ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.892C>T (p.Arg298Ter) (rs146816935)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Ambry Genetics RCV000130865 SCV000185764 pathogenic Hereditary cancer-predisposing syndrome 2018-09-21 criteria provided, single submitter clinical testing The p.R298* pathogenic mutation (also known as c.892C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 892. This changes the amino acid from an arginine to a stop codon within coding exon 4. One study reported this mutation in a 53 year-old female whose endometrial tumor was MSI-H and demonstrated abnormal IHC (Goodfellow PJ et al. J. Clin. Oncol. 2015 Dec;33:4301-8). This mutation was also identified in a woman with breast and endometrial cancer who was one of 10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). One patient with this mutation was found to have MSI-H colon cancer at age 68 that demonstrated loss of MSH2 and MSH6 on IHC in addition to a somatic MSH3 mutation and several other somatic missense alterations in MSH6 (Morak M et al. Fam. Cancer 2017 May 20;[epub ahead of print]). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
CSER _CC_NCGL, University of Washington RCV000075043 SCV000196740 likely pathogenic Lynch syndrome 2014-06-01 criteria provided, single submitter research
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).
Invitae RCV000551832 SCV000625018 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-09-24 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000075043 SCV000713260 pathogenic Lynch syndrome 2019-04-19 criteria provided, single submitter clinical testing The p.Arg298X variant in MSH6 has been reported in at least 2 individuals with MSH6-associated cancers (Goodfellow 2015, Susswein et al. 2016) and has also been identified in 1/15278 African chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 298, which is predicted 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-approved InSiGHT expert panel (ClinVar SCV000108264.2). In summary, this variant meets 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. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PVS1.
Color Health, Inc RCV000130865 SCV000905447 pathogenic Hereditary cancer-predisposing syndrome 2020-08-25 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 26552419, 26681312, 28528517, 29212164). This variant has also been identified in 2/251272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000149892 SCV001134460 pathogenic not provided 2019-05-17 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient in literature, and found in general population data that is consistent with pathogenicity.
Mayo Clinic Laboratories, Mayo Clinic RCV000149892 SCV000257307 pathogenic not provided no assertion criteria provided research

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