Submissions for variant NM_000251.3(MSH2):c.1276G>A (p.Gly426Arg)

dbSNP: rs879254234

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236876	SCV000293922	likely pathogenic	not provided	2024-11-14	criteria provided, single submitter	clinical testing	Located in a critical functional domain: Lever domain and region known for interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011) Not observed in large population cohorts (Lek 2016) Exonic splice site variant shown through cDNA analysis to result in two transcripts, the prominent full-length transcript and a less prominent transcript involving a partial in-frame deletion of 16 amino acids in exon 7 through use of a cryptic splice site (Vargas-Parra 2017) Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Vargas-Parra 2017)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001061266	SCV001226004	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-11-29	criteria provided, single submitter	clinical testing	This sequence change affects codon 426 of the MSH2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 15 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). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 28577310, 35676339; internal data). ClinVar contains an entry for this variant (Variation ID: 246389). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 28577310). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in exon 7 (PMID: 28577310, 35676339; internal data). 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.	RCV003454720	SCV004186648	likely pathogenic	Lynch syndrome 1	2023-08-01	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28577310, 35676339]. This variant is expected to disrupt protein structure [Myriad internal data].
Ambry Genetics	RCV004943823	SCV005450724	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-11-01	criteria provided, single submitter	clinical testing	The c.1276G>A variant (also known as p.G426R), located in coding exon 7 of the MSH2 gene, results from a G to A substitution at nucleotide position 1276. The amino acid change results in glycine to arginine at codon 426, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 16 amino acids (Meulemans L et al. J Med Genet, 2023 May;60:450-459); however the impacted region is critical for protein function (Ambry internal data). This variant has been identified in a probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH2 and MSH6 expression by immunohistochemistry (Li S et al. J. Med. Genet. 2020 Jan;57:62-69; Morak M et al. Eur J Hum Genet, 2022 Sep;30:1051-1059; external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.