Re‐evaluating the pathogenicity of the c.783+2T>C BAP1 germline variant

BAP1 germline pathogenic sequence variants (PSVs) underlie a unique tumor predisposition syndrome (BAP1‐TPDS) associated with an increased lifetime risk for developing primarily pleural and peritoneal mesothelioma and uveal and cutaneous melanoma. Overwhelmingly, BAP1 PSVs are unique, family‐specifi...

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Published in:	Human mutation Vol. 42; no. 5; pp. 592 - 599
Main Authors:	Goldberg, Yael, Laitman, Yael, Ben David, Merav, Bazak, Lily, Lidzbarsky, Gabriel, Salmon, Lina B., Shkedi‐Rafid, Shiri, Barshack, Iris, Avivi, Camila, Darawshe, Malak, Shomron, Noam, Bruchim, Revital, Vinkler, Chana, Yannoukakos, Drakoulis, Fostira, Florentia, Bernstein‐Molho, Rinat, Friedman, Eitan
Format:	Journal Article
Language:	English
Published:	United States Hindawi Limited 01-05-2021
Subjects:	allelic loss Alternative splicing BAP1 germline sequence variant Bioinformatics Gastric cancer Genetic Predisposition to Disease Germ-Line Mutation Humans Melanoma Melanoma - genetics Melanoma - pathology Mesothelioma Pathogenicity Peritoneum Polymerase chain reaction Protein expression protein somatic expression patterns Skin Neoplasms Tumor Suppressor Proteins - genetics Tumors Ubiquitin Thiolesterase - genetics Uveal Neoplasms - pathology variant of unknown significance allelic loss protein somatic expression patterns BAP1 germline sequence variant alternative splicing variant of unknown significance
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Summary:	BAP1 germline pathogenic sequence variants (PSVs) underlie a unique tumor predisposition syndrome (BAP1‐TPDS) associated with an increased lifetime risk for developing primarily pleural and peritoneal mesothelioma and uveal and cutaneous melanoma. Overwhelmingly, BAP1 PSVs are unique, family‐specific inactivating variants. We identified seven families, six of Jewish Iraqi origin, harboring an identical BAP1 splice variant (c.783+2T>C), currently assigned a “likely pathogenic” status. Given a nonclassical BAP1‐TPDS tumor type clustering and low penetrance in these families, the pathogenicity of this variant was re‐evaluated by a combined approach including literature analysis, revised bioinformatics analysis, allelic loss, effect on the transcript, and tumor protein expression patterns. None of the three available tumors showed an allelic loss, there was no discernable effect on alternative splicing based on reverse‐transcription polymerase chain reaction, and there was no decrease or loss of somatic protein expression in 2/3 analyzed tumors. This led to assigning a Benign Strong (BS) criteria, BS4, supporting BS3 criteria, and weakening the Pathogenic Supporting (PP) criteria PP5. Combined, these data suggest that this sequence variant should be reclassified as a variant of unknown significance by American College of Medical Genetics (ACMG) criteria.
Bibliography:	Yael Goldberg and Yael Laitman contributed equally to this study. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1059-7794 1098-1004
DOI:	10.1002/humu.24189