ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1030C>G (p.Gln344Glu) (rs730881815)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160714 SCV000211346 uncertain significance not provided 2014-10-06 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1030C>G at the cDNA level, p.Gln344Glu (Q344E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gln344Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Gln344Glu occurs at a position that is conserved across species and is located within the region for binding sites of MSH2 (Kariola 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Gln344Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000465512 SCV000551266 uncertain significance Lynch syndrome 2016-12-21 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 344 of the MSH6 protein (p.Gln344Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182658). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV001179479 SCV001344146 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-19 criteria provided, single submitter clinical testing

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