Submissions for variant NM_000251.3(MSH2):c.1511-2A>G

dbSNP: rs267607962

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076184	SCV000107201	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration causing frameshift: full inactivation of variant allele
Ambry Genetics	RCV000491325	SCV000580440	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-17	criteria provided, single submitter	clinical testing	The c.1511-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 10 in the MSH2 gene. This mutation, also designated as IVS9-2A>G, has been reported in multiple HNPCC/Lynch syndrome families in the literature (Wijnen J et al. Am. J. Hum. Genet. 1997 Aug;61:329-35; Bianchi F et al. Int. J. Gynecol. Cancer; 2006 May-Jun;16:1419-23; Bianchi F et al. Clin. Genet. 2007 Feb;71:158-64; Wagner A et al. J. Med. Genet. 2002 Nov;39:833-7; Choi YH et al. Hered Cancer Clin Pract. 2009 Aug;7:14). In several studies, mRNA analysis indicated that this mutation results in abnormal splicing causing a frameshift (Casey G et al. JAMA. 2005 Feb 16;293:799-809; Bianchi F et al. Int. J. Gynecol. Cancer; 2006 May-Jun;16:1419-23; Jansen AM et al. Eur. J. Hum. Genet., 2018 Aug;26:1143-1150). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor 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.
Invitae	RCV001388415	SCV001589394	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-10-19	criteria provided, single submitter	clinical testing	Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16803540). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 9311737, 16803540, 19698169). ClinVar contains an entry for this variant (Variation ID: 90688). This variant is present in population databases (rs267607962, ExAC 0.001%). This sequence change affects an acceptor splice site in intron 9 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.
Myriad Genetics, Inc.	RCV003452838	SCV004186688	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.
Baylor Genetics	RCV003452838	SCV004193926	pathogenic	Lynch syndrome 1	2023-10-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000583875	SCV000691905	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000583875	SCV001958932	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000583875	SCV001971760	pathogenic	not provided		no assertion criteria provided	clinical testing