MSH3

Inheritance Pattern: AR

Disease ID:MONDO:0044300

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0044300

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0044300

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0044300

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005835

Submitter: ClinGen

MSH3 was first reported in relation to autosomal dominant Lynch syndrome in 2011 (Duraturo et al., PMID:21128252). Of note, this gene has also been associated with autosomal recessive familial adenomatous polyposis 4 (MSH3-related FAP4). 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 and autosomal recessive FAP4 was curated separately. Although several MSH3 missense variants have been identified from probands with colorectal cancer in published literature (PMIDs 21128252, 25142776, 27300758, 29212164, 28944238), the pedigrees did not show significant segregation, many variants were considered too high population frequency to cause disease, and no functional assays supported a damaging effect on the gene or protein product. This gene-disease relationship has been studied in at least one case-control studies (PMID 34250384) at the aggregate variant level. This study found no association of any cancer in individuals with heterozygous MSH3 variants (OR 0.9 [95% CI 0.4-1.9]) (PMID 34250384). Therefore, no points were assigned to the genetic evidence and it provides contradictory evidence. Only experimental evidence is scored in this curation (0.5 Points). Acharya et al showed a physical interaction of MSH3 with MSH2 and MSH6, two MMR genes associated with colorectal cancer. As a result of this reevaluation, the classification has been downgraded due to lack of significant evidence in association with Lynch syndrome and new case control data (PMID 34250384). In summary, the evidence supporting the relationship between MSH3 and autosomal dominant Lynch syndrome has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role MSH3 plays in this disease. This gene-disease pair was originally evaluated as limited by the Colon Cancer GCEP on November 13, 2017. This re-curation was approved by the ClinGen Hereditary Cancer GCEP on May 24, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0044300

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0018812

Submitter: Orphanet