ClinVar

Description

Variant summary: MSH2 c.1847C>G (p.Pro616Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) domain of the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251478 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (6.8e-05 vs 0.00057), allowing no conclusion about variant significance. c.1847C>G has been reported in the literature in patients with colorectal cancer and other cancer phenotypes (examples: Raskin_2017, Yurgelun_2017, DeRychke_2017, etc). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variants have been reported (MSH2 large deletion, Cheng_2017; RAD51C c.934C>T, p.Arg312Trp, Germani_2020), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=3, VUS n=7). Based on the evidence outlined above, the variant was classified as likely benign.