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

Our plain-English summary of Re-evaluating the pathogenicity of the c.783+2T>C BAP1 germline variant, by Y. Goldberg, Y. Laitman, M. Ben David, et al (Human Mutation, 2021).

The study

• Authors: Y. Goldberg, Y. Laitman, M. Ben David, L. Bazak, G. Lidzbarsky, L.B. Salmon, S. Shkedi-Rafid, I. Barshack, C. Avivi, M. Darawshe, N. Shomron, R. Bruchim, C. Vinkler, D. Yannoukakos, F. Fostira, R. Bernstein-Molho, E. Friedman
• Journal: Human Mutation
• Published: 2021;42(5):592-599
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

© 2021 Wiley Periodicals LLC.

In plain English

This study re-examined whether one inherited change in the BAP1 gene, called c.783+2T>C, should be treated as cancer-causing. Harmful BAP1 changes are linked to a syndrome that raises the risk of pleural and peritoneal mesothelioma and melanoma. Databases list this variant as "likely pathogenic." It was found in seven families, six of Jewish Iraqi origin and one Greek non-Jewish. The cancers recorded in carriers were mainly breast and colorectal cancers, a pattern the authors called distinct from the classic syndrome. The study did not examine asbestos exposure. Blood RNA from two carriers showed the same splicing patterns as two non-carriers, though the authors noted abnormal RNA might have decayed too fast to detect. Three tumor samples showed no loss of the normal gene copy. Two of three tumors stained normally for BAP1 protein. Of the published reports behind the current classification, only one gave clinical details: a carrier with pleural mesothelioma, with no family history given. The authors concluded that the variant should be reclassified as a "variant of unknown significance" rather than likely pathogenic.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory and database re-evaluation of one inherited gene variant in carrier families, combining literature analysis, bioinformatics, allelic loss testing, RNA (transcript) analysis and tumor protein staining
• Who was studied: Seven families carrying the BAP1 c.783+2T>C variant, six of Jewish Iraqi origin and one Greek non-Jewish, identified over about 3 years through genetic counseling with multigene panel testing or through whole-exome sequencing
• Exposure: No asbestos exposure was assessed. The factor studied was the inherited BAP1 splice-site variant c.783+2T>C.
• Main results:
  • In blood cells from two carriers (probands of Families 4 and 5), BAP1 splicing patterns were identical to those of two non-carrier controls. The authors noted this could reflect either no change in splicing or rapid decay of an abnormally spliced transcript. All five sequenced PCR clones showed the expected normal (wild-type) sequence.
  • Tumor and matching non-tumor DNA from breast cancer cases (n = 2, Family 1) and a case with colonic polyps (n = 1, Family 4) showed retention of heterozygosity, meaning no allelic loss. The data were not shown.
  • Diffuse nuclear BAP1 protein staining was seen in 2 of 3 tumors stained. In one high nuclear grade breast DCIS, there was a focal reduction of staining.
  • The variant was found in 2/251,252 individuals in the gnomAD database and in 3/640 exomes at the Rabin Medical Center Genetic Institute, Israel. All three of those carriers were Iraqi Jews.
  • Three splice prediction tools predicted a damaging effect on splicing. SpliceAI predicted a less damaging effect, with a donor gain score of 0.6 and a donor loss score of 0.08.
  • Of the publications supporting the current 'likely pathogenic' listing, only one (Betti et al., 2018) gave clinical details of a carrier, who had pleural mesothelioma. That report gave no family history or co-segregation details.
  • Two carrier mothers in the study families were cancer-free at ages 81 and 85.
• The authors' conclusion: The authors concluded that BAP1 c.783+2T>C should be reclassified as a variant of unknown significance (VUS) rather than likely pathogenic. They said initial pathogenicity assignments need re-validation as data accumulate and as better prediction tools become available.
• Limitations the authors state:
  • The authors noted that identical splicing patterns could reflect rapid decay of an abnormally spliced transcript rather than no change in splicing.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Germline Mutation, BAP1 Tumor Predisposition Syndrome, Peritoneal Mesothelioma.

Related studies

• Germline BAP1-positive patients: the dilemmas of cancer surveillance and a proposed interdisciplinary consensus monitoring strategy — P. Star, A. Goodwin, et al. (2018)
• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)
• Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation — C. Ribeiro, S. Campelos, et al. (2013)
• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Ocular melanoma and the BAP1 hereditary cancer syndrome: implications for the dermatologist — L.M. Martorano, R.R. Winkelmann, et al. (2014)
• Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations — M. Carbone, H.I. Pass, et al. (2022)

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