ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2762C>T (p.Ala921Val) (rs1060502936)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473774 SCV000551270 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 921 of the MSH6 protein (p.Ala921Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 410516). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
Ambry Genetics RCV000571747 SCV000670011 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000780483 SCV000917769 uncertain significance not specified 2018-08-17 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2762C>T (p.Ala921Val) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245700 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2762C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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