Loss-of-function variants in POT1 predispose to uveal melanoma

Pathogenic germline variants in protection of telomeres 1 (POT1) result in a tumour predisposition syndrome (POT1-TPDS), which includes cutaneous melanoma (CM), glioma, chronic lymphocytic leukaemia (CLL), colorectal cancer, thyroid cancer and sarcoma. Through whole-genome sequencing (WGS) of 20 Australian individuals affected with both CM and uveal melanoma (UM), our study identified two truncating variants in POT1. Functional analyses assessing telomere length indicated longer telomeres in variant carriers, compared with healthy age-matched controls, similar to observations in CM patients with loss-of-function POT1 variants.