Submissions for variant NM_000251.3(MSH2):c.2635-1G>T

dbSNP: rs267608020

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076525	SCV000107556	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical acceptor splice site
Invitae	RCV000629741	SCV000750697	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 15 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 2624141, 15849733, 21286823, 27601186, 29690800; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91023). 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 the deletion of the first four nucleotides of exon 16 and introduces a new termination codon (PMID: 31332305). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002426638	SCV002741269	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-19	criteria provided, single submitter	clinical testing	The c.2635-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 16 of the MSH2 gene. In a study of 1,721 German probands suspected of HNPCC/Lynch syndrome, this alteration was detected in one family that either met Bethesda criteria or Amsterdam II criteria (excluding the age criterion) (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702). This nucleotide position is highly conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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/]). RNA studies demonstrated that this alteration induced a deletion of the first four nucleotides of exon 16 with 50% intensity (Morak M et al. Eur J Hum Genet, 2019 12;27:1808-1820). 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. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein. As such, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003452929	SCV004186672	likely pathogenic	Lynch syndrome 1	2023-08-10	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.