Submissions for variant NM_000251.3(MSH2):c.1216C>T (p.Arg406Ter)

dbSNP: rs63751108

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030238	SCV000107079	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing a premature termination codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030238	SCV000052905	pathogenic	Lynch syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Ambry Genetics	RCV000162489	SCV000212867	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	The p.R406* pathogenic mutation (also known as c.1216C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1216. This changes the amino acid from an arginine to a stop codon within coding exon 7. This mutation has been detected in multiple families meeting Amsterdam criteria. Tumor samples from two of these affected exhibited loss of the MSH2 protein by IHC (De Lellis L et al. PLoS ONE. 2013 Nov;8(11):e81194; Chong G et al. Hum. Mutat. 2009 Aug;30(8):E797-812; Casey G et al. JAMA. 2005 Feb;293(7):799-809). One study detected this mutation in three HNPCC families and noted that it was not observed in 180 healthy control individuals (Pastrello C et al. Genet. In Med. 2011 Feb;13(2):115-24). This mutation was also seen in an individual affected with urinary bladder cancer at age 58 in addition to colorectal cancer at ages 33 and 34; authors suggested that MSH2 mutations may confer a higher risk of urinary tract cancer (van der Post RS et al. J. Med. Genet. 2010 Jul;47(7);464-70). This mutation has been reported in an individual with gallbladder cancer (Cloyd JM et al. Gastrointest Cancer. 2018 Mar;49(1):93-96) and in individuals with soft tissue sarcoma and sebaceous adenoma (Latham A et al. J Clin Oncol. 2018 Oct;JCO1800283). 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.
GeneDx	RCV000202291	SCV000292622	pathogenic	not provided	2021-10-05	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; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Leach 1993, Kuismanen 2000, Kurzawski 2002, Casey 2005, Lagerstedt Robinson 2007, Grindedal 2009, Pastrello 2011, De Lellis 2013, Bashyam 2014, Ponti 2016, Brennan 2017, Vargas-Parra 2017); Not observed in large population cohorts (Lek et al., 2016); 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: 10793088, 24278394, 11879922, 21239990, 15713769, 28577310, 28944238, 29025352, 20591884, 18841495, 17312306, 8261515, 27016151, 25420488, 26300997, 26850131, 15849733, 19760518, 28449805, 20223024, 24710284, 28874130, 29238914, 24969397, 28491141, 31615790)
Invitae	RCV000524334	SCV000548281	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg406*) 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 (PMID: 8261515, 15713769, 20223024, 20591884, 24710284). ClinVar contains an entry for this variant (Variation ID: 1755). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000001825	SCV000677733	pathogenic	Lynch syndrome 1	2017-05-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202291	SCV000888199	pathogenic	not provided	2015-11-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763491	SCV000894277	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	RCV000162489	SCV001345237	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-07	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 reported in multiple individuals affected with Lynch syndrome (PMID: 8261515, 12362047, 15713769, 15849733, 19459153, 20223024, 20591884, 21239990, 21590452, 24278394, 24278394, 24710284, 27016151, 30376427). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000202291	SCV001447750	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000202291	SCV001449714	pathogenic	not provided	2018-03-19	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000001825	SCV003924406	pathogenic	Lynch syndrome 1	2023-05-17	criteria provided, single submitter	clinical testing	The pathogenic MSH2 family variant was detected in this specimen. This sequence change creates a premature translational stop signal (p.Arg406*) 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 (PMID: 10793088,24278394, 11879922, 21239990, 15713769, 28577310, 28944238, 29025352, 20591884, 18841495, 17312306, 8261515, 27016151, 25420488, 26300997, 26850131, 15849733, 19760518, 28449805, 20223024, 24710284, 28874130, 29238914, 24969397, 28491141, 31615790). ClinVar contains an entry for this variant (Variation ID: 1755). For these reasons, this variant has been classified as Pathogenic. Pathogenic/likely pathogenic mutations in the MSH2 gene cause Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC), also known as Lynch Syndrome.
Myriad Genetics, Inc.	RCV000001825	SCV004018424	pathogenic	Lynch syndrome 1	2023-03-24	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.
Genetics and Molecular Pathology, SA Pathology	RCV000001825	SCV004175549	pathogenic	Lynch syndrome 1	2022-11-25	criteria provided, single submitter	clinical testing	The MSH2 c.1216C>T variant is classified as Pathogenic (PVS1, PS4, PM2, PP4, PP5) The MSH2 c.1216C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 406 (PVS1). The variant has been frequently reported in probands with a clinical presentation of colorectal cancer (PS4). This variant is absent from population databases (PM2). The clinical features of this case are highly specific for the MSH2 gene due to loss of expression of MSH2/MSH in IHC tumour staining (PP4). The variant has been reported in dbSNP (rs63751108) and in the HGMD database: CM930497. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 1755), including the InSiGHT group (PP5).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000030238	SCV004847844	pathogenic	Lynch syndrome	2017-12-05	criteria provided, single submitter	clinical testing	The p.Arg406X variant in MSH2 has been reported in >15 individuals with MSH2-associated cancers and segregated with disease in at least 1 affected relative (Leach 1993, Liu 1994, Weber 1997, Dunlop 1997, Wahlberg 1999, Pistoriu 2000, Mangold 2005, Casey 2005, Kurzawski 2006, Spaepen 2006, Guillem 2007, Choi 2009, Grindedal 2009, van der Post 2010, and Ponti 2014). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 406, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH2 gene is an established disease mechanism in individuals with Lynch syndrome. In addition, this variant was classified as pathogenic on Sept 13, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107079.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon reports in literature and absence from controls. ACMG/AMP Criteria applied: PVS1; PS4; PM2.
OMIM	RCV000001825	SCV000021981	pathogenic	Lynch syndrome 1	1993-12-17	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000202291	SCV000257126	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000677885	SCV000592492	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Arg406X variant was identified in 8 of 2328 proband chromosomes (frequency: 0.003) from Polish, German, Belgian, Uruguayan, British and Canadian individuals or families with Lynch Syndrome (Sarroca 2005, Kurzawski 2006, Mangold 2005, Spaepen 2006, Taylor 2003, Choi 2009). The variant was also identified in dbSNP (ID: rs63751108) “With Pathogenic allele”, Clinvitae database (classification pathogenic), COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic and reviewed by an expert panel, submitters: InSiGHT, Ambry Genetics, LabCorp, OMIM, and Mayo Clinic), and UMD (18x with a “causal” classification). The p.Arg406X variant leads to a premature stop codon at position 406, 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 disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000001825	SCV000745638	pathogenic	Lynch syndrome 1	2017-08-10	no assertion criteria provided	clinical testing
3DMed Clinical Laboratory Inc	RCV000677885	SCV000804046	pathogenic	Carcinoma of colon	2017-05-31	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000202291	SCV001919844	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202291	SCV001955382	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000202291	SCV001963335	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162204	SCV002758536	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research