P059 Familial melanoma germline testing in a specialist dermatology genetics clinic

Abstract Nearly 15% of melanomas occur in patients with a family history, and a subset of these have a germline mutation in a melanoma-predisposing gene (CDKN2A being the most common). In 2022, a strategy was outlined for embedding genomics in the National Health Service over 5 years, through upskilling of specialties to request genetic testing. Consequently, we set up a regional dermatology melanoma genetics clinic for diagnostic testing. Predictive testing remains under the remit of clinical genetics. We reviewed patients referred from January 2022 to November 2024. The UK National Genomic Test Directory criteria for familial melanoma (R254) include a panel of four genes: CDKN2A, CDK4, POT1 and BAP1 [NHS England. National Genomic Test Directory. Available at: https://www.england.nhs.uk/publication/national-genomic-test-directories (last accessed 12 February 2025)]. At the time of this study there were seven testing criteria, dependent on the number of melanomas in an individual or family, age at melanoma diagnosis, atypical moles, and pancreatic cancer. Specific testing for BAP1-associated tumour predisposition syndrome (R422) was dependent on the diagnosis of BAP1-related tumours. Overall, 107 patients (of the 109 referred) met the eligibility criteria for testing (57 female, 50 male; median age 59 years, range 24–89). Of these, 17 (16%) declined testing. The number of melanomas in an individual ranged from 0 to 10. The number of family members with melanoma ranged from 0 to 5. Most patients (46) had at least one family member with melanoma. In total, 92 patients were eligible for R254 testing. Results were available for 61 of 64 tested: 34% (21) of these met multiple eligibility criteria (at least two), of whom 52% (11) had a diagnosis of at least three melanomas. Diagnosis of at least three melanomas was the most common criterion met overall (46% of cases, 28). Nine patients (15%) tested positive (eight for CDKN2A and one for POT1) and one had a POT1 variant of uncertain significance. Five positive patients met multiple eligibility criteria, accounting for 23% (five of 21) of those meeting multiple criteria. Six of nine (67%) had at least three melanomas, and five of nine had a family history of melanoma. Three of 28 (11%) with at least three melanomas as the sole criterion had a positive germline result. Fifteen patients were eligible for R422 (BAP1 testing), of whom 13 were tested. Two patients had positive results, and both had more than one BAP1-inactivated skin lesion removed. In conclusion, almost 15% of those tested had a positive result for the familial melanoma panel, the majority had at least three melanomas, and more than half met multiple eligibility criteria. Further work is required to establish which criteria, either alone or in combination, are the most valuable in predicting positive tests. Dermatologists should be aware of familial melanoma testing criteria and referral to specialist dermatology genetics clinics for genetic counselling.