Submissions for variant NM_000251.3(MSH2):c.892C>T (p.Gln298Ter)

dbSNP: rs63750934

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076744	SCV000107781	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000478579	SCV000568624	pathogenic	not provided	2021-05-26	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 in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene and other cancers in published literature (Wahlberg 1999, Buchanan 2014, Rosty 2014, Therkildsen 2015, Whitworth 2016, Lagerstedt-Robinson 2016).; This variant is associated with the following publications: (PMID: 20215533, 26177554, 26659639, 25648859, 27013479, 24323032, 10495924, 25525159, 25117503, 28528517, 27601186, 22949379, 28790115)
Ambry Genetics	RCV000490887	SCV000580442	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-13	criteria provided, single submitter	clinical testing	The p.Q298* pathogenic mutation (also known as c.892C>T), located in coding exon 5 of the MSH2 gene, results from a C to T substitution at nucleotide position 892. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This mutation has been identified in multiple families meeting Amsterdam criteria and/or with early onset Lynch-associated cancers (Wahlberg S et al, 1999;3:259-64; Wagner A et al. Am J Hum Genet, 2003 May;72:1088-100; Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83; Walsh MD et al. Clin Cancer Res, 2010 Apr;16:2214-24; Stojcev Z et al. Acta Biochim Pol, 2013 Jun;60:195-8; Buchanan DD et al. J. Clin. Oncol., 2014 Jan;32:90-100; Therkildsen C et al. Eur. J. Neurol., 2015 Apr;22:717-24; Tzortzatos G et al. Gynecol Oncol, 2015 Sep;138:717-22; Whitworth J et al. JAMA Oncol, 2016 Mar;2:373-9; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Georgeson P et al. Mol Genet Genomic Med, 2019 07;7:e00781). This mutation has also been detected in multiple individuals with prostate cancer whose tumors exhibited absent MSH2 and MSH6 via immunohistochemisty (Rosty C et al. Fam. Cancer, 2014 Dec;13:573-82; Dominguez-Valentin M et al. BMC Urol, 2016 Mar;16:15). 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	RCV000629714	SCV000750670	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-09-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91239). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln298*) 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).
Genetics and Molecular Pathology, SA Pathology	RCV003447488	SCV004175594	pathogenic	Lynch syndrome 1	2023-01-18	criteria provided, single submitter	clinical testing	The MSH2 c.892C>T variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) The MSH2 c.892C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 298 (PVS1). The variant has been reported in individuals with a clinical presentation of Lynch syndrome-related cancers such as colorectal cancer (PMID: 25117503, 17312306, 34680242) and endometrial cancer (PMID: 24323032) (PS4_Mod). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs63750934) and in the HGMD database: CM011418. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 91239).
Myriad Genetics, Inc.	RCV003447488	SCV004187912	pathogenic	Lynch syndrome 1	2023-07-28	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.
Color Diagnostics, LLC DBA Color Health	RCV000490887	SCV004356640	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-30	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 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 and families affected with Lynch Syndrome-associated cancers (PMID: 12658575, 31162827, 33977078), breast cancer (PMID: 20215533), endometrial cancer (PMID: 24323032, 26659639), prostate cancer (PMID: 25117503, 27013479, 28790115), and glioblastoma (PMID: 25648859). This variant has been reported in individuals affected with breast, endometrial, and prostate cancer that have demonstrated loss of MSH2 and MSH6 proteins by immunohistochemistry analyses (PMID: 20215533, 24323032, 27013479, 28790115). 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.
3DMed Clinical Laboratory Inc	RCV000677887	SCV000804048	pathogenic	Sigmoid colon cancer	2017-12-27	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357211	SCV001552603	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Gln298X variant was identified in 8 of 3362 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome associated cancers, endometrial cancer, prostate cancer, and glioblastoma (Dominguez-Valentin 2016, Therkildsen 2015, Buchanan 2014, Walsh 2010, Lagerstedt Robinson 2007, Wagner 2003, Wahlberg 1999); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in the following databases: dbSNP (ID: rs63750934) as "With Pathogenic allele", ClinVar (3x pathogenic), Clinvitae (3x pathogenic), Insight Colon Cancer Gene Variant Database (11x, pathogenic), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (17x pathogenic). The variant was not identified in Cosmic, MutDB, UMD-LSDB, or the Zhejiang Colon Cancer Database. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.892C>T variant leads to a premature stop codon at position 298 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 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.