Submissions for variant NM_000251.3(MSH2):c.792+1G>A

dbSNP: rs267607934

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076709	SCV000107745	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration interrupting known functional domains (full inactivation of variant allele)
Ambry Genetics	RCV001026957	SCV001189437	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-01	criteria provided, single submitter	clinical testing	The c.792+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the MSH2 gene. This variant has been identified in individuals meeting Amsterdam criteria with microsatellite unstable tumors also demonstrating loss of MSH2 and MSH6 protein expression by immunohistochemistry analysis (Cunningham JM et al. Am. J. Hum. Genet. 2001 Oct;69:780-90; Casey G et al. JAMA, 2005 Feb;293:799-809; Rosty C et al. Fam. Cancer 2014 Dec;13:573-82; Ambry internal data). The colon tumor of one of these patients was also found to have a somatic MSH2 mutation ("1165C>T, R389 stop") (Cunningham JM et al. Am. J. Hum. Genet. 2001 Oct;69:780-90). Additionally, conversion analysis confirmed that the c.792+1G>A variant results in coding exon 4 skipping (Casey G et al. JAMA 2005 Feb;293:799-809). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001026957	SCV001354533	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-24	criteria provided, single submitter	clinical testing	This variant (also known as IVS4+1G>A) causes a G>A nucleotide substitution at the +1 position of intron 4 of the MSH2 gene. Functional RNA studies have shown that this variant causes exon 4 skipping resulting in loss of DNA binding domain (PMID: 15713769). This variant has been reported in individuals affected with colorectal cancer and Lynch syndrome (PMID: 11524701, 15713769, 23752102, 25117503). 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. Based on the available evidence, this variant is classified as Pathogenic.
Invitae	RCV001233639	SCV001406243	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with colorectal cancer (PMID: 15713769, 25117503). ClinVar contains an entry for this variant (Variation ID: 91205). Studies have shown that disruption of this splice site results in partial intron inclusion due to the activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001588899	SCV001822507	likely pathogenic	not provided	2021-01-04	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of the critical connector domains (Lutzen 2008, Kansikas 2011); Not observed in large population cohorts (Lek 2016); Reported in individuals with colon cancer with concordant mismatch repair immunohistochemistry results reported to result in skipping of exon 4 (Cunningham 2001, Casey 2005, Rosty 2014).; This variant is associated with the following publications: (PMID: 32390703, 11524701, 23752102, 25117503, 15713769, 25525159)
Myriad Genetics, Inc.	RCV003452966	SCV004188014	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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15713769].