ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
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 Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000524330 SCV000548280 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-23 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 RCV000221364 SCV000905225 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192613 SCV001360858 pathogenic Hereditary nonpolyposis colon cancer 2019-04-03 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. The variant was absent in 246250 control chromosomes (gnomAD) but has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer and endometrial cancer (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. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. In addition, a reputable database (InSight) classifies this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Genetic Testing 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.