ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2600T>G (p.Val867Gly) (rs139598980)

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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 RCV000130173 SCV000185010 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
GeneDx RCV000222583 SCV000279104 uncertain significance not provided 2017-11-06 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2600T>G at the cDNA level, p.Val867Gly (V867G) at the protein level, and results in the change of a Valine to a Glycine (GTA>GGA). This variant has been observed in at least one individual with mismatch repair deficient rectal cancer (de Rosa 2016). MSH6 Val867Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Glycine share similar properties, this is considered a conservative amino acid substitution. MSH6 Val867Gly occurs at a position that is not conserved across species and is located in the lever domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Val867Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000238642 SCV000296880 uncertain significance Lynch syndrome 2015-11-19 criteria provided, single submitter clinical testing
Invitae RCV000524147 SCV000551103 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 867 of the MSH6 protein (p.Val867Gly). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs139598980, ExAC 0.01%). This variant has been reported in an individual affected with colorectal cancer (PMID: 27432916). ClinVar contains an entry for this variant (Variation ID: 141589). An algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggests that this missense change is likely to be tolerated. However, this prediction has 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.
Color RCV000130173 SCV000685301 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-02 criteria provided, single submitter clinical testing

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