Submissions for variant NM_000251.3(MSH2):c.1477C>T (p.Gln493Ter)

dbSNP: rs63750936

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076173	SCV000107189	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000129104	SCV000183815	pathogenic	Hereditary cancer-predisposing syndrome	2019-02-12	criteria provided, single submitter	clinical testing	The p.Q493* pathogenic mutation (also known as c.1477C>T), located in coding exon 9 of the MSH2 gene, results from a C to T substitution at nucleotide position 1477. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This pathogenic mutation has been reported in several individuals with HNPCC/Lynch syndrome (Mangold E et al. Int. J. Cancer 2005 Sep;116(5):692-702; Barrow E et al. Histopathology, 2010 Feb;56:331-44) including one person whose colorectal tumor exhibited high microsatellite instability and absence of MSH2 protein on IHC (Mangold E et al. J. Pathol. 2005 Dec;207(4):385-95). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076173	SCV000696216	pathogenic	Lynch syndrome	2017-03-30	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.1477C>T (p.Gln493X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 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 (e.g. c.1576delA, p.Thr526fsX17; c.1705_1706delGA, p.Glu569fsX2; c.1777C>T, p.Gln593X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121236 control chromosomes and has been reported in multiple affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000630148	SCV000751104	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln493*) 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: 11975096, 15849733, 16216036, 20459533, 27978560, 28514183). ClinVar contains an entry for this variant (Variation ID: 90677). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759818	SCV000889413	pathogenic	not provided	2017-12-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129104	SCV000905228	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 9 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 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.
Myriad Genetics, Inc.	RCV003452836	SCV004186897	pathogenic	Lynch syndrome 1	2023-08-02	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356325	SCV001551460	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Gln493X variant was identified in 7 of 3008 proband chromosomes (frequency: 0.02) from individuals or families with HNPCC, and was not identified in 80 control chromosomes from healthy individuals (Hedge_2005, Mangold_2005, Mangold_2005). The variant was also identified in dbSNP (ID rs63750936) as “With Pathogenic Allele”; in the clinvitae and, ClinVar databases as pathogenic by InSIGHT and Ambry Genetics; in GeneInsight – COGR database as Lynch Syndrome by ARUP Laboratories; InSiGHT Colon Cancer Gene Variant Database (LOVD) 8X as Class 5; and in Mismatch Repair Genes Variant Database 3X. The variant was not identified in COSMIC, Zhejiang Colon Cancer Database (LOVD), UMD and MMR Gene Unclassified Variants Database. In addition, the variant was not identified in the 1000 Genomes Project, The NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium database (August 8, 2016). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Gln493X variant leads to a premature stop codon at position 493, 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.