ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.728G>A (p.Arg243His) (rs370157832)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160655 SCV000211261 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.728G>A at the cDNA level, p.Arg243His (R243H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been reported in an individual with ovarian cancer and at least one individual with advanced cancer (Lu 2015, Mandelker 2017). MSH6 Arg243His 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 Arg243His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000459365 SCV000551257 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 243 of the MSH6 protein (p.Arg243His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs370157832, ExAC 0.01%). This variant has been reported in an individual affected with ovarian cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 182611). General algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). An algorithm developed specifically for the MSH6 gene predicts that this missense change is likely to be tolerated (PMID: 23621914). These predictions have not been confirmed by published functional studies. 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.
Ambry Genetics RCV000568587 SCV000662495 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000568587 SCV000685517 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing

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