ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2569G>A (p.Asp857Asn) (rs368437140)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233195 SCV000283758 uncertain significance Lynch syndrome 2016-02-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 857 of the MSH6 protein (p.Asp857Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs368437140, ExAC 0.02%) but has not been reported in the literature in individuals with a MSH6-related disease. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithm developed specifically for mismatch repair genes or the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000568833 SCV000662469 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence

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