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

gnomAD frequency: 0.00001  dbSNP: rs146816935

Total submissions: 14

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	2021-12-29	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. This mutation has been reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, including patients whose tumors demonstrated high microsatellite instability and/or loss of MSH2/MSH6 staining by immunohistochemistry (IHC) (Goodfellow PJ et al. J Clin Oncol, 2015 Dec;33:4301-8; Susswein LR et al. Genet Med, 2016 08;18:823-32; Morak M et al. Fam Cancer, 2017 Oct;16:491-500; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Long B et al. Gynecol Oncol, 2019 01;152:20-25; Salvador MU et al. J Clin Oncol, 2019 03;37:647-657; Pearlman R et al. J Med Genet, 2019 07;56:462-470; Bennett JA et al. Am J Surg Pathol, 2019 02;43:235-243). 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	2023-06-29	criteria provided, single submitter	clinical testing	Observed in individuals with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Goodfellow et al., 2015; Morak et al., 2017; Raskin et al., 2017; Bennett et al., 2019; Georgeson et al., 2019; Long et al., 2019; Pearlman et al., 2019; Salvador et al., 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26552419, 29922827, 28888541, 25637381, 26681312, 28528517, 29212164, 26633542, 30702970, 31162827, 30612635, 30256257, 30063919, 30877237, 31589614, 33087929, 30787465, 31447099)
Invitae	RCV000551832	SCV000625018	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-05	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. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is present in population databases (rs146816935, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with endometrial cancer (PMID: 26552419). ClinVar contains an entry for this variant (Variation ID: 89574). 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, Mass General Brigham 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 Diagnostics, LLC DBA Color Health	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.
Revvity Omics, Revvity	RCV000149892	SCV003820223	pathogenic	not provided	2022-11-04	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000149892	SCV004024787	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450996	SCV004188198	pathogenic	Lynch syndrome 5	2023-08-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV003466953	SCV004195835	pathogenic	Endometrial carcinoma	2023-02-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000149892	SCV000257307	pathogenic	not provided		no assertion criteria provided	research