ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1276G>A (p.Gly426Arg) (rs879254234)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236876 SCV000293922 uncertain significance not provided 2016-02-09 criteria provided, single submitter 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.
Invitae RCV001061266 SCV001226004 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-02-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 426 of the MSH2 protein (p.Gly426Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 7 of the MSH2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with ovarian cancer (PMID: 28577310). A different variant at this position (c.1276G>C, p.Gly426Arg) has been observed in an individual with clinical features of Lynch syndrome (PMID: 20937110). ClinVar contains an entry for this variant (Variation ID: 246389). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 28577310). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 28577310). 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.

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