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

Yael Goldberg, Yael Laitman, Merav Ben David, Lily Bazak, Gabriel Lidzbarsky, Lina B. Salmon, Shiri Shkedi-Rafid, Iris Barshack, Camila Avivi, Malak Darawshe, Noam Shomron, Revital Bruchim, Chana Vinkler, Drakoulis Yannoukakos, Florentia Fostira, Rinat Bernstein-Molho, Eitan Friedman

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish
Pages (from-to)592-599
Number of pages8
JournalHuman Mutation
Issue number5
StatePublished - May 2021
Externally publishedYes

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  • BAP1 germline sequence variant
  • allelic loss
  • alternative splicing
  • protein somatic expression patterns
  • variant of unknown significance


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