TY - JOUR
T1 - Re-evaluating the pathogenicity of the c.783+2T>C BAP1 germline variant
AU - Goldberg, Yael
AU - Laitman, Yael
AU - Ben David, Merav
AU - Bazak, Lily
AU - Lidzbarsky, Gabriel
AU - Salmon, Lina B.
AU - Shkedi-Rafid, Shiri
AU - Barshack, Iris
AU - Avivi, Camila
AU - Darawshe, Malak
AU - Shomron, Noam
AU - Bruchim, Revital
AU - Vinkler, Chana
AU - Yannoukakos, Drakoulis
AU - Fostira, Florentia
AU - Bernstein-Molho, Rinat
AU - Friedman, Eitan
N1 - Publisher Copyright: © 2021 Wiley Periodicals LLC
PY - 2021/5/1
Y1 - 2021/5/1
N2 - 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.
AB - 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.
KW - BAP1 germline sequence variant
KW - allelic loss
KW - alternative splicing
KW - protein somatic expression patterns
KW - variant of unknown significance
UR - http://www.scopus.com/inward/record.url?scp=85101882285&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/humu.24189
DO - https://doi.org/10.1002/humu.24189
M3 - مقالة
C2 - 33600035
SN - 1059-7794
VL - 42
SP - 592
EP - 599
JO - Human Mutation
JF - Human Mutation
IS - 5
ER -