The aim of this study was to profile and compare the SBS18+SBS36 and SBS30 mutational signatures in adenomas and CRCs from biallelic MUTYH and biallelic NTHL1 cases, respectively, with sporadic adenomas and CRCs from participants without a hereditary CRC/polyposis syndrome to determine their discriminatory potential and ability to inform variant classification. Here, NTHL1 is linked to colorectal carcinoma.