Submissions for variant NM_000179.3(MSH6):c.3202C>T (p.Arg1068Ter)

gnomAD frequency: 0.00002  dbSNP: rs63749843

Total submissions: 32

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074817	SCV000108028	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000201960	SCV000211314	pathogenic	not provided	2022-10-22	criteria provided, single submitter	clinical testing	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Plaschke et al., 2002; Steinke et al., 2008; Baglietto et al., 2010; McIlvried et al., 2010; Talseth-Palmer et al., 2010; Hinrichsen et al., 2013; Goodfellow et al., 2015; Morak et al., 2017; Salvador et al., 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23733757, 24323032, 20487569, 11807791, 18301448, 25741868, 25525159, 21247423, 20028993, 28152038, 26552419, 23403630, 15483016, 28002797, 20379851, 28528517, 29360161, 29489754, 30702970, 30324682, 30322717, 31447099, 34426522, 34178123, 31742824, 30787465)
Pathway Genomics	RCV000172816	SCV000223782	pathogenic	Lynch syndrome 1	2014-10-30	criteria provided, single submitter	clinical testing
Invitae	RCV000524156	SCV000253778	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1068*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal cancer, endometrial cancer, pancreatic cancer, and renal cancer (PMID: 11807791, 18301448, 20028993, 20379851, 24323032). ClinVar contains an entry for this variant (Variation ID: 89352). For these reasons, this variant has been classified as Pathogenic.
Vantari Genetics	RCV000160692	SCV000267056	pathogenic	Hereditary cancer-predisposing syndrome	2015-10-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160692	SCV000537682	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 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 or Lynch syndrome associated cancers (PMID: 11807791, 18301448, 20028993, 20379851, 20487569, 20937110, 24323032, 29967336). This variant has not been identified 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.
Ambry Genetics	RCV000160692	SCV000580090	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-12	criteria provided, single submitter	clinical testing	The p.R1068* pathogenic mutation (also known as c.3202C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3202. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families, several with tumors showing high microsatellite instability and/or absent MSH6 protein expression on IHC (Plaschke J et al. Int. J. Cancer, 2002 Feb;97:643-8; Steinke V et al. Eur J Hum Genet, 2008 May;16:587-92; Baglietto L et al. J Natl Cancer Inst, 2010 Feb;102:193-201; Talseth-Palmer BA et al. Hered Cancer Clin Pract, 2010 May;8:5; McIlvried DE et al. Fam. Cancer, 2010 Sep;9:377-81; Thodi G et al. BMC Cancer, 2010 Oct;10:544; Ward RL et al. J Clin Oncol, 2013 Jul;31:2554-62; Buchanan DD et al. J Clin Oncol, 2014 Jan;32:90-100; Goodfellow PJ et al. J Clin Oncol, 2015 Dec;33:4301-8; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Iordache PD et al. J Cell Mol Med, 2018 12;22:6068-6076; Dudley B et al. Cancer, 2018 04;124:1691-1700; Salvador MU et al. J Clin Oncol, 2019 03;37:647-657; Xu Y et al. BMC Cancer, 2021 Jan;21:45). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000201960	SCV000604284	pathogenic	not provided	2017-05-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000607176	SCV000743212	pathogenic	Lynch syndrome 5	2014-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000607176	SCV000744295	pathogenic	Lynch syndrome 5	2017-05-31	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000607176	SCV000840012	pathogenic	Lynch syndrome 5	2018-01-30	criteria provided, single submitter	clinical testing	This c.3202C>T variant in the MSH6 gene has been reported in multiple rectal cancer, HNPCC and Lynch syndrome patients [PMID:18301448, 20028993, 24323032] while not observed in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidence, this c.3202C>T (p.Arg1068*) in the MSH6 gene is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000201960	SCV000889487	pathogenic	not provided	2023-01-21	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MSH6 protein synthesis. The frequency of this variant in the general population, 0.00002 (3/152096 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with Lynch syndrome- associated cancers (PMIDs: 11807791 (2002), 18301448 (2008), 24323032 (2014), 28528517(2017), 29360161 (2018), 30324682 (2018), 30702970 (2019), 33422027 (2021), and 34178123 (2021)). Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763497	SCV000894283	pathogenic	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003389678	SCV000917784	pathogenic	Hereditary nonpolyposis colon cancer	2023-10-10	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3202C>T (p.Arg1068X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251326 control chromosomes. c.3202C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Baglietto_2010, Dudley_2018, Plaschke_2002, Steinke_2008, Talseth-Palmer_2010, Thodi_2010). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20028993, 29360161, 11807791, 18301448, 20487569, 20937110, 24362816, 25525159). 19 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000607176	SCV001251422	pathogenic	Lynch syndrome 5	2023-07-03	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM2_SUP,PP4
