Submissions for variant NM_000251.3(MSH2):c.943-1G>T

dbSNP: rs12476364

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468897	SCV000548146	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-09-19	criteria provided, single submitter	clinical testing	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: 408461). This variant disrupts the c.943-1G nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 11151427, 15849733, 20233461, 26866578). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change affects an acceptor splice site in intron 5 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 Lynch syndrome (PMID: 28874130).
Ambry Genetics	RCV000491423	SCV000580403	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-21	criteria provided, single submitter	clinical testing	The c.943-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 6 of the MSH2 gene. Two other alterations at the same nucleotide position, (c.943-1G>C and c.943-1G>A), have been reported in probands with Lynch syndrome (Mangold E et al. Int J Cancer. 2005 Sep 20;116(5):692-702; Pistorius SR et al. Int J Colorectal Dis. 2000 Nov;15(5-6):225-63). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985819	SCV001134381	pathogenic	not provided	2019-03-27	criteria provided, single submitter	clinical testing	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, and not found in general population data.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194032	SCV001363268	pathogenic	Hereditary nonpolyposis colon cancer	2019-11-29	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.943-1G>T 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: Five predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251346 control chromosomes (gnomAD). c.943-1G>T has been reported in the literature in individuals affected with Lynch Syndrome (Rossi_2017, Cruz-Correa_2015). Other variants affecting the same nucleotide (c.943-1G>C and c.943-1G>A) have been classified as likely pathogenic by the InSiGHT expert panel in ClinVar (IDs: 91253 and 91252). 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. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003449129	SCV004186703	pathogenic	Lynch syndrome 1	2023-07-28	criteria provided, single submitter	clinical testing	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. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV003449129	SCV004196200	pathogenic	Lynch syndrome 1	2023-10-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000776	SCV004818081	pathogenic	Lynch syndrome	2024-03-21	criteria provided, single submitter	clinical testing	The c.943-1G>T variant in 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: 28874130, 25782445). Other variants (c.943-1G>C and c.943-1G>A) affecting the same splicing acceptor site have been reported in individuals with Lynch syndrome (PMID: 15849733, 11151427). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733). Therefore, the c.943-1G>T variant of MSH2 is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004000776	SCV004848533	likely pathogenic	Lynch syndrome	2021-05-07	criteria provided, single submitter	clinical testing	The c.943-1G>T variant in MSH2 has been reported in at least 4 individuals with clinical features of Lynch Syndrome (Rossi 2017 PMID: 28874130, Cruz-Correa 2015 PMID: 25782445). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 408461) and was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Other variants affecting the same nucleotide (c.943-1G>C and c.943-1G>A) have been identified in individuals with Lynch syndrome and were classified as likely pathogenic by the InSiGHT expert panel as well as other clinical laboratories in ClinVar (Variation IDs: 91253 and 91252). Loss of function of the MSH2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PS4_Supporting, PM2_supporting, PVS1_Strong, PM5_Supporting.