Submissions for variant NM_000251.3(MSH2):c.577C>T (p.Gln193Ter)

dbSNP: rs63751326

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076645	SCV000107680	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000490948	SCV000580608	pathogenic	Hereditary cancer-predisposing syndrome	2018-10-31	criteria provided, single submitter	clinical testing	The p.Q193* pathogenic mutation (also known as c.577C>T), located in coding exon 3 of the MSH2 gene, results from a C to T substitution at nucleotide position 577. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This mutation was detected once in a cohort of 1,721 unrelated German index patients suspected of hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome based on personal and/or family history of cancer (Mangold, E et al. Int J Cancer. 2005 Sep 20;116(5):692-702). 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	RCV000629870	SCV000750826	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-07-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 91141). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15849733). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln193*) 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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284655	SCV001470555	pathogenic	not provided	2019-10-11	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 with expected phenotype for this gene, and not found in general population data.
GeneDx	RCV001284655	SCV001771858	pathogenic	not provided	2020-01-29	criteria provided, single submitter	clinical testing	Nonsense 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; Truncated variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Mangold 2005); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 15849733, 25525159)
Myriad Genetics, Inc.	RCV003452952	SCV004186986	pathogenic	Lynch syndrome 1	2023-07-27	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.