ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1162C>G (p.His388Asp) (rs770386388)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204403 SCV000259508 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 388 of the MSH6 protein (p.His388Asp). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is present in population databases (rs770386388, ExAC 0.03%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 219569). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000519465 SCV000618483 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1162C>G at the cDNA level, p.His388Asp (H388D) at the protein level, and results in the change of a Histidine to an Aspartic Acid (CAC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 His388Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the mismatch binding domain and nuclear localization signals (Warren 2007, Gassman 2011, Kansikas 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 His388Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574858 SCV000662413 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence

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