Abstract
Germline mutations in MBD4, which, like MUTYH and NTHL1, encodes a glycosylase of the DNA based excision repair system, cause an autosomal recessive syndrome characterised by increased risk of acute myeloid leukaemia, gastrointestinal polyposis, colorectal cancer (CRC) and, to a lesser extent, uveal melanoma and schwannomas. To better define the phenotypic spectrum and tumour molecular features associated with biallelic MBD4-associated cancer predisposition, and study if heterozygous variants are associated with gastrointestinal tumour predisposition, we evaluated germline MBD4 status in 728 patients with CRC, polyposis, and other suggestive phenotypes (TCGA and in-house cohorts). Eight CRC patients carried rare homozygous or heterozygous germline variants in MBD4. The information gathered on mode of inheritance, variant nature, functional effect of the variant, and tumour mutational characteristics suggested that none of the patients included in the study had an MBD4-associated hereditary syndrome and that the heterozygous variants identified were not associated with the disease.