Combined germline and tumor mutation signature testing identifies new families with NTHL1 tumor syndrome.

tumor syndrome is an autosomal recessive rare disease caused by biallelic inactivating variants in the gene and which presents a broad tumor spectrum. To contribute to the characterization of the phenotype of this syndrome, we studied 467 index patients by KASP assay or next-generation sequencing, including 228 patients with colorectal polyposis and 239 patients with familial/personal history of multiple tumors (excluding multiple breast/ovarian/polyposis). Three tumor syndrome families were identified in the group of patients with polyposis and none in patients with familial/personal history of multiple tumors. Altogether, we identified nine affected patients with polyposis (two of them diagnosed after initiating colorectal cancer surveillance) with biallelic pathogenic or likely pathogenic variants, as well as two index patients with one pathogenic or likely pathogenic variant in concomitance with a missense variant of uncertain significance. Here we identified a novel inframe deletion classified as likely pathogenic using the ACMG criteria, supported also by tumor mutational signature analysis. Our findings indicate that the tumor syndrome is a multi-tumor syndrome strongly associated with polyposis and not with multiple tumors without polyposis.