ClinVar Genomic variation as it relates to human health

This pathogenic variant is denoted MSH2 c.792+1delG or IVS4+1delG and consists of a single nucleotide deletion at the +1 position of intron 4 of the MSH2 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the current evidence, we consider MSH2 c.792+1delG to be pathogenic.

Variant summary: MSH2 c.792+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250880 control chromosomes. To our knowledge, no occurrence of c.792+1delG in individuals affected with Hereditary Nonpolyposis Colorectal Cancer has been reported in the literature and no experimental evidence demonstrating its impact on protein function have been reported. However, the variant has been reported in inviduals in the UMD database. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This variant is also known as c.792+1del. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 419862). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (Splice site) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).

The c.792+1delG pathogenic mutation, results from a deletion of the first nucleotide downstream of coding exon 4 in the MSH2 gene. A different alteration impacting the same position, c.792+1G>A, has been identified in a family meeting Amsterdam I criteria with tumors exhibiting loss of MSH2 and MSH6 on IHC (Casey G et al., JAMA. 2005; 293(7): 799-809). Using the BDGP and ESEfinder splice site prediction tools, the c.792+1delG alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15713769].