"Palma","year":"2008","journal-title":"Cancer Res."},{"key":"2019070301125877300_ref7","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/humu.22938","article-title":"The contribution of whole gene deletions and large rearrangements to the mutation Spectrum in inherited tumor predisposing syndromes","volume":"37","author":"Smith","year":"2016","journal-title":"Hum. Mutat."},{"key":"2019070301125877300_ref8","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22752","article-title":"Germline large deletion of BAP1 and decreased expression in non-tumor choroid in uveal melanoma patients with high risk for inherited cancer","author":"Boru","year":"2019","journal-title":"Genes Chromosomes Cancer"},{"key":"2019070301125877300_ref9","doi-asserted-by":"crossref","first-page":"34179","DOI":"10.1074\/jbc.M109.046755","article-title":"The deubiquitinating enzyme BAP1 regulates cell growth via interaction with HCF-1","volume":"284","author":"Machida","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2019070301125877300_ref10","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1128\/MCB.01517-08","article-title":"Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1","volume":"29","author":"Misaghi","year":"2009","journal-title":"Mol. Cell Biol."},{"key":"2019070301125877300_ref11","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/sj.onc.1201861","article-title":"BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression","volume":"16","author":"Jensen","year":"1998","journal-title":"Oncogene"},{"key":"2019070301125877300_ref12","doi-asserted-by":"crossref","first-page":"5071","DOI":"10.1128\/MCB.00396-10","article-title":"The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression","volume":"30","author":"Yu","year":"2010","journal-title":"Mol. Cell Biol."},{"key":"2019070301125877300_ref13","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/nrc3459","article-title":"BAP1 and cancer","volume":"13","author":"Carbone","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"2019070301125877300_ref14","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1136\/jclinpath-2016-203866","article-title":"Gene of the month: BAP1","volume":"69","author":"Wang","year":"2016","journal-title":"J. Clin. Pathol."},{"key":"2019070301125877300_ref15","doi-asserted-by":"crossref","first-page":"6953","DOI":"10.1158\/0008-5472.CAN-08-0365","article-title":"BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization","volume":"68","author":"Ventii","year":"2008","journal-title":"Cancer Res."},{"key":"2019070301125877300_ref16","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1038\/s41556-018-0178-0","article-title":"BAP1 links metabolic regulation of ferroptosis to tumour suppression","volume":"20","author":"Zhang","year":"2018","journal-title":"Nat. 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Med."},{"key":"2019070301125877300_ref35","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms15869","article-title":"Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis","volume":"8","author":"Savola","year":"2017","journal-title":"Nat. Commun."},{"key":"2019070301125877300_ref36","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/28\/14\/2415\/28885743\/ddz076.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T05:08:26Z","timestamp":1590037706000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/28\/14\/2415\/5434900"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,10]]},"references-count":36,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2019,4,10]]},"published-print":{"date-parts":[[2019,7,15]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddz076","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,7,15]]},"published":{"date-parts":[[2019,4,10]]}}}