A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma

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.