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A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma
Author(s) -
Wadt Karin,
Choi Jiyeon,
Chung JoonYong,
Kiilgaard Jens,
Heegaard Steffen,
Drzewiecki Krzysztof T.,
Trent Jeffrey M.,
Hewitt Stephen M.,
Hayward Nicholas K.,
Gerdes AnneMarie,
Brown Kevin M.
Publication year - 2012
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12006
Subject(s) - bap1 , germline mutation , germline , missense mutation , cancer research , frameshift mutation , paraganglioma , melanoma , biology , splice , mutation , genetics , medicine , pathology , gene
Summary Inactivating germ line BRCA 1‐associated protein‐1 ( BAP1 ) mutations have recently been reported in families with uveal or cutaneous malignant melanoma ( UMM , CMM ), mesothelioma, and meningioma. Although apparently predisposing to a wide range of tumors, the exact tumor spectrum associated with germ line BAP1 mutations has yet to be established. Here, we report a novel germ line BAP1 splice mutation, c.1708 C > G (p.Leu570fs*40), in a multiple‐case D anish UMM family with a spectrum of other tumors. Whole‐exome sequencing identified an apparent missense mutation of BAP1 in UMM , CMM , as well as paraganglioma, breast cancer, and suspected mesothelioma cases in the family. Bioinformatic analysis and splicing assays demonstrated that this mutation creates a strong cryptic splice donor, resulting in aberrant splicing and a truncating frameshift of the BAP1 transcript. Somatic loss of the wild‐type allele was also confirmed in the UMM and paraganglioma tumors. Our findings further support BAP1 as a melanoma susceptibility gene and extend the potential predisposition spectrum to paraganglioma.