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

dbSNP: rs879254234

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001061266	SCV001226004	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-12-31	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. 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. 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; Invitae). 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). ClinVar contains an entry for this variant (Variation ID: 246389). This variant has been observed in individual(s) with colon cancer and/or ovarian cancer (PMID: 28577310; Invitae). This variant is not present in population databases (gnomAD no frequency).
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].
GeneDx	RCV000236876	SCV000293922	uncertain significance	not provided	2016-02-09	flagged submission	clinical testing	This variant is denoted MSH2 c.1276G>A at the cDNA level, p.Gly426Arg (G426R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in an MSH2 absent sebaceous neoplasm in an individual with colon cancer and an MSH2 absent sebaceous neoplasm (Joly 2015). MSH2 Gly426Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Gly426Arg occurs at a position that is conserved across species and is located in the lever domain and the region of interaction with MSH3 and MSH6 (Lützen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function; however, multiple splicing models predict that this variant destroys the nearby splice donor site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MSH2 Gly426Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.