Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents.

Recently, biallelic germline variants of the DNA glycosylase genes and were linked to polyposis susceptibility. Significant fractions remain without a molecular explanation, warranting searches for underlying causes. We used exome sequencing to investigate clinically well-defined adenomatous polyposis cases and families from Finland (N=34), Chile (N=21), and Argentina (N=12), all with known susceptibility genes excluded. Nine index cases (13%) revealed germline variants with proven or possible pathogenicity in the DNA glycosylase genes, involving (mono- or biallelic) in 3 cases, (monoallelic) in 3 cases, (biallelic) in 1 case, and (monoallelic) in 2 cases. was affected with the well-established, pathogenic c.268C>T, p.(Gln90Ter) variant. A recurrent heterozygous c.506G>A, p.(Gly169Asp) variant was observed in two families. In a Finnish family, the variant occurred with a truncating variant (c.821delT). In an Argentine family, the variant co-occurred with a genomic deletion of exons 2 - 11 of . Mutational signatures in tumor tissues complied with biological functions reported for . Our results suggest that germline variants in DNA glycosylase genes may occur in a non-negligible proportion of unexplained colon polyposis cases and may predispose to tumor development.