ClinVar

Description

Variant summary: MSH2 c.1862G>T (p.Arg621Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes. c.1862G>T has been reported in the literature in several individuals affected with Lynch Syndrome and Lynch syndrome-associated cancers (e.g., Salvador_2019, Li_2020, Fokkema_2011). These data indicate that the variant is likely to be associated with disease. At least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH6 c.3699_3702delAGAA, p.Lys1233fsX6; internal testing). At least one publication reports experimental evidence evaluating an impact on mismatch repair (MMR) function, suggesting the variant may have a deleterious effect (e.g., Jia_2021). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as pathogenic (n = 1)/likely pathogenic (n = 3). Based on the emerging consensus evidence outlined above, the variant was re-classified as likely pathogenic.