ClinVar Miner

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

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Total submissions: 6
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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 colorectal neoplasms 2019-12-17 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 2019-04-19 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000563123 SCV001342494 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192425 SCV001360538 likely benign not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2765G>A (c.2765G>A) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250952 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2765G>A has been reported in the literature in individuals affected with colorectal cancer and Lynch Syndrome associated cancers (Houlleberghs_2017, Jun_2017). However, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with another pathogenic variant have been reported (MSH6 c.2805dup , p.Asp936X) in the literature for this variant (Houlleberghs_2017) , providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Houlleberghs_2017). Four submitters including one expert panel (InSiGHT) have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (3x uncertain significance and 1x Likely benign-InSiGHT). Based on the evidence outlined above, the variant was classified as likely benign.

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