MSH3 encodes a protein that partners with MSH2 to form MutS beta, a key component of the DNA mismatch repair system that recognizes and corrects errors made during DNA replication. It acts as a tumor suppressor: loss of MSH3 function leads to mismatch repair deficiency, an elevated mutation rate, and increased cancer risk, and the gene is frequently altered in mismatch repair-deficient colorectal cancers. Defects in MSH3 are linked to susceptibility to endometrial cancer, and inherited mutations are associated with an autosomal recessive form of familial adenomatous polyposis, with minimal evidence for a role in Lynch syndrome. Tumors with mismatch repair deficiency, including those involving MSH3, tend to respond well to immune checkpoint inhibitor therapies.
This synonymous MSH3 variant occurs in a gene involved in MutS beta mismatch repair and associated with autosomal recessive familial adenomatous polyposis and mismatch-repair deficiency.
PM2 supporting: maximum observed gnomAD population allele frequency is 6.27113e-05, below 0.0001. VUS: one supporting criterion does not satisfy a generic ACMG/AMP pathogenic or benign combination rule.
European (non-Finnish) 74 / 1,180,010 |
0.0063% |
Remaining individuals 2 / 62,470 |
0.0032% |
African/African American 1 / 74,922 |
0.0013% |
European (non-Finnish) 6 / 129,122 |
0.0046% |
African/African American 1 / 24,964 |
0.004% |
