ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2131C>T (p.Arg711Ter) (rs63750636)

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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) RCV000076405 SCV000107434 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Ambry Genetics RCV000129341 SCV000184105 pathogenic Hereditary cancer-predisposing syndrome 2018-06-05 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000524377 SCV000253805 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg711*) 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 reported in patients and families affected with non-polyposis colorectal cancer, and with Muir-Torre syndrome (PMID: 12132870, 12362047, 15849733, 16451135, 17569143, 18289827, 15235030, 17473388). ClinVar contains an entry for this variant (Variation ID: 90903). 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 RCV000202062 SCV000292625 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2131C>T at the cDNA level and p.Arg711Ter (R711X) 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 individuals with early-onset familial colorectal, endometrial, and other Lynch syndrome-associated cancers, with some patients exhibiting the Muir-Torre variant phenotype (Kurzawski 2002, Mangold 2004, Apessos 2005, Papp 2007, Pedroni 2007, Rios 2014, Tanyi 2014, Nowak 2016, Pearlman 2016). Most tumor studies reported in the literature demonstrate microsatellite instability and loss of MSH2 protein expression (Pedroni 2007, Rios 2014, Tanyi 2014, Nowak 2016, Pearlman 2016). We consider this variant to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076405 SCV000592536 pathogenic Lynch syndrome 2013-03-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202062 SCV000601456 pathogenic not provided 2015-10-20 criteria provided, single submitter clinical testing
Color RCV000129341 SCV000685015 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076405 SCV000696236 pathogenic Lynch syndrome 2017-01-10 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2131C>T (p.Arg711X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. c.2152C>T(p.Gln718X), c.2633_2634delA(p.Glu878fsX3), etc.). This variant is absent in 121400 control chromosomes from ExAC. In literature and clinical databases, this variant is reported as a pathogenic variant and is found in several HNPCC families/patients, including one patient with Muir-Torre Syndrome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
GeneKor MSA RCV000129341 SCV000821737 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This is a point mutation replacing one nucleotide in the position 2131 of the MSH2 gene, leading in the replacement of Arginine with a termination stop codon in the position 711 of the MSH2 protein. This particular variant has been described in international literature in families with Lynch syndrome and with Muir-Torre syndrome (PMID: 17569143, PMID: 17473388, PMID: 16451135, PMID: 15235030). The mutation database ClinVar contains an entry for this variant (Variation ID: 90903).
Mendelics RCV000076405 SCV000837849 pathogenic Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763494 SCV000894280 pathogenic Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000076405 SCV000914304 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000186 SCV001156679 pathogenic not specified 2019-04-30 criteria provided, single submitter clinical testing The MSH2 c.2131C>T; p.Arg711Ter variant (rs63750636) is reported in several individuals with Lynch syndrome and an individual with Muir-Torre syndrome (Rios 2014, Rossi 2017, Schneider 2018, see LOVD InSiGHT link). This variant is classified as pathogenic by multiple laboratories in ClinVar (Variation ID: 90903). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to InSiGHT database: Rios CA et al. Muir-Torre syndrome: case report and molecular characterization. Sao Paulo Med J. 2014;132(1):61-4. Rossi BM et al. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer. 2017 Sep 5;17(1):623. Schneider NB et al. Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome. Cancer Med. 2018 May;7(5):2078-2088.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202062 SCV000257170 pathogenic not provided no assertion criteria provided research
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249926 SCV001423943 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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