ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2038C>T (p.Arg680Ter) (rs63749932)

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Total submissions: 15
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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 2018-12-30 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH2 c.2038C>T at the cDNA level and p.Arg680Ter (R680X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 Arg680Ter has been reported in association with Lynch syndrome and related cancers, including several individuals whose tumors showed microsatellite instability and/or loss of MSH2 protein on mismatch repair immunohistochemistry (Farrington 1998, Cai 2001, Barnetson 2006, Hampel 2008, Walsh 2010, Brieger 2011, Pal 2012, Dominguez-Valentin 2016, Zhang 2016). We, therefore, consider this variant to be pathogenic.
Ambry Genetics RCV000115515 SCV000184869 pathogenic Hereditary cancer-predisposing syndrome 2019-02-13 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.
Invitae RCV000524372 SCV000219114 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-09-24 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. This variant is present in population databases (rs63749932, ExAC 0.001%). This variant has been reported in individuals and families affected with Lynch syndrome (PMID: 9311737, 15849733, 20587412, 18270343, 21598002), ovarian cancer (PMID: 23047549), prostate cancer (PMID: 20233461) and breast cancer (PMID: 20215533). ClinVar contains an entry for this variant (Variation ID: 36572). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000115515 SCV000537647 pathogenic Hereditary cancer-predisposing syndrome 2020-09-28 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 affected with Lynch syndrome (PMID: 12547705, 20215533, 20587412, 21879275, 24344984, 25430799, 27013479, 27601186), ovarian cancer (PMID: 23047549), and prostate cancer (PMID: 19723918). 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 ( Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202174 SCV000601450 pathogenic not provided 2020-04-03 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 patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Counsyl RCV000576755 SCV000677735 pathogenic Lynch syndrome I 2017-05-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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,; 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.
3DMed Clinical Laboratory Inc RCV000677886 SCV000804047 pathogenic Malignant tumor of ascending colon 2018-01-04 criteria provided, single submitter clinical testing
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: 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 Karolinska University Hospital,Karolinska University Hospital RCV000202174 SCV001450222 pathogenic not provided 2017-03-30 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202174 SCV000257165 pathogenic not provided no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000202174 SCV000592529 uncertain significance not provided 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

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