ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2963G>A (p.Arg988His) (rs115386788)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214813 SCV000279452 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2963G>A at the cDNA level, p.Arg988His (R988H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as a known germline variant; however, it has been reported in two hypermutated brain tumors (Johnson 2017). MSH6 Arg988His was observed at an allele frequency of 0.04% (9/22,466) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the Clamp domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg988His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000534216 SCV000624806 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 988 of the MSH6 protein (p.Arg988His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs115386788, ExAC 0.05%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 234538). 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 histidine 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.
Ambry Genetics RCV000566696 SCV000669956 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-07 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000566696 SCV000904024 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-17 criteria provided, single submitter clinical testing

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