ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3400G>C (p.Gly1134Arg) (rs1114167697)

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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 RCV000491586 SCV000580120 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-22 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
GeneDx RCV000519619 SCV000618343 uncertain significance not provided 2017-03-17 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3400G>C at the cDNA level, p.Gly1134Arg (G1134R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>CGA). This variant was observed in at least one individual undergoing multi-gene panel testing (LaDuca 2017). MSH6 Gly1134Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly1134Arg occurs at a position that is conserved across species and is located within the ATPase domain and within the ATP-binding motif (Kariola 2002). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Gly1134Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001050564 SCV001214679 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-02-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1134 of the MSH6 protein (p.Gly1134Arg). 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 an individual affected with endometrial cancer (Invitae). ClinVar contains an entry for this variant (Variation ID: 428300). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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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