ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.892C>T (p.Arg298Ter) (rs146816935)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130865 SCV000185764 pathogenic Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CSER_CC_NCGL; University of Washington Medical Center RCV000075043 SCV000196740 likely pathogenic Lynch syndrome 2014-06-01 criteria provided, single submitter research
Color RCV000130865 SCV000905447 pathogenic Hereditary cancer-predisposing syndrome 2018-05-11 criteria provided, single submitter clinical testing
GeneDx RCV000149892 SCV000211266 pathogenic not provided 2018-03-21 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.892C>T at the cDNA level and p.Arg298Ter (R298X) at the protein level. The substitution creates a nonsense variant, changing an Arginine to a premature stop codon (CGA>TGA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in at least three individuals with either a colon or endometrial cancer that demonstrated microsatellite instability (MSI-H) and is considered pathogenic (Goodfellow 2015, Morak 2017, Raskin 2017).
Integrated Genetics/Laboratory Corporation of America RCV000075043 SCV000695930 pathogenic Lynch syndrome 2016-03-14 criteria provided, single submitter clinical testing Variant summary: This c.892C>T variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein. Heterozygous loss-of-function mutations in this gene is an established disease mechanism in Lynch Syndrome (LS) or LS-associated cancers. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg482X, p.Arg911X, p.Arg1035X, etc.). This variant was found in 1/13006 control chromosomes from NHLBI ESP at a frequency of 0.0000769, which is lower than the maximal expected frequency of a pathogenic allele (0.0001421) in this gene. It was not found in approximately 121148 chromosomes from the broad and large populations from ExAC. This variant has been reported in two cases in literature, one known to be diagnosed with Endometrial Cancer with high risk of Lynch Syndrome based on the family history (Goodfellow_2015, Retterer_2015). In addition, the variant has been reported in 10 individuals in UMD database and in two individual by a clinical laboratory (Mayo Clinic Genetic Testing Laboratories) without information about clinical diagnosis. Multiple reputable databases and clinical laboratories have classified this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075043 SCV000108264 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000551832 SCV000625018 pathogenic Hereditary nonpolyposis colon cancer 2018-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg298*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with endometrial cancer (PMID: 26552419). ClinVar contains an entry for this variant (Variation ID: 89574). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000075043 SCV000713260 pathogenic Lynch syndrome 2017-07-13 criteria provided, single submitter clinical testing The p.Arg298X variant in MSH6 has been reported in 1 individual with Lynch syndr ome-associated cancers (breast and endometrial; Susswein et al. 2016) and has al so been identified in 1/15278 African chromosomes by the genome Aggregation Data base (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs146816935). This nonsens e variant leads to a premature termination codon at position 298, which is predi cted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in Lynch syndrome. Moreover, this variant was classified as pathogenic on September 5, 2013 by the ClinGen-ap proved InSiGHT expert panel (ClinVar SCV000108264.2). In summary, this variant m eets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon the predicted impact on the protein and low frequency in controls.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000149892 SCV000257307 pathogenic not provided no assertion criteria provided research

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