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253564	SCV001429346	pathogenic	Endometrial carcinoma	2019-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000201960	SCV001449723	pathogenic	not provided	2018-03-27	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000607176	SCV001984869	pathogenic	Lynch syndrome 5	2020-07-03	criteria provided, single submitter	clinical testing	This nonsense variant found in exon 5 of 10 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been reported in multiple individuals and families with Lynch syndrome-associated cancers such as colorectal cancer, endometrial cancer, pancreatic cancer and renal cancer (PMID: 11807791, 24323032, 20379851, 18301448, 20028993). This variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.3202C>T (p.Arg1068Ter) variant is classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000607176	SCV002761612	pathogenic	Lynch syndrome 5	2022-04-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000201960	SCV003820256	pathogenic	not provided	2022-04-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000201960	SCV004011166	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MSH6: PVS1, PM2, PS4:Moderate
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000201960	SCV004026071	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing	PS4_MOD, PVS1
Myriad Genetics, Inc.	RCV000607176	SCV004187404	pathogenic	Lynch syndrome 5	2023-08-22	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	RCV001253564	SCV004195677	pathogenic	Endometrial carcinoma	2023-07-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074817	SCV004842817	pathogenic	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	The c.3202C>T (p.Arg1068*) variant in the MSH6 gene is located on the exon 5 and introduces a premature translation termination codon (p.Arg1068*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with Lynch syndrome-associated cancers (PMID: 30324682, 29360161, 33422027, 28528517, 20487569). Loss-of-function variants of MSH6 are known to be pathogenic, and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with Lynch syndrome-associated cancers (PMID: 30376427, 18269114, 29345684). The variant is reported in ClinVar as pathogenic (ID: 89352) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.3202C>T (p.Arg1068*) variant of MSH6 has been classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000201960	SCV000257241	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353539	SCV000592625	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Arg1068X variant was identified in 8 of 3948 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome and endometrial cancer, and is classified as pathogenic in the literature (Buchanan 2014, Plaschke 2002, Plaschke 2004, Steinke 2008, Talseth Palmer 2010, Ward 2013, Castillejo 2011, Mcllvried 2010). The variant was also identified in the following databases: dbSNP (ID: rs63749843) as “With Pathogenic allele”, ClinVar (10x as pathogenic, reviewed by an expert panel), Clinvitae (4x as pathogenic), COGR, Cosmic (4x in colon cancer), UMD-LSDB (12x as "causal"), Insight Colon Cancer Gene Variant Database (15 x as pathogenic), and Mismatch Repair Genes Variant Database. The variant was not identified in MutDB, Zhejiang Colon Cancer Database, or Insight Hereditary Tumors Database. The variant was also identified by our laboratory in 2 individuals with uterine and endometrial cancer. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Arg1068X variant leads to a premature stop codon at position 1068, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000607176	SCV000734217	pathogenic	Lynch syndrome 5		no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249973	SCV001423987	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000201960	SCV001951712	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000201960	SCV002035556	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162474	SCV002758079	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research