Original Articles: Translational ResearchEvaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanomaJohansson, Peter A.a; Nathan, Vaishnavia; Bourke, Lauren M.a; Palmer, Jane M.a; Zhang, Tongwuf; Symmons, Juditha; Howlie, Madeleinea; Patch, Ann-Marieb; Read, Jazlyna; Holland, Elizabeth A.d,,e; Schmid, Helend,,e; Warrier, Sunilc; Glasson, Williamc; Höiom, Veronicag; Wadt, Karinj; Jönsson, Göranh; Olsson, Håkanh; Ingvar, Christiani; Mann, Grahamd,,e; Brown, Kevin M.f; Hayward, Nicholas K.a; Pritchard, Antonia L.a,,kAuthor Information aOncogenomics Group bMedical Genomics, QIMR Berghofer Medical Research Institute cQueensland Ocular Oncology Service, The Terrace Eye Centre, Brisbane, Queensland dCentre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Westmead eMelanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia fLaboratory of Translational Genomics, National Cancer Institute, National Institutes of Health, Division of Cancer Epidemiology and Genetics, Bethesda, Maryland, USA gDepartment of Oncology and Pathology, Karolinska Institutet, Stockholm hDepartment of Oncology, Clinical Sciences, Lund University and Skåne University Hospital iDepartment of Surgery, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden jDepartment of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark kGenetics and Immunology, An Lòchran, University of the Highlands and Island, Inverness, UK Received 28 September 2018 Accepted 16 March 2019 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.melanomaresearch.com. Correspondence to Antonia L. Pritchard, Genetics and Immunology Group, An Lòchran, University of the Highlands and Islands, Inverness, Scotland IV2 5NA, UK Tel: + 44 146 327 9319; e-mails: [email protected], [email protected] Melanoma Research: October 2019 - Volume 29 - Issue 5 - p 483-490 doi: 10.1097/CMR.0000000000000613 Buy SDC Metrics Abstract Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.