ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1012G>C (p.Gly338Arg) (rs63751004)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218258 SCV000277051 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-06 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000255930 SCV000322179 uncertain significance not provided 2016-06-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1012G>C at the cDNA level, p.Gly338Arg (G338R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>CGA). This variant has been reported in a woman with a history of both colon and endometrial cancer; tumor testing on the endometrial tumor showed it was MSI-H with loss of MSH2 (Moline 2013). Gammie et al. (2007) showed that the yeast equivalent of MSH2 Gly338Arg results in low levels of MSH2 protein and loss of interaction with MSH2 partners. While this functional data points towards pathogenicity, what effects that MSH2 Gly338Arg could have on MSH2 protein structure and functions remain to be determined since the human equivalent was not assessed. MSH2 Gly338Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Gly338Arg occurs at a position that is conserved across species and is located in the Lever domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Gly338Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV001232403 SCV001404960 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-09-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 338 of the MSH2 protein (p.Gly338Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with Lynch syndrome cancers (PMID: 16736289, 23612316) and has been found to segregate with disease in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 232810). This variant has been reported to affect MSH2 protein function (PMID: 17720936). 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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