ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3930G>C (p.Glu1310Asp) (rs267608129)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129017 SCV000172916 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000524194 SCV000218999 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 1310 of the MSH6 protein (p.Glu1310Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs267608129, ExAC 0.002%). This variant has been reported in the literature in individuals affected with Lynch syndrome cancers (PMID: 18269114, 25980754). It has also been observed in an individual with rectosigmoid polyposis and breast cancer (Invitae). However, in that individual a pathogenic allele was also identified in PMS2, which suggests that this c.3930G>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 89482). 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"), while an algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). These predictions have not been confirmed by published functional studies. 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.
Color RCV000129017 SCV000685462 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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