Submissions for variant NM_000251.3(MSH2):c.2005+2T>C

dbSNP: rs267607987

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076341	SCV000107367	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV002415558	SCV002720451	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-14	criteria provided, single submitter	clinical testing	The c.2005+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 12 in the MSH2 gene. This alteration has been reported in a family meeting Amsterdam I criteria in which the proband had MSI-H colorectal cancer that showed absent MSH2 protein expression on IHC (Mueller-Koch Y et al. Gut. 2005 Dec;54:1733-40). This mutation has also been reported in a cohort of German patients with HNPCC and in an individual with the Muir-Torre variant of Lynch syndrome (Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Mangold E et al. J. Med. Genet. 2004 Jul;41:567-72). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV003452874	SCV004186715	likely pathogenic	Lynch syndrome 1	2023-08-04	criteria provided, single submitter	clinical testing	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.
Invitae	RCV003593898	SCV004293896	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 12 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: 16142001, 21642682; Invitae). ClinVar contains an entry for this variant (Variation ID: 90839). 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.
Color Diagnostics, LLC DBA Color Health	RCV002415558	SCV004356715	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +2 position of intron 12 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant has demonstrated to result in partial in-frame skipping of exon 12 in a cell-based minigene assay, with 53% of transcripts demonstrating the exon 12 skipping (PMID: 36113988). Two out-of-frame transcripts were also observed in this assay. A methylation tolerance assay showed the in-frame exon skipping variant had similar survival scores to the pathogenic controls (PMID: 36113988). This variant has been reported in an individual affected with Lynch syndrome whose tumor displayed loss of MSH2 protein via immunohistochemistry (PMID: 15955785) and in a German cohort of individuals affected with Lynch syndrome or suspected of Lynch syndrome (PMID: 15849733). This variant has also been reported in an individual affected with Muir Torre syndrome with a family history of colorectal cancer (PMID: 15235030). 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 Pathogenic.