Submissions for variant NM_000251.3(MSH2):c.2634+1G>A

dbSNP: rs267608019

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076518	SCV000107548	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Ambry Genetics	RCV000491073	SCV000580451	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	The c.2634+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 15 of the MSH2 gene. This mutation has been reported in at least one proband who met Amsterdam I/II criteria for Lynch syndrome (Bonadona V et al. JAMA 2011 Jun;305:2304-10; Kurzawski G et al. Clin. Genet. 2006 Jan;69:40-7; Liu B et al. Cancer Res. 1994 Sep;54:4590-4). In addition, published in vitro analyses indicated that this substitution lead to the skipping of coding exon 15 (Liu B et al. Cancer Res. 1994 Sep;54:4590-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. 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 pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506677	SCV000604260	pathogenic	not specified	2016-10-06	criteria provided, single submitter	clinical testing
Invitae	RCV000688047	SCV000815644	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-12	criteria provided, single submitter	clinical testing	Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 15 and introduces a premature termination codon (PMID: 8062247). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91016). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 8062247, 16451135, 20587412, 21642682, 25980754; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 15 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076518	SCV000919702	pathogenic	Lynch syndrome	2018-05-16	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2634+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: Four predict the variant abolishes a 5' splicing donor site. One publication reports experimental evidence showing exon 15 deletion associated with this variant (Liu_1994). The variant was absent in 121394 control chromosomes (ExAC). The variant, c.2634+1G>A, has been reported in the literature in several individuals affected with Lynch Syndrome (Bonadona_2011, Dymerska_2010, Liu_1994, Yurgelun_2015). These data indicate that the variant is likely associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV002222380	SCV002499793	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing	Canonical splice site variant shown to result in loss of exon 15 and premature truncation in patient-derived cDNA (Liu 1994) in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Liu 1994, Kurzawski 2006, Bonadona 2011, Yurgelun 2015); This variant is associated with the following publications: (PMID: 25525159, 33809179, 21642682, 8062247, 25980754, 16451135, 15555211, 27284491, 20007843)
Myriad Genetics, Inc.	RCV003452923	SCV004187920	pathogenic	Lynch syndrome 1	2023-08-09	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: 3658675]. 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	RCV003452923	SCV004196886	pathogenic	Lynch syndrome 1	2022-11-12	criteria provided, single submitter	clinical testing