Germline variants of BAP1 in the Australian population: Journal of Clinical Oncology

Sebastian Walpole, Antonia Pritchard, Jane Palmer, Madeleine Howlie, Judith Symmons, Hayley Hamilton, William Glasson, Sunil Warrier, Olivia Rolfe, Andrew Stark, Matthew D'Mellow, Nicholas Hayward

Research output: Contribution to journalMeeting abstract


e13534 Background: Germline mutations in the BRCA1-associated protein (BAP1) gene are linked to a large spectrum of cancers, defined as the BAP1 tumour predisposition syndrome (BAP1-TPDS). The cancers usually occurring in kindreds with BAP1-TPDS are uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, cholangiocarcinoma and meningioma. A 2017 review identified only 87 probands worldwide with germline BAP1 mutations. Methods: To better understand the frequency of BAP1-TPDS, we took a systematic BAP1 sequencing approach of a defined population. We screened Queensland uveal melanoma probands and their families for mutations in BAP1 (n = 64), identified variants from published studies from Australia and liaised with clinical genetics services Australia-wide to ascertain BAP1 germline variants. Only variants with a population frequency of <0.0005 were considered. Results: We identified 2 truncating, 1 missense, 2 synonymous, 1 intronic and 1 promoter variant in the sequencing screen (7/64). Two truncating variants were referred by the clinical genetics services and finally, 13 published variants in Australian families were identified. The 4 truncating variants occur in kindreds with classical features of BAP1-TPDS and are disease causing. Of the total 11 missense variants, only 1 occurs in a family with BAP1-TPDS phenotype, which has been previously published (p.T173C) and is predicted to impair ubiquitin hydrolase activity. In silico prediction suggests 8/9 unique missense and 1 synonymous variants either alter splicing or damage protein structure, which requires functional confirmation. The intronic variant lies 8bp into intron 13 and is of unknown consequence. Finally, the promoter variant has been reported in an Italian family with the phenotype; however, in the Australian family, incomplete family history for the proband does not allow for a full assessment. Conclusions: The detection of six definite and two likely deleterious variants in this focused assessment of BAP1 in Australia suggests mutations may be more common than indicated by literature review. This study highlights a need for a comprehensive worldwide database of germline BAP1 variants and cancers present in carriers and development of a guide to clinical testing.
Original languageEnglish
Pages (from-to)e13534-e13534
JournalJournal of Clinical Oncology
Issue number15 Suppl
Publication statusE-pub ahead of print - 1 Jun 2018


Dive into the research topics of 'Germline variants of BAP1 in the Australian population: Journal of Clinical Oncology'. Together they form a unique fingerprint.

Cite this