ClinVar

Description

The c.301_306delGAAGTT variant (also known as p.E101_V102del) is located in coding exon 2 of the MSH2 gene. This variant results from an in-frame six base pair deletion between nucleotide positions 301 and 306. This results in the deletion of a glutamic acid residue and a valine residue, two highly conserved amino acids, between codons 101 and 102. This alteration has been previously reported in multiple families meeting Amsterdam and/or Bethesda criteria and included family members with colon tumors that demonstrated absent MSH2 staining on immunohistochemistry and high microsatellite instability (MSI-H) (Glasl et al. Hum Mutat. 2000 Jul;16(1):91-2; Goldberg et al. Fam Cancer. 2008;7(4):309-17; Ambry internal data). This alteration has been classified as likely pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15). Of note, this variant is also referred to as 300-305delAGTTGA and c.297_302delAGTTGA in published literature. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.