Submissions for variant NM_000251.3(MSH2):c.1511-1G>A

dbSNP: rs267607964

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758599	SCV000887353	pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.1511-1G>A has a 99.4% 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000758599	SCV000919715	likely pathogenic	Lynch syndrome	2018-08-31	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1511-1G>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: Three predict the variant abolishes the canonical 3' acceptor site and introduces a cryptic 3' acceptor site 1bp into the exon. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246146 control chromosomes (gnomAD). The variant, c.1511-1G>A, has been reported in the literature in individuals affected with Lynch Syndrome (Vargas-Parra_2017, Yurgelun_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002388377	SCV002709776	pathogenic	Hereditary cancer-predisposing syndrome	2019-04-08	criteria provided, single submitter	clinical testing	The c.1511-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 10 of the MSH2 gene. This alteration was identified in an individual diagnosed with colorectal cancer, multiple sebaceous neoplasms that displayed high microsatellite instability (MSI-H) with loss of both MSH2/MSH6 on immunohistochemistry (IHC), and MSI-H renal cancer (Ambry internal data). This alteration was reported in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149(3):604-13.e20). This alteration was also detected in a patient meeting Bethesda criteria who was diagnosed with MSI-H colorectal cancer at age 56y, breast cancer at age 60y, endometrial cancer at age 61y and the colorectal cancer demonstrated loss of both MSH2/MSH6 protein expression on IHC (Vargas-Parra GM et al. Int J Cancer. 2017 Oct 1;141(7):1365-1380). This alteration has been classified as likely pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). 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.	RCV003453546	SCV004186624	likely pathogenic	Lynch syndrome 1	2023-08-02	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.