Submissions for variant NM_000251.3(MSH2):c.119del (p.Gly40fs)

dbSNP: rs63750984

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076059	SCV000107073	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing a premature termination codon
Invitae	RCV000818363	SCV000958973	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly40Alafs*24) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 11385712, 12626904, 24278394, 26300997). ClinVar contains an entry for this variant (Variation ID: 90563). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002345384	SCV002647028	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-05	criteria provided, single submitter	clinical testing	The c.119delG pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 119, causing a translational frameshift with a predicted alternate stop codon (p.G40Afs*24). This mutation has been reported in multiple patients with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome; including at least one patient whose tumor demonstrated microsatellite instability and had a family history meeting Amsterdam criteria (Caluseriu O et al. Hum Mutat, 2001 Jun;17:521; Pucciarelli S et al. Dis Colon Rectum, 2003 Mar;46:305-12; De Lellis L et al. PLoS One, 2013 Nov;8:e81194; Simbolo M et al. Hered Cancer Clin Pract, 2015 Aug;13:18). 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.
Myriad Genetics, Inc.	RCV003452806	SCV004186770	pathogenic	Lynch syndrome 1	2023-07-26	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Color Diagnostics, LLC DBA Color Health	RCV002345384	SCV004356570	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 1 of the MSH2 gene, creating a frameshift and 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 and Lynch syndrome-associated cancer (PMID: 11385712, 12626904, 21642682, 24278394, 26300997). 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.