Germline POT1 variants are associated with long telomeres and an unexpected broad spectrum of malignancies

This study aimed to expand the clinical and biological understanding of POT1 tumor predisposition syndrome and raise awareness of its broad tumor spectrum and association with ultralong telomeres.

We conducted a retrospective analysis of 44 individuals carrying pathogenic or likely pathogenic POT1 variants identified between 2018 and 2025. Clinical, pathologic, and demographic data were extracted from medical records. Telomere length was assessed using in-gel hybridization of telomeric restriction fragments.

Of 44 heterozygotes, 31 had the c.233T>C; p.(Ile78Thr) variant, 8 had c.1672dup; p.(Tyr558Leufs∗6), and 5 had other frameshifting, likely loss-of-function variants. Cancer was diagnosed in 27 heterozygotes (61%), totaling 84 primary malignancies (range: 0-8 per person), with most cases (79%) occurring after the age of 50 years. Melanoma (34%) and breast cancer in females (45%) were the most common. Additional tumors included papillary thyroid carcinoma, desmoid tumors, and diverse malignant and benign neoplasms. Colonic polyps were frequent. POT1 heterozygotes with the p.(Ile78Thr) variant exhibited significantly longer telomeres than control participants, with a 62-year-old woman showing comparable or even longer telomeres than her children.

POT1 pathogenic variants confer susceptibility to a wide tumor spectrum, notably melanoma and, unexpectedly, breast cancer. At least some of these variants are linked to ultralong telomeres, consistent with findings from this study and others. These findings support incorporating POT1 into multigene panels and suggest telomere length as a potential biomarker for diagnosis.