Submissions for variant NM_000251.3(MSH2):c.1777C>T (p.Gln593Ter)

dbSNP: rs63750200

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076282	SCV000107303	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV000540595	SCV000625312	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90783). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15235038, 27601186). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln593*) 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).
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269629	SCV001449749	pathogenic	not provided	2019-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399463	SCV002711206	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-10	criteria provided, single submitter	clinical testing	The p.Q593* pathogenic mutation (also known as c.1777C>T), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1777. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This mutation has been reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, including patients meeting Amsterdam criteria and/or whose tumors demonstrated loss of MSH2 by immunohistochemistry (IHC) (Naseem H et al. Clin Genet, 2006 Nov;70:388-95; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Sunga AY et al. Cancer Genet, 2017 04;212-213:1-7; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Tian W et al. Int J Cancer, 2019 09;145:1290-1298; Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199). 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.	RCV003452857	SCV004188140	pathogenic	Lynch syndrome 1	2023-08-03	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.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249920	SCV001423937	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing