ClinVar Genomic variation as it relates to human health

Interrupts canonical donor splice site

MSH2 NM_000251.2:c.1760-1G>A has a 98.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.

The c.1760-1G>A variant in MSH2 has been reported in 1 individual with MSH2-asso ciated cancer (Hu et al. 2011) and was absent from large population studies. Thi s variant occurs in the invariant region (+/- 1,2) of the splice consensus seque nce and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the MSH2 gene is an established diseas e mechanism in Lynch syndrome. In addition, this variant was classified as likel y pathogenic on Sept 13, 2013 by the ClinGen-approved InSiGHT expert panel (Clin Var SCV000107297.2). In summary, although additional studies are required to ful ly establish its clinical significance, the c.1760-1G>A variant is likely pathog enic. ACMG/AMP Criteria applied: PVS1; PM2.

This variant is considered likely 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.

This sequence change affects an acceptor 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 individual(s) with clinical features of Lynch syndrome (PMID: 20459533, 22166501; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90773). 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.1760-1G>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 3' acceptor site. Three predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 1612342 control chromosomes (gnomAD v4). c.1760-1G>A has been reported in the literature in individuals affected with Lynch Syndrome or Lynch-syndrome associated cancers (e.g., Hu_2011, Barrow_2010, Kansikas_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20459533, 22166501, 36875157, 31447099). ClinVar contains an entry for this variant (Variation ID: 90773). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The c.1760-1G>A variant of the MSH2 gene is predicted to affect mRNA splicing and result in an absent or disrupted protein product. This variant has been reported in individuals with Lynch syndrome (PMID: 20459533, 22166501). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncating variants in MSH2 are known to be pathogenic (PMID: 15849733). Therefore, the c.1760-1G>A variant of MSH2 gene is classified as likely pathogenic.

The c.1760-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide before coding exon 12 of the MSH2 gene. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability and/or loss of MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). This variant has also been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2/MSH6 expression by immunohistochemistry (Barrow E et al. Histopathology, 2010 Feb;56:331-44; Ambry internal data). In addition, this variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome (Hu P et al. Ann. Clin. Lab. Sci., 2011;41:321-30; 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 acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, 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.

MSH2: PVS1, PM2, PS4:Moderate

This variant is denoted MSH2 c.1760-1G>A or IVS11-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 11 of the MSH2 gene. This variant destroys a canonical splice acceptor 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 been reported in at least one proband meeting Amsterdam criteria for Lynch syndrome (Hu 2011). Based on the currently available information, we consider MSH2 c.1760-1G>A to be a likely pathogenic variant.

The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient in literature, and not found in general population data.

This variant causes a G to A nucleotide substitution at the -1 position of intron 11 of the MSH2 gene. Splice site prediction tools suggest 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 Lynch syndrome (PMID: 20459533, 22166501). 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.