Submissions for variant NM_000251.3(MSH2):c.1034G>A (p.Trp345Ter)

dbSNP: rs63751027

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076004	SCV000107015	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variant introducing a premature termination codon
Invitae	RCV000691659	SCV000819446	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-11-29	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: 90509). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 12624141, 14970868, 15713769, 16142001). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp345*) 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).
Ambry Genetics	RCV002390221	SCV002699710	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	The p.W345* pathogenