ClinVar

Description

Variant summary: MSH2 c.67T>C (p.Phe23Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 246202 control chromosomes, predominantly within the South Asian subpopulation in the gnomAD database at a frequency of 0.0049, including 2 homozygotes. This frequency within South Asian control individuals is approximately 9-fold above the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant has been reported in a patient with gastrointestinal stromal cancer, but without evidence of causality. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.