Submissions for variant NM_000251.3(MSH2):c.645+1G>A

dbSNP: rs267607689

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076659	SCV000107694	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000491616	SCV000580415	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	clinical testing	The c.645+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the MSH2 gene. This mutation has been reported in multiple individuals and families with HNPCC (Gille JJ et al. Br. J. Cancer, 2002 Oct;87:892-7; Choi YH et al. Hered Cancer Clin Pract, 2009 Aug;7:14; Akoum R et al. Int. J. Gynecol. Cancer;16:1516-21). In addition, an in vitro splicing assay showed that this alteration led to a 154 base pair deletion in an Australian colon cancer family (Thompson BA et al. Hum Mutat. 2013 Jan;34(1):200-9). Of note, this alteration is also designated as IVS3+1G>A in published literature. 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	RCV000985815	SCV001134372	pathogenic	not provided	2019-02-12	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.
Invitae	RCV001854335	SCV002154936	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12373605, 16451135, 16884359, 25117503, 29752822). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS3+1G>A. ClinVar contains an entry for this variant (Variation ID: 91155). Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 16451135, 22949379). This variant disrupts the p.Leu187 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15849733, 16327991, 17101317, 18951462, 28422960). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000985815	SCV000592472	pathogenic	not provided		no assertion criteria provided	clinical testing	The MSH2 c.645+1G>A variant was identified in 1 of 892 proband chromosomes (frequency: 0.001) from individuals or families with familial colon cancer (Choi 2009). The variant was also identified in ClinVar (classified as pathogenic by InSiGHT expert panel, Ambry Genetics, and our laboratory). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). This nucleotide substitution occurs in the invariant region of the splice consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the elimination of the 5’ splice site at this location. Further, this variant has been shown to result in multiple alternate transcripts, including exon 3 skipping (causing an in-frame deletion: p.Ala123_Gln215del) as well as alternate use of a nearby cryptic donor splice site (Thompson 2013). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.