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

dbSNP: rs63749849

Total submissions: 23

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	2021-08-02	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 mutation has been detected in multiple HNPCC/Lynch syndrome families, and several had tumors demonstrating microsatellite instability and/or absence of MSH2 protein on immunohistochemistry (Buerstedde JM et al. J. Med. Genet., 1995 Nov;32:909-12; Heinimann K et al. Cancer, 1999 Jun;85:2512-8; Lamberti C et al. Gut, 1999 Jun;44:839-43; Lin X et al. Dig. Dis. Sci., 1999 Mar;44:553-9; Pistorius SR et al. Int J Colorectal Dis, 2000 Nov;15:255-63; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Hampel H et al. N Engl J Med, 2005 May;352:1851-60; Mangold E et al. J Pathol, 2005 Dec;207:385-95; Spaepen M et al. Fam Cancer, 2006;5:179-89; South CD et al. J. Natl. Cancer Inst., 2008 Feb;100:277-81; Jasperson KW et al. Fam Cancer, 2010 Jun;9:99-107; Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Buerki N et al. Genes Chromosomes Cancer, 2012 Jan;51:83-91; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2013 Dec;11:18; Rosty C et al. Fam. Cancer, 2014 Dec;13:573-82; Tzortzatos G et al. Hered Cancer Clin Pract, 2014;12:14; Goldberg Y et al. Fam Cancer, 2014 Mar;13:65-73; Xiong HY et al. Science, 2015 Jan;347:1254806; Goldberg Y et al. Clin Genet, 2015 Jun;87:549-53; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Tian W et al. Int J Cancer, 2019 09;145:1290-1298; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199; Vietri MT et al. Med Oncol, 2021 Jan;38:13). This mutation has also been identified in a cohort of high-risk breast/ovarian cancer patients (Castéra L et al. Eur J Hum Genet, 2014 Nov;22:1305-13). 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	RCV000524330	SCV000548280	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	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. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome, prostate cancer, and breast and/or ovarian cancer (PMID: 8592341, 15849733, 15872200, 23990280, 24344984, 24549055, 25117503, 25430799). ClinVar contains an entry for this variant (Variation ID: 90554). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000202261	SCV000568625	pathogenic	not provided	2023-08-02	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; Identified in individuals with personal and/or family histories consistent with Lynch syndrome (Buerstedde et al., 1995; Corleto et al., 2005; Jasperson et al., 2010; Rosty et al., 2014); 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: 24851142, 11093816, 11151427, 19731080, 24344984, 15872200, 31830689, 28888541, 25525159, 16437731, 25117503, 8592341, 21642682, 25194673, 25430799, 23990280, 23741719, 10375096, 22034109, 18270343, 10080150, 16736289, 10323887, 11179758, 11208710, 15955785, 17453009, 16996571, 27601186, 28502729, 28874130, 30521064, 31054147, 31615790, 33372952, 33484353, 30787465, 35264596, 31332305)
Counsyl	RCV000576748	SCV000677755	pathogenic	Lynch syndrome 1	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 1; Mismatch repair cancer syndrome 1; Muir-Torré syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000221364	SCV000905225	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-17	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. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 15 individuals and families affected with Lynch syndrome and associated cancers (PMID: 8592341, 10080150, 10323887, 11151427, 15872200, 16736289, 16996571, 19731080, 21642682, 24344984, 23990280, 25117503) and in three individuals and families affected with breast and ovarian cancer (PMID: 22034109, 24549055). This variant has been reported to segregate with disease in multiple families (combined segregation likelihood ratio for pathogenicity of 150.3:1; InSiGHT database). 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 (clinicalgenome.org). 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.
Genetics and Molecular Pathology, SA Pathology	RCV000576748	SCV002761478	pathogenic	Lynch syndrome 1	2022-07-07	criteria provided, single submitter	clinical testing	The Arg383* variant has been identified in numerous patients with Lynch syndrome and a function study has shown that the variant results in loss of the allele through nonsense mediated decay. The variant is absent from the GnomAD population database and is listed as a class 5 (pathogenic) variant in InSiGHT. The clinical features and IHC results of this case are highly specific for variants in the MSH2 gene. Variant not detected in blood.
CeGaT Center for Human Genetics Tuebingen	RCV000202261	SCV003916103	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	MSH2: PVS1, PM2, PS4:Moderate
Myriad Genetics, Inc.	RCV000576748	SCV004018412	pathogenic	Lynch syndrome 1	2023-03-23	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000576748	SCV004035138	pathogenic	Lynch syndrome 1	2023-09-17	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. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with prostate cancer, breast , ovarian cancer and  multiple HNPCC/Lynch syndrome families, and several had tumors demonstrating microsatellite instability and/or absence of MSH2 protein on immunohistochemistry (PMID: 24851142, 11093816, 11151427, 19731080, 24344984, 15872200, 31830689, 28888541, 25525159, 16437731, 25117503, 8592341, 21642682, 25194673, 25430799, 23990280, 23741719, 10375096, 22034109, 18270343, 10080150, 16736289, 10323887, 11179758, 11208710, 15955785, 17453009, 16996571, 27601186, 28502729, 28874130, 30521064, 31054147, 31615790, 33372952, 33484353, 30787465, 35264596, 31332305). ClinVar contains an entry for this variant (Variation ID: 90554) classified as pathogenic . For these reasons, this variant has been classified as Pathogenic. ​​​​​​​​​​​​​​
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000202261	SCV005196742	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202261	SCV001956191	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000202261	SCV001972917	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537287	SCV004716806	pathogenic	MSH2-related disorder	2024-01-31	no assertion criteria provided	clinical testing	The MSH2 c.1147C>T variant is predicted to result in premature protein termination (p.Arg383*). This nonsense variant has been previously reported in several individuals with a personal or family history of Lynch syndrome and various cancers including urinary tract cancer, colorectal cancer, prostate cancer, and breast cancer (Wischhusen et al. 2020. PubMed ID: 31615790; Jiang et al. 2019. PubMed ID: 30521064; Rosty et al. 2014. PubMed ID: 25117503; Castera et al. 2014. PubMed ID: 24549055). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/90554/). Nonsense variants in MSH2 are expected to be pathogenic. This variant is interpreted as pathogenic.