ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1316A>G (p.Asp439Gly) (rs786202363)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165132 SCV000215842 uncertain significance Hereditary cancer-predisposing syndrome 2014-07-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000465468 SCV000551189 likely pathogenic Hereditary nonpolyposis colon cancer 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 439 of the MSH6 protein (p.Asp439Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with constitutional mismatch repair deficiency syndrome, and several individuals affected with Lynch syndrome (PMID: 30013564, Invitae). ClinVar contains an entry for this variant (Variation ID: 185673). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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