ClinVar Genomic variation as it relates to human health

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19685281, 31822864, 33615670)

This sequence change affects a donor splice site in intron 1 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). 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: 428559). Disruption of this splice site has been observed in individuals with Lynch syndrome (LS) or clinical features of LS (PMID: 19685281; Invitae). This variant is not present in population databases (gnomAD no frequency).

The c.211+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the MSH2 gene. This mutation has been identified in a proband who met Amsterdam I criteria for Lynch syndrome (Raygada M et al. Am J Med Genet A, 2021 04;185:1282-1287). In a study of 1,721 German probands suspected of hereditary nonpolyposis colorectal cancer, this mutation was detected in one family (Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Arnold AM et al. Eur J Hum Genet, 2020 05;28:597-608). A different alteration at the same donor site (c.211+1G>C) has been identified in an individual diagnosed with Lynch syndrome and was determined to create a cryptic splice site 17 nucleotides upstream by a functional minigene splicing assay (Naruse H et al. Fam Cancer, 2009 Aug;8:509-17). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor 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.

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: 19685281].

ACMG criteria used to clasify this variant: PVS1, PM2_SUP, PS4