ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2950A>G (p.Asn984Asp) (rs146359682)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483801 SCV000566324 uncertain significance not provided 2018-08-24 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2950A>G at the cDNA level, p.Asn984Asp (N984D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asn984Asp was not observed in large population cohorts (Lek 2016). Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Asn984Asp is located in the clamp domain (Warren 2007, 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 information, it is unclear whether MSH6 Asn984Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000546084 SCV000624804 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 984 of the MSH6 protein (p.Asn984Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an MSH6-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000574429 SCV000669903 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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