In contrast to the previously described BER defect caused by MUYTH deficiency, multiple tumor types from carriers of germline bi-allelic NTHL1 LoF variants exhibit a distinctive somatic mutation pattern (Single Base Substitution Signature 30 [SBS30] in the COSMIC database1,6) characterized by an abundance of C > T transitions at non-CpG sites, indicating that an NTHL1-driven BER defect was the predominant mutational process driving the development of these tumors. This evidence concerns the gene NTHL1 and neoplasm.