ClinVar

Description

The c.792+1_792+2delGTinsAC pathogenic mutation results from a deletion of GT nucleotides and insertion of AC nucleotides at positions c.792+1 to c.792+2 and involves the canonical splice donor site after coding exon 4 of the MSH2 gene. The canonical splice donor site is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site resulting in skipping of coding exon 4; however, direct evidence is unavailable. The resulting transcript is predicted to preserve the reading frame and is not expected to trigger nonsense-mediated mRNAdecay. However, the impacted region is critical for protein function (Ambry internal data). Other alterations impacting the same donor site (c.792+1delG and c.792+1G>A) have been detected in patients meeting Amsterdam criteria with tumors demonstrating loss of MSH2 and MSH6 protein expression by IHC (Cunningham JM et al. Am. J. Hum. Genet. 2001 Oct;69:780-90; Casey G et al. JAMA, 2005 Feb;293:799-809; Rosty C et al. Fam. Cancer 2014 Dec;13:573-82). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.