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

gnomAD frequency: 0.00001  dbSNP: rs63750636

Total submissions: 25

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	2021-06-23	criteria provided, single submitter	clinical testing	The p.R711* pathogenic mutation (also known as c.2131C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2131. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been detected in the germline of multiple patients with HNPCC/Lynch syndrome-associated malignancies and several of these individuals had tumors exhibiting a loss of MSH2 on immunohistochemistry (IHC) and/or microsatellite instability (Kurzawski G et al. J Med Genet, 2002 Oct;39:E65; Parc Y et al. J Med Genet, 2003 Mar;40:208-13; Mangold E et al. J. Med. Genet., 2004 Jul;41:567-72; Apessos A et al. Br J Cancer, 2005 Jan;92:396-404; Lagerstedt Robinson K et al. J Natl Cancer Inst, 2007 Feb;99:291-9; Papp J et al. World J Gastroenterol, 2007 May;13:2727-32; Tang R et al. Clin Genet, 2009 Apr;75:334-45; Tanyi M et al. Eur J Surg Oncol, 2008 Dec;34:1322-7; Rios CA et al. Sao Paulo Med J, 2014;132:61-4; Carneiro da Silva F et al. PLoS One, 2015 Oct;10:e0139753; Nowak JA et al. J Mol Diagn, 2017 01;19:84-91; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Bannon SA et al. Cancer Prev Res (Phila), 2018 11;11:679-686; Ponz de Leon M et al. Scand J Gastroenterol, 2018 Jan;53:31-37; Schneider NB et al. Cancer Med, 2018 05;7:2078-2088; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Georgeson P et al. Mol Genet Genomic Med, 2019 07;7:e00781; Velázquez C et al. J Transl Med, 2020 06;18:232; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199; Xu Y et al. BMC Cancer, 2021 Jan;21:45). 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	RCV000524377	SCV000253805	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-12	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. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is present in population databases (rs63750636, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Muir-Torre syndrome and/or non-polyposis colorectal cancer (PMID: 12132870, 12362047, 15235030, 15849733, 16451135, 17473388, 17569143, 18289827). ClinVar contains an entry for this variant (Variation ID: 90903). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000202062	SCV000292625	pathogenic	not provided	2022-09-22	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; 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: 24474082, 25194673, 15949004, 12132870, 21868491, 26143115, 25107687, 15655560, 12362047, 15849733, 24344984, 23752102, 15235030, 21387278, 19419416, 27300758, 26666765, 27863258, 27601186, 27978560, 28127413, 28247034, 17473388, 17569143, 9739019, 28944238, 28874130, 29575718, 30274973, 30521064, 29025352, 31159747, 24969397, 31615790, 32338768, 30787465, 32522261, 31830689, 34178123, 32549215)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202062	SCV000601456	pathogenic	not provided	2020-03-23	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. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Color Diagnostics, LLC DBA Color Health	RCV000129341	SCV000685015	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-29	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. This variant has been reported in individuals affected with pancreatic cancer (PMID: 30274973), colorectal cancer (PMID: 21868491, 30521064), Lynch syndrome (PMID: 15849733, 16451135, 17312306, 17569143, 18289827, 19419416, 28874130, 29575718), or Muir-Torre syndrome (PMID: 15235030, 24474082). This variant has been identified in 1/31380 chromosomes 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	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 1; Mismatch repair cancer syndrome 1; 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: https://databases.lovd.nl/shared/variants/MSH2#object_id=VariantOnTranscript%2CVariantOnGenome&id=MSH2&order=VariantOnTranscript%2FDNA%2CASC&search_transcriptid=00013950&search_VariantOnTranscript/DNA=c.2131C%3ET&page_size=100&page=1 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.
Revvity Omics, Revvity	RCV000202062	SCV002017563	pathogenic	not provided	2021-07-22	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272055	SCV002556617	pathogenic	Lynch syndrome 1	2021-01-11	criteria provided, single submitter	clinical testing	PVS1, PS4, PP5.
MGZ Medical Genetics Center	RCV002272055	SCV002579365	pathogenic	Lynch syndrome 1	2021-07-29	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV002272055	SCV002758565	pathogenic	Lynch syndrome 1	2022-10-24	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PM2, PS4
Myriad Genetics, Inc.	RCV002272055	SCV004188002	pathogenic	Lynch syndrome 1	2023-08-07	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.
Baylor Genetics	RCV002272055	SCV004196933	pathogenic	Lynch syndrome 1	2021-10-06	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV002272055	SCV004805308	uncertain significance	Lynch syndrome 1	2024-03-25	criteria provided, single submitter	research
All of Us Research Program, National Institutes of Health	RCV000076405	SCV004825658	pathogenic	Lynch syndrome	2024-01-05	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. This variant has been reported in individuals affected with pancreatic cancer (PMID: 30274973), colorectal cancer (PMID: 21868491, 30521064), Lynch syndrome (PMID: 15849733, 16451135, 17312306, 17569143, 18289827, 19419416, 28874130, 29575718), or Muir-Torre syndrome (PMID: 15235030, 24474082). This variant has been identified in 1/31380 chromosomes 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202062	SCV000257170	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202062	SCV000592536	pathogenic	not provided		no assertion criteria provided	clinical testing	The p.Arg711X variant has been previously reported in the literature in numerous publications in families with Lynch syndrome (selected publications: Levati 1998, Mangold 2005, Parc 2003, Tanyi 2008). This variant leads to a premature stop codon at position 711, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of Lynch syndrome and this is the type of DNA alteration expected to cause the disorder. In summary, based on the above information, this variant meets our criteria to be classified as pathogenic.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249926	SCV001423943	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202062	SCV001953353	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000202062	SCV001976052	pathogenic	not provided		no assertion criteria provided	clinical testing