ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1046A>G (p.Gln349Arg) (rs869312797)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000210099 SCV000266198 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000220598 SCV000275964 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-24 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000524098 SCV000283695 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 349 of the MSH6 protein (p.Gln349Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a single family affected with colon cancer. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224578). 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. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000523088 SCV000616789 uncertain significance not provided 2017-11-01 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1046A>G at the cDNA level, p.Gln349Arg (Q349R) at the protein level,and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant has been observed in at least oneindividual with early-onset colon cancer (Shirts 2016). MSH6 Gln349Arg was not observed in large population cohorts(Lek 2016). Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acidsubstitution. MSH6 Gln349Arg occurs at a position that is not conserved and is located within the Nuclear localizationsignal (Gassman 2011). In silico analyses are inconsistent regarding the effect this variant may have on proteinstructure and function. Based on currently available evidence, it is unclear whether MSH6 Gln349Arg is a pathogenicor benign variant. We consider it to be a variant of uncertain significance.
Color RCV000220598 SCV000908368 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-23 criteria provided, single submitter clinical testing

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