A pathogenic role of MBD4 variants and their effect on the tumor mutational landscape, possibly consistent with its role in avoiding mutability at CpG sites [3, 32, 33], is confirmed by our finding of increased frequency of C:G > T:A transitions in CRC cases with MBD4 mutation or combined MBD4 plus major MMR gene mutations, compared to both CRC cases with MLH1 variants and CRC cases with no mutation in MBD4 or major MMR gene (Fig. 3). This evidence concerns the gene MLH1 and colorectal carcinoma.