MSH2 NM_000251.3:c.1661+1G>A, Splice_Site

This sequence change affects a donor splice site in intron 10 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 12624141, 16034045, 16142001, 21642682). This variant is also known as IVS10+1G>A. ClinVar contains an entry for this variant (Variation ID: 90719). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.

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: 18561205].

The c.1661+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 10 of the MSH2 gene. This variant has been reported in multiple Lynch syndrome/HNPCC families and is also referred to as IVS10+1G>A (Bécouarn Y et al. Gastroenterol. Clin. Biol.;29:667-75; Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13; Stormorken AT et al. J. Clin. Oncol., 2005 Jul;23:4705-12; Bonadona V et al. JAMA, 2011 Jun;305:2304-10). Two pathogenic variants, c.1661+1G>T and c.1661+2T>C, which also affect this canonical splice site, have also been reported (Papp J et al. World J. Gastroenterol. 2007 May;13(19):2727-32; Ambry internal data). 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. Variants 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 variant is classified as a disease-causing mutation.