Background: 5 to 10% of all cutaneous melanomas develop in melanoma families with an autosomal dominant inheritance pattern with incomplete penetrance. The first gene associated with melanoma susceptibility was cyclin dependent kinase inhibitor 2A (CDKN2A). Between 5 and 20% of melanoma families have CDKN2A germline mutations. Within melanoma families with germline mutated CDKN2A, some members do not carry the mutation but develop melanoma, these cases are called phenocopies. The aim of the study is to analyze the characteristics of phenocopies within melanoma families with germline mutations in CDKN2A. Methods: A retrospective cohort study was conducted. All the phenocopies in the context of melanoma families with germline mutations in CDKN2A, from 2010 to 2023, were included. We analyzed the basal clinical characteristics, phenotype, and studied the following melanoma susceptibility genes: CDK4 (exon 2), MC1R, MITF (exon 9), BAP1, POT1, ACD, TERF2IP, TERT promoter and include the opportunistic testing of BRCA1, BRCA2, MLH1, MSH2, MSH6. Results: In the period of the study 9 phenocopies were identified. Women were predominant (66%) and the median age at diagnosis of cutaneous melanoma was 33 years. Concerning the phenotype, all the patients were Caucasians and most had high total body nevus count. MC1R polymorphisms were found in 100% of the phenocopies with no other genetic mutations identified. Conclusions: The fact that there are phenocopies within melanoma families with CDKN2A mutations, shows that the known mutation is not the only factor that led to the development of melanoma, but that there are other aspects related such as fair skin, high total body nevus count and MC1R polymorphisms, among others. Due to the multifactorial etiology, in the case of a family member with a negative genetic test, the risk of developing melanoma should not be underestimated. Clinical follow-up, total body photography and digital dermoscopy should be carried out, according to individual risk factors, for the early detection of melanoma.

Phenocopies in melanoma families with germline mutations in CDKN2A are associated to MC1R polymorphisms and high total body nevus count