ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2765G>A (p.Arg922Gln) (rs752839086)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000461564 SCV000920448 likely benign Lynch syndrome 2018-12-19 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability < 0.05 (0.028)
Invitae RCV000791412 SCV000551263 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 922 of the MSH6 protein (p.Arg922Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs752839086, ExAC 0.006%). This variant has been observed in individuals with Lynch syndrome-associated cancers (PMID: 28531214, 28206961). However, in one of these individuals a pathogenic allele was also identified in MSH6, which suggests that this c.2765G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 410514). This variant has been reported not to substantially affect MSH6 protein function (PMID: 28531214). 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.
GeneDx RCV000487150 SCV000572548 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2765G>A at the cDNA level, p.Arg922Gln (R922Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). Although this variant has not been reported as a germline variant to our knowledge, MSH6 Arg922Gln has been published as a somatic variant in an endometrial tumor and gastric tumor (Wang 2011, Mehnert 2016).MSH6 Arg922Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Arg922Gln occurs at a position that is not conserved and is located in domain III of the MutS domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Arg922Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563123 SCV000669915 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient evidence

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