ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1565A>G (p.Gln522Arg) (rs63751009)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214996 SCV000276335 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000214996 SCV000903942 likely benign Hereditary cancer-predisposing syndrome 2016-10-28 criteria provided, single submitter clinical testing
Counsyl RCV000662803 SCV000785627 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-10-16 criteria provided, single submitter clinical testing
GeneDx RCV000219119 SCV000279097 uncertain significance not provided 2016-03-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1565A>G at the cDNA level, p.Gln522Arg (Q522R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). MSH6 Gln522Arg demonstrated significantly higher mismatch repair (MMR) activity in an in vitro MMR cell-free assay compared to repair-deficient controls (Drost 2012). This variant has been observed in at least four cases of early-onset colorectal cancers, most exhibiting normal MSI and/or IHC analyses, with no corresponding family having met Amsterdam I or II criteria for Lynch Syndrome (Berends 2002, Domingo 2005, Niessen 2006). MSH6 Gln522Arg 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 Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Gln522Arg occurs at a position that is conserved across species and is located at the MSH2 binding site and in domain II of the MutS domain (Kariola 2002, Terui 2013). 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 Gln522Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074663 SCV000107865 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000556355 SCV000624666 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 522 of the MSH6 protein (p.Gln522Arg). 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 the literature in individuals affected with colorectal cancer (PMID: 11709755, 15782118). ClinVar contains an entry for this variant (Variation ID: 89200). An experimental study has shown that this missense change does not significantly affect the mismatch repair activity of the MSH6 protein (PMID: 22102614). 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.

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