Monoallelic NTHL1 p.(Gln90*) and cancer risk: evidence from a large Turkish cohort

Biallelic loss-of-function variants in NTHL1 are associated with an autosomal recessive cancer predisposition syndrome, whereas the cancer risk associated with monoallelic NTHL1 variants remains uncertain. The recurrent truncating variant p.(Gln90*), the first described and most frequently observed pathogenic NTHL1 variant, is commonly detected in the monoallelic state in population databases and diagnostic multigene panels, creating a clinical challenge in cancer risk interpretation. We aimed to assess the cancer risk associated with monoallelic NTHL1 p.(Gln90*) in a large Turkish cohort. We retrospectively analyzed 8,100 individuals who underwent hereditary cancer syndrome multigene panel testing and 10,000 individuals analyzed by exome sequencing for non-oncologic indications at a tertiary referral center. Carriers of the NTHL1 c.268C>T, p.(Gln90*) (rs150766139) variant were evaluated. Carrier frequencies were compared between cohorts and with population-based datasets using a carrier-rate-based analytical approach. The NTHL1 p.(Gln90*) variant was identified in 0.36% of individuals in the hereditary cancer testing cohort and in 0.27% of individuals in the exome sequencing cohort, with no significant difference in carrier frequency. Monoallelic NTHL1 p.(Gln90*) carriers were not enriched in the hereditary cancer testing cohort compared with population-based controls. All biallelic carriers presented with colorectal and/or breast cancer, consistent with established phenotypes. Notably, 19.2% of monoallelic carriers harbored additional pathogenic or likely pathogenic variants in established cancer susceptibility genes. In conclusion, the absence of enrichment among monoallelic carriers compared with hereditary cancer testing and population-based control cohorts, together with the frequent detection of co-occurring pathogenic variants, supports a zygosity-dependent interpretation of the NTHL1 p.(Gln90*) variant. Monoallelic NTHL1 p.(Gln90*) and Cancer Risk: Evidence From a Large Turkish Cohort.