MUTYH is a DNA glycosylase involved in the base excision DNA repair pathway. Monoallelic germline MUTYH variants were first reported in relation to colorectal cancer (MONDO:0005575) in 2004 (Croitoru et al., PMID: 15523092). Of note, bi-allelic variants in MUTYH are associated with autosomal recessive familial adenomatous polyposis 2 (MONDO:0012041). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split the association of MUTYH and recessive familial adenomatous polyposis 2 in another curation due to phenotypic differences and inheritance mechanism.
Summary of Case-Control Data: 3 points Given the potential for phenocopies due to the high population incidence of colorectal cancer, case-level reports were not scored for this curation. Instead, case-control studies and cohort studies were considered the strongest form of genetic evidence. In total, four case-control studies and one cohort study were included in this curation. The case-control studies included meta-analyses, aggregate variant analyses and single variant analyses. Some studies suggested a slightly increased risk for colorectal cancer in monoallelic MUTYH variant carriers compared to controls (PMID: 21063410, 24444654, 23946381) and other studies suggested no increased risk for colorectal cancer in monoallelic MUTYH variant carriers (29478780, 33309985).
Summary of Experimental Data: 3 points There is experimental evidence showing a role for MUTYH in DNA repair (base excision and mismatch repair) pathways, including a null mouse model (PMID: 17638869) which is also a model for the recessive disorder, and in vitro functional studies (PMIDs: 24569162, 15199168, 11801590).
Overall Summary In summary, given that case-control studies show either a slightly increased risk, or no increased risk for colorectal cancer in monoallelic MUTYH variant carriers, and limited experimental data support this gene-disease relationship, the Hereditary Cancer GCEP has disputed this gene-disease association. More evidence is needed to either support or entirely refute the role MUTYH plays in autosomal dominant colorectal cancer. This gene-disease pair was originally evaluated (in relation to autosomal dominant familial adenomatous polyposis 2) as moderate by the Colon Cancer GCEP on 10/09/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 03/24/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.