ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2408A>G (p.Asp803Gly) (rs63751450)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130124 SCV000184956 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148651 SCV000190366 uncertain significance Colorectal cancer 2014-06-01 no assertion criteria provided research
Color RCV000130124 SCV000537593 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing
Counsyl RCV000410826 SCV000488182 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-01-27 criteria provided, single submitter clinical testing
GeneDx RCV000586083 SCV000211297 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2408A>G at the cDNA level, p.Asp803Gly (D803G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAC>GGC). This variant has been observed in an individual with rectal cancer and a family history of colorectal cancer, as well as in an individuals with a personal history of glioblastoma, pancreatic, or breast cancer (Kolodner 1999, Grant 2015, Lu 2015, Tung 2015). A functional study found that this variant appears to uncouple the mismatch binding and ATP hydrolysis activities of the MSH2-MSH6 heterodimer (Cyr 2008). MSH6 Asp803Gly was observed at an allele frequency of 0.089% (9/10,136) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located in the lever domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Asp803Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586083 SCV000695812 uncertain significance not provided 2016-11-04 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2408A>G (p.Asp803Gly) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 11/121424 control chromosomes, predominantly observed in the South Asian subpopulation in ExAC at a frequency of 0.0003637 (6/16496). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant has been reported in affected individuals in the literature, without strong evidence for causality (Kolodner_1999, Grant_2015). In addition, functional studies found the variant to affect the ability to be cross linked to ATP, suggesting the mutant appears to uncouple the mismatch binding and ATPhydrolysis activities of the heterodimer (Cyr_2008). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Due to conflicting data regarding population frequency and potential functional effects, this variant is classified as VUS until more information becomes available..
Invitae RCV000524143 SCV000261326 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 803 of the MSH6 protein (p.Asp803Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs63751450, 0.04%). This variant has been reported in individuals affected with colorectal cancer (PMID: 10537275), glioblastoma multiforme (PMID: 26689913), pancreatic cancer (PMID: 25479140), and breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 89281). Experimental studies have shown that this missense change reduces the ATP hydrolysis activity of the MSH6-MSH2 heterodimer (PMID: 18790734). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212666 SCV000539712 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Classified as VUS by expert panel in 2013; no new evidence supporting pathogenicity since then
Mendelics RCV000074746 SCV000837896 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212666 SCV000601531 uncertain significance not specified 2017-03-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586083 SCV000888255 uncertain significance not provided 2018-04-16 criteria provided, single submitter clinical testing

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