Submissions for variant NM_000251.3(MSH2):c.2485del (p.His829fs)

dbSNP: rs63751117

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076487	SCV000107516	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985804	SCV001134356	pathogenic	not provided	2018-10-26	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data.
Ambry Genetics	RCV001015712	SCV001176576	pathogenic	Hereditary cancer-predisposing syndrome	2019-09-23	criteria provided, single submitter	clinical testing	The c.2485delC pathogenic mutation, located in coding exon 15 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 2485, causing a translational frameshift with a predicted alternate stop codon (p.H829Mfs*12). This alteration has been classified as pathogenic using the following lines of evidence, as available: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067777	SCV001232856	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-10-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 90985). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.His829Metfs*12) in the MSH2 gene. It is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509200	SCV002819564	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-12-15	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2485delC (p.His829MetfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251420 control chromosomes. c.2485delC has been reported in the literature in individuals affected with Lynch Syndrome (Thompson_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003452915	SCV004187821	pathogenic	Lynch syndrome 1	2023-08-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.