ClinVar Genomic variation as it relates to human health

Interrupts canonical donor splice site

This variant disrupts a canonical splice-donor site and interferes with normal MSH2 mRNA splicing. In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 28944238 (2017)) and epithelial ovarian cancer (PMID: 24728189 (2014)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

This variant causes a G to A nucleotide substitution at the +1 position of intron 11 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with colorectal cancer (PMID: 28874130, 28944238). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

This sequence change affects a donor splice site in intron 11 of the MSH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 11772966, 24728189, 28944238; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90766). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Variant summary: MSH2 c.1759+1G>A 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 245802 control chromosomes (gnomAD). This variant has been reported in the literature in individuals affected with Lynch Syndrome (Song_2014, Rossi_2017, DeRycke_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

PVS1, PM2

The c.1759+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the MSH2 gene. This mutation has been detected in multiple individuals with hereditary non-polyposis colorectal cancer/Lynch syndrome; several whose tumors demonstrated loss of MSH2 and MSH6 staining by immunohistochemistry (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.