ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.984C>G (p.Ser328Arg) (rs138143769)

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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 RCV000130197 SCV000185034 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000679242 SCV000566940 uncertain significance not provided 2018-06-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.984C>G at the cDNA level, p.Ser328Arg (S328R) at the protein level, and results in the change of a Serine to an Arginine (AGC>AGG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Ser328Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the nuclear localization signals (Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Ser328Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000630133 SCV000751089 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-25 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 328 of the MSH6 protein (p.Ser328Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 141606). 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.
PreventionGenetics,PreventionGenetics RCV000679242 SCV000805911 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing
Color RCV000130197 SCV000908363 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-26 criteria provided, single submitter clinical testing

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