In 2 affected members of a family (family 2) and in 2 affected members of an unrelated family from a second cohort (pedigree 2) with tumor predisposition syndrome-3 (TPDS3; 615848), DeBoy et al. (2023) identified a germline heterozygous c.233T-C transition (chr7.124,510,987A-G, GRCh37) in the POT1 gene, resulting in an ile78-to-thr (I78T) substitution at a conserved domain in the OB1 domain that interacts with telomere DNA. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the families. The mutation was present at a low frequency in the gnomAD database (4 of 246,852 alleles, frequency of 1.6 x 10(-5)). Patient cells showed decreased POT1 expression and defective binding to telomere DNA, consistent with a loss of function and haploinsufficiency. Mutation carriers, even those without tumors, had long telomeres compared to nonmutation carriers.
Wong et al. (2019) identified a heterozygous I78T mutation (chr7.124,870,933A-G, GRCh38) in the POT1 gene in 4 affected individuals from 3 unrelated families with TPDS3. The mutation segregated with the disorder in the families, although there was evidence of incomplete penetrance. In vitro functional studies showed that the variant impaired POT1 binding to telomere-like probes. Expression of the mutation into cells in vitro resulted in elongated telomeres. The probands in all families had melanoma, and some affected family members had chronic lymphocytic leukemia, thyroid cancer, and cutaneous T-cell lymphoma. All tumors were adult-onset. Examination of melanoma and nevi tissue from 2 of the patients showed accumulation of somatic events in several driver genes, many of which were involved in the MAPK pathway. All families were of Jewish descent, and haplotype analysis suggested a founder effect.
