ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.115G>C (p.Gly39Arg) (rs751838296)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567789 SCV000662380 likely benign Hereditary cancer-predisposing syndrome 2017-11-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000567789 SCV000904011 likely benign Hereditary cancer-predisposing syndrome 2017-06-08 criteria provided, single submitter clinical testing
Counsyl RCV000663030 SCV000786063 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-02-14 criteria provided, single submitter clinical testing
GeneDx RCV000481267 SCV000565207 uncertain significance not specified 2016-12-22 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.115G>C at the cDNA level, p.Gly39Arg (G39R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gly39Arg 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. MSH6 Gly39Arg occurs at a position that is not conserved and is not located in a known functional domain (Terui 2013, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Gly39Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000459919 SCV000551191 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 39 of the MSH6 protein (p.Gly39Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs751838296, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 410476). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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