Submissions for variant NM_000251.3(MSH2):c.873_876del (p.Thr292fs)

dbSNP: rs587779191

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076741	SCV000107778	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000575858	SCV000673904	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-12	criteria provided, single submitter	clinical testing	The c.873_876delGACT pathogenic mutation, located in coding exon 5 of the MSH2 gene, results from a deletion of 4 nucleotides at nucleotide positions 873 to 876, causing a translational frameshift with a predicted alternate stop codon (p.T292Lfs*8). This mutation was identified in a patient with colorectal cancer at age 42 that was MSI-H and demonstrated loss of MSH2 and MSH6 by immunohistochemistry, and the patient's family history meet Amsterdam criteria I (Kunstmann E et al. BMC Med. Genet. 2004 Jun;5:16). 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	RCV000629801	SCV000750757	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-05-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr292Leufs*8) 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: 15217520, 15849733). ClinVar contains an entry for this variant (Variation ID: 91236). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657243	SCV000778972	pathogenic	not provided	2023-09-29	criteria provided, single submitter	clinical testing	Frameshift 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: 15849733, 15217520, 30787465, 21642682)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657243	SCV002050047	pathogenic	not provided	2020-12-13	criteria provided, single submitter	clinical testing	The MSH2 c.873_876delGACT; p.Thr292LeufsTer8 variant (rs587779191) has been reported in the literature in at least one individual with Lynch syndrome (Kunstmann 2004, Mangold 2005). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 91236) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so it 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 Kunstmann E et al. HNPCC: six new pathogenic mutations. BMC Med Genet. 2004 Jun 24;5:16. Mangold E et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005 Sep 20;116(5):692-702.
Myriad Genetics, Inc.	RCV003452972	SCV004188983	pathogenic	Lynch syndrome 1	2023-07-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.