MUTYH is a DNA glycosylase involved in the base excision DNA repair pathway. Biallelic and monoallelic variants in MUTYH were linked to multiple types of cancer and/or tumor, including hereditary breast cancer, familial ovarian cancer, familial adenomatous polyposis and colorectal cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split these associations into different curations due to phenotypic differences and/or inheritance mechanism. Therefore, this curation solely focuses on autosomal dominant hereditary breast cancer and given the frequency of variants and the cancer phenotype the curation focuses on case-control studies.
Summary of Case-Control Data: 0 point This gene-disease relationship has been studied in at least 4 case-control studies at the aggregate or single variant level. In 2021, a large case-control study [BCAC, with more than 48 thousand cases and controls (PMID: 33471991)] did not identify a significant association of aggregate loss of function (LOF) variants in MUTYH and autosomal dominant breast cancer. Likewise, another large case-control study published in 2022 did not find significant association with autosomal dominant breast cancer (PMID: 34981295). In addition, PMIDs: 22297469, 27466510 showed no significant association of monoallelic MUTYH variants with breast cancer although with a small population.
Overall Summary: In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between MUTYH and autosomal dominant hereditary breast cancer.
This gene-disease pair was originally evaluated as no known disease relationship by the Breast/Ovarian Cancer GCEP on 05/25/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 06/23/2023 (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).
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