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 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-14 criteria provided, single submitter clinical testing
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 The p.R922Q variant (also known as c.2765G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2765. The arginine at codon 922 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in an individual with an adenocarcinoma of the small intestine that showed loss of MSH2 and MSH6 proteins via immunohistochemistry; however, this individual was also found to carry five MSH2 alterations and six additional MSH6 alterations, so the role of the MSH6 p.R922Q variant in the formation of this individual's tumor could not be determined (Jun SY et al. Oncotarget, 2017 Mar;8:21483-21500). This alteration has been detected in conjunction with a known pathogenic mutation in a mismatch repair gene, and identified as not affecting mismatch repair function based on an in-vitro assay measuring cells survival in response to DNA damaging agent 6-thioguanine (6TG) exposure (Houlleberghs H et al. PLoS Genet., 2017 May;13:e1006765). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, the CoDP in silico tool predicts this alteration to have minor impact on molecular function, with a score of 0.020 (Terui H et al. J. Biomed. Sci. 2013;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000563123 SCV001342494 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-08 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 922 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported this variant protein to exhibit wild-type activity in DNA mismatch repair in vitro and in a mouse cell sensitivity assay to 6-thioguanine treatment (PMID: 28531214, 31965077). This variant has been observed in an individual affected with rectal cancer with tumor pathology consistent with DNA mismatch repair proficiency (UMD database), an individual affected with colorectal cancer who has a pathogenic MSH6 variant that could explain the observed phenotype (PMID: 28531214), and an individual affected with small intestinal adenocarcinoma (PMID: 28206961). This variant has been identified in 2/250952 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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