ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218258 SCV000277051 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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
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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.