ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3270G>C (p.Glu1090Asp) (rs876660165)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216891 SCV000277360 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-21 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000457746 SCV000551185 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-02-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 1090 of the MSH6 protein (p.Glu1090Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. 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: 233061). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Mendelics RCV000708886 SCV000837913 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001136 SCV001158280 uncertain significance not specified 2019-03-13 criteria provided, single submitter clinical testing The MSH6 c.3270G>C; p.Glu1090Asp variant (rs876660165), to our knowledge, is not described as a germline variant in the medical literature but contains an entry in ClinVar (Variation ID: 233061). It is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 1090 is moderately conserved, but computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. However, due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty.

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