Submissions for variant NM_000251.3(MSH2):c.2038C>T (p.Arg680Ter)

dbSNP: rs63749932

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030248	SCV000107394	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030248	SCV000052915	pathogenic	Lynch syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
GeneDx	RCV000202174	SCV000149424	pathogenic	not provided	2023-06-01	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; 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: 20215533, 12547705, 15713769, 25648859, 20587412, 24344984, 32549215, 31830689, 29922827, 28888541, 34761457, 31615790, 9311737, 21598002, 23047549, 12414824, 16807412, 18809606, 9718327, 11524701, 11854906, 11208710, 27318266, 18270343, 27013479, 16616355, 15345113, 15849733, 20233461, 19723918, 17312306, 15926618, 12658575, 12112654, 18566915, 27601186, 25980754, 25430799, 26681312, 28176205, 28944238, 29489754, 28874130, 30521064, 30322717, 31939059, 29625052, 31447099, 34178123, 30217226, 32719484, 30787465, 30998989)
Ambry Genetics	RCV000115515	SCV000184869	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	clinical testing	The p.R680* pathogenic mutation (also known as c.2038C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2038. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been identified in multiple individuals/families with HNPCC/Lynch syndrome (Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98; Levi Z et al. Am. J. Transplant. 2007 Feb;7:476-9; Brieger A et al. Fam. Cancer. 2011 Sep;10:591-5; Pal T et al. Br. J. Cancer. 2012 Nov;107:1783-90; Goldberg Y et al. Clin. Genet. 2015 Jun;87:549-53; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; DeRycke MS et al. Mol. Genet. Genomic Med. 2017 Jul;5:553-569; Rossi BM et al. BMC Cancer. 2017 Sep;17:623). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524372	SCV000219114	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg680*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is present in population databases (rs63749932, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 9311737, 15849733, 18270343, 20215533, 20233461, 20587412, 21598002, 23047549). ClinVar contains an entry for this variant (Variation ID: 36572). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202174	SCV000257165	pathogenic	not provided	2024-03-15	criteria provided, single submitter	clinical testing	PP4, PM2_moderate, PS3_supporting, PS4_moderate, PVS1
Color Diagnostics, LLC DBA Color Health	RCV000115515	SCV000537647	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 13 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with Lynch syndrome and/or Lynch syndrome-associated disease (PMID: 12547705, 20587412, 21879275, 23047549, 24344984, 25430799, 27013479, 27601186), as well as in individuals affected with breast cancer or prostate cancer whose tumors displayed abnormal MSH2/MSH6 protein via immunohistochemistry (PMID: 19723918, 20215533). This variant has been identified in 1/251446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 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	RCV000202174	SCV000601450	pathogenic	not provided	2024-07-12	criteria provided, single submitter	clinical testing	The MSH2 c.2038C>T (p.Arg680*) variant causes the premature termination of MSH2 protein synthesis. This variant has been reported in the published literature in multiple individuals and/or families with Lynch syndrome (LS) (PMID: 15849733 (2005), 20215533 (2010), 21598002 (2011), 30521064 (2019)) and LS-associated cancers (PMID: 20587412 (2010), 23047549 (2012), 30521064 (2019)). The frequency of this variant in the general population, 0.000004 (1/251446 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Counsyl	RCV000576755	SCV000677735	pathogenic	Lynch syndrome 1	2017-05-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000030248	SCV000711431	pathogenic	Lynch syndrome	2017-03-20	criteria provided, single submitter	clinical testing	The p.Arg680X variant in MSH2 has been reported in at least 5 individuals with L ynch syndrome-associated cancers (Hendriks 2003, Walsh 2010, Sjursen 2010, Pal 2 012, Dominguez-Valentin 2016). In addition, tumors sampled from 3 individuals sh owed microsatellite instability and lacked MSH2 and MSH6 expression. This varian t has also been identified in 1/66702 of European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs63749932). This nonsense variant leads to a premature termination codon at position 680, which is predicted to lead to a truncated or absent protein. Heterozygous loss of func tion of the MSH2 gene is an established disease mechanism in individuals with Ly nch Syndrome. Furthermore, the p.Arg680X variant has been classified as pathogen ic on by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107394.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch S yndrome in an autosomal dominant manner based upon the predicted impact to the p rotein.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000202174	SCV000884132	pathogenic	not provided	2017-09-08	criteria provided, single submitter	clinical testing	The MSH2 c.2038C>T, p.Arg680Ter variant (rs63749932) is a recurrent alteration in families with Lynch syndrome (Brieger 2011, Wijnen 1997, InSiGHT LOVD database). It is listed as pathogenic in ClinVar (Variation ID: 36572) by the International Society for Gastrointestinal Hereditary Tumours (Thompson 2014), and observed once in the Genome Aggregation Database general population database (1/246216 alleles). The variant introduces a premature termination codon, and predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References InSiGHT LOVD database: http://chromium.lovd.nl/LOVD2/colon_cancer/variants.php?action=search_unique Brieger A et al. Malignant fibrous histiocytoma is a rare Lynch syndrome-associated tumor in two German families. Fam Cancer. 2011; 10(3):591-5. Thompson B et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet. 2014; 46(2):107-15. Wijnen J et al. Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations. Am J Hum Genet. 1997; 61(2):329-35.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000202174	SCV001450222	pathogenic	not provided	2017-03-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000202174	SCV003822149	pathogenic	not provided	2022-02-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576755	SCV004018423	pathogenic	Lynch syndrome 1	2023-03-24	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	RCV000576755	SCV004196169	pathogenic	Lynch syndrome 1	2024-03-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000202174	SCV004699464	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MSH2: PVS1, PM2, PS4:Moderate, PP4, PS3:Supporting
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004555850	SCV005045096	pathogenic	Lynch syndrome 4	2024-01-03	criteria provided, single submitter	clinical testing	The MSH2 c.2038C>T (p.Arg680Ter) variant has been reported in many individuals affected with Lynch syndrome (Álvarez K et al., PMID: 32549215; Goldberg Y et al., PMID: 25430799; Jiang W et al., PMID: 30521064; Lagerstedt-Robinson K et al., PMID: 27601186; Zhang J et al., PMID: 35939113). This variant has been reported in the ClinVar database as a germline pathogenic variant by 16 submitters, including an expert panel. This variant is only observed on 1/251,446 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000576755	SCV005090952	pathogenic	Lynch syndrome 1	2024-07-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg680*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is present in population databases (rs63749932, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 20215533, 12547705, 15713769, 25648859, 20587412, 24344984, 32549215, 31830689, 29922827, 28888541, 34761457, 31615790, 9311737, 21598002, 23047549, 12414824, 16807412, 18809606, 9718327, 11524701, 11854906, 11208710, 27318266, 18270343, 27013479, 16616355, 15345113, 15849733, 20233461, 19723918, 17312306, 15926618, 12658575, 12112654, 18566915, 27601186, 25980754, 25430799, 26681312, 28176205, 28944238, 29489754, 28874130, 30521064, 30322717, 31939059, 29625052, 31447099, 34178123, 30217226, 32719484, 30787465, 30998989) . ClinVar contains an entry for this variant (Variation ID: 36572). 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. For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202174	SCV000592529	uncertain significance	not provided		no assertion criteria provided	clinical testing
3DMed Clinical Laboratory Inc	RCV000677886	SCV000804047	pathogenic	Malignant tumor of ascending colon	2018-01-04	no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001250040	SCV001423965	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing