Submissions for variant NM_000251.3(MSH2):c.2096C>G (p.Ser699Ter)

dbSNP: rs587779136

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076387	SCV000107414	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV002228185	SCV000548141	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser699*) 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 variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 90885). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000490933	SCV000580562	pathogenic	Hereditary cancer-predisposing syndrome	2018-06-08	criteria provided, single submitter	clinical testing	The p.S699* pathogenic mutation (also known as c.2096C>G), located in coding exon 13 of the MSH2 gene, results from a C to G substitution at nucleotide position 2096. This changes the amino acid from a serine to a stop codon within coding exon 13. This mutation has been identified in a patient with early onset colorectal cancer and a family history of Lynch syndrome-related cancers (Pearlman R et al. JAMA Oncol. 2017 Apr 1;3:464-471). 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.
GeneDx	RCV000657578	SCV000779315	pathogenic	not provided	2014-12-30	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH2 c.2096C>G at the cDNA level and p.Ser699Ter (S699X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000657578	SCV000806024	pathogenic	not provided	2017-10-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657578	SCV001134348	pathogenic	not provided	2019-05-17	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient, and not found in general population data.
Myriad Genetics, Inc.	RCV003452888	SCV004188039	pathogenic	Lynch syndrome 1	2023-08-07	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.
Baylor Genetics	RCV003452888	SCV004196923	pathogenic	Lynch syndrome 1	2021-12-07	criteria provided, single submitter	clinical testing