ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1147C>T (p.Arg383Ter) (rs63749849)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076049 SCV000107062 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing a premature termination codon
Ambry Genetics RCV000221364 SCV000275097 pathogenic Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing The p.R383* pathogenic mutation (also known as c.1147C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1147. This changes the amino acid from an arginine to a stop codon within coding exon 7. This pathogenic mutation was first described in two individuals from a family with HNPCC (Buerstedde JM et al. J. Med. Genet. 1995 Nov;32:909-912). It has since been described in multiple individuals with Lynch syndrome and Muir-Torre related cancers (Banville N et al. Human Pathology. 2006 Nov;37:1498-1502; South CD et al. J. Natl. Cancer Inst. 2008 Feb;100:277-281; Tzortzatos G et al. Hered. Cancer Clin. Pract 2014;12:14; Rosty C et al. Fam. Cancer 2014 Dec;13(4):573-82). Tumors of individuals with this pathogenic mutation have exhibited microsatellite instability and/or absence of MSH2 protein on immunohistochemistry (Mangold E et al. J. Pathol. 2005 Dec;207:385-395; Spaepen M et al. Fam. Cancer 2006;5:179-189; Jasperson KW et al. Fam. Cancer 2010 Jun;9(2):99-107). 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 RCV000524330 SCV000548280 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-09-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg383*) in the MSH2 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 observed in individuals affected with Lynch syndrome, prostate cancer, and breast and/or ovarian cancer (PMID: 8592341, 23990280, 25117503, 25430799, 24344984, 15849733, 15872200, 24549055). ClinVar contains an entry for this variant (Variation ID: 90554). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000202261 SCV000568625 pathogenic not provided 2018-05-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH2 c.1147C>T at the cDNA level and p.Arg383Ter (R383X) 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. This variant has been reported in association with Lynch syndrome (Buerstedde 1995, Corleto 2005, Jasperson 2010, Rosty 2014), and is considered pathogenic.
Counsyl RCV000576748 SCV000677755 pathogenic Lynch syndrome I 2016-11-28 criteria provided, single submitter clinical testing
Mendelics RCV000076049 SCV000837827 pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000202261 SCV000884130 pathogenic not provided 2017-08-10 criteria provided, single submitter clinical testing The MSH2 c.1147C>T, p.Arg383Ter variant (rs63749849) is a recurrent alteration in families with hereditary nonpolyposis colorectal cancer (Buerstedde 1995, Heiniman 2000, Lamberti 1999, Lin 1999, Mangold 2005, Mangold 2005b, Mueller-Koch 2005, Overbeek 2007, Pistorius 2000, Spaepen 2006, Terdiman 2001). It is classified as pathogenic in ClinVar by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (Variation ID: 90554). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References Buerstedde J et al. Detection of new mutations in six out of 10 Swiss HNPCC families by genomic sequencing of the hMSH2 and hMLH1 genes. J Med Genet. 1995; 32(11):909-12. Heinimann K et al. Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer. Cancer. 1999; 85(12):2512-8. Lamberti C et al. Microsatellite instability-a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer. Gut. 1999; 44(6):839-43. Lin X et al. Reduction in hMSH2 mRNA levels by premature translation termination: implications for mutation screening in hereditary nonpolyposis colorectal cancer. Dig Dis Sci. 1999; 44(3):553-9. Mangold E et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005; 116(5):692-702. Mangold E et al. Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining. J Pathol. 2005b; 207(4):385-95. Mueller-Koch Y et al. Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut. 2005; 54(12):1733-40. Overbeek L et al. Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer. Br J Cancer. 2007 May 21;96(10):1605-12. Epub 2007 Apr 24. Pistorius S et al. Clinical consequences of molecular diagnosis in families with mismatch repair gene germline mutations. Int J Colorectal Dis. 2000; 15(5-6):255-63. Spaepen M et al. Germline mutations of the hMLH1 and hMSH2 mismatch repair genes in Belgian hereditary nonpolyposis colon cancer (HNPCC) patients. Fam Cancer. 2006; 5(2):179-89. Terdiman J et al. Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology. 2001; 120(1):21-30.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202261 SCV000888198 pathogenic not provided 2018-03-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763490 SCV000894276 pathogenic Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000221364 SCV000905225 pathogenic Hereditary cancer-predisposing syndrome 2020-09-03 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 7 of the MSH2 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 (PMID: 18270343, 19731080, 21642682, 22034109, 24549055, 24851142, 25117503, 25430799, 28874130). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192613 SCV001360858 pathogenic Hereditary nonpolyposis colon cancer 2021-04-13 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1147C>T (p.Arg383X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251460 control chromosomes. c.1147C>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome and associated tumors (example, Rossi_2017, Bonadona_2011, Banville_2006, Mangold_2005, Buerstedde_1995). These data indicate that the variant is very likely to be associated with disease. Banville et al (2006) showed loss of expression of MSH2 and MSH6 in tumor samples from a patient carrying this variant. Thompson et al (2014) reported a truncated polypeptide of MSH2 following protein truncation testing performed on patient RNA. Multiple clinical diagnostic laboratories and an expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202261 SCV000257123 pathogenic not provided 2018-01-04 no assertion criteria provided clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249954 SCV001423968 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001257542 SCV001434368 pathogenic Rhabdomyosarcoma 2020-09-01 no assertion criteria provided provider interpretation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000202261 SCV001551278 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000202261 SCV001956191 pathogenic not provided no assertion criteria provided clinical testing

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