RESUMEN
Importance: The protection of telomeres 1 protein (POT1) is a critical component of the shelterin complex, a multiple-protein machine that regulates telomere length and protects telomere ends. Germline variants in POT1 have been linked to familial melanoma, and somatic mutations are associated with a range of cancers including cutaneous T-cell lymphoma (CTCL). Objective: To characterize pathogenic variation in POT1 in families with melanoma to inform clinical management. Design, Setting, and Participants: In this case study and pedigree evaluation, analysis of the pedigree of 1 patient with melanoma revealed a novel germline POT1 variant (p.I78T, c.233T>C, chromosome 7, g.124870933A>G, GRCh38) that was subsequently found in 2 other pedigrees obtained from the GenoMEL Consortium. Main Outcomes and Measures: (1) Identification of the POT1 p.I78T variant; (2) evaluation of the clinical features and characteristics of patients with this variant; (3) analysis of 3 pedigrees; (4) genomewide single-nucleotide polymorphism genotyping of germline DNA; and (5) a somatic genetic analysis of available nevi and 1 melanoma lesion. Results: The POT1 p.I78T variant was found in 3 melanoma pedigrees, all of persons who self-reported as being of Jewish descent, and was shown to disrupt POT1-telomere binding. A UV mutation signature was associated with nevus and melanoma formation in POT1 variant carriers, and somatic mutations in driver genes such as BRAF, NRAS, and KIT were associated with lesion development in these patients. Conclusions and Relevance: POT1 p.I78T is a newly identified, likely pathogenic, variant meriting screening for in families with melanoma after more common predisposition genes such as CDKN2A have been excluded. It could also be included as part of gene panel testing.