Submissions for variant NM_000251.3(MSH2):c.2459-2A>G

dbSNP: rs267608011

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478491	SCV000567436	pathogenic	not provided	2015-07-27	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH2 c.2459-2A>G or IVS14-2A>G and consists of a A>G nucleotide substitution at the -2 position of intron 14 of the MSH2 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature.
Ambry Genetics	RCV000491654	SCV000580518	pathogenic	Hereditary cancer-predisposing syndrome	2018-04-12	criteria provided, single submitter	clinical testing	The c.2459-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 15 in the MSH2 gene. This mutation was observed in 1/397 Hispanic colorectal cancer patients referred for genetic cancer risk assessment (Sunga AY et al. Cancer Genet. 2017 Apr;212-213:1-7). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379380	SCV001577174	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-08-13	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 14 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 12 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. 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: 28449805, 35430768; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 419555). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 15 (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV003449196	SCV004186716	likely pathogenic	Lynch syndrome 1	2023-08-08	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.