094 BUB1B germline variant predisposes to cutaneous melanoma and multiple other primary malignancies

Although several inherited melanoma predisposition syndromes have been identified, a subset of melanoma families lack pathogenic variants in known highly penetrant predisposition genes, including CDKN2A, CDK4, and BAP1. We describe a patient with multiple melanomas and other primary tumors with a germline pathogenic variant in BUB1B. A 76-year-old woman presented with a history of multiple, distinct primary tumors, including childhood thymoma, thyroid cancer, two melanomas, two breast cancers, a solitary fibrous tumor, and metastasized lung cancer. Family history included brothers with breast cancer, prostate cancer and cutaneous melanoma, maternal relatives with breast and colon cancer, and father with urinary tract cancer. Germline testing of 75 cancer risk genes, including hereditary melanoma and breast cancer genes, and additional whole-exome sequencing (WES) revealed only one germline pathogenic variant, c.2316C>G, in BUB1B. WES of melanoma revealed somatic variants, including in CDKN2A and NRAS.Immunohistochemistry of BUB1B of normal skin, nevus, and melanoma samples did not reveal significant differences in BUB1B expression levels in patient versus control tissues. BUB1B encodes a kinase involved in spindle checkpoint function, a process dysregulated in many cancer types. To date, germline pathogenic variants in BUB1B have rarely been implicated in inherited tumor predisposition. We propose that heterozygous pathogenic BUB1B variants may increase susceptibility to multiple primary tumors, including melanoma, and may explain this patient’s significant history of multiple cancers. Identification of novel genes associated with hereditary cancer risk is integral for optimal genetic counseling and appropriate cancer screening in at-risk individuals.