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Germline mutation of the  BRCA1  associated protein-1 ( BAP1 ) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced  BAP1  in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30  BAP1  variants in total, of which 27 were rare (ExAc allele frequency &lt;0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and five in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of  BAP1 -associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying  BAP1  loss-of-function variants also had melanomas with histopathological features suggestive of a germline  BAP1  mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic  BAP1 -associated histopathological appearances, but may still represent less penetrant variants. Germline  BAP1  alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in cutaneous melanoma.

A population-based analysis of germline BAP1 mutations in melanoma