Submission Details

MSH3 was first reported in relation to autosomal recessive familial adenomatous polyposis 4 in 2016 (Adam et al., PMID: 27476653). MSH3-related familial adenomatous polyposis 4 is characterized by attenuated polyposis and increased susceptibility to colorectal cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the gene-disease relationship between MSH3 - Lynch syndrome (MONDO:0005835) and autosomal recessive FAP4 was curated separately. Nineteen variants (nonsense, frameshift, large deletion, splicing, missense) that have been reported in 10 probands in 6 publications (PMIDs 27476653, 37597744, 35675019, 38243056, 34250384, 37402566) are included in this curation. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by expression studies, in vitro functional assays, and animal models (PMIDs: 18922920, 24013230, 10706084, 27476653). These studies show that biallelic loss of MSH3 leads to impaired DNA double strand break repair and formation of presumably microsatellite-stable adenomas that contain a unique EMAST signature (a distinct form of microsatellite instability). Knockout mouse models display increased intestinal tumor formation. In summary, there is definitive evidence supporting the relationship between MSH3 and autosomal recessive familial adenomatous polyposis 4. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated as Moderate by the Hereditary Cancer GCEP on March 6, 2024. This re-curation at Definitive was approved by the ClinGen Hereditary Cancer GCEP on May 24, 2024 (SOP Version 10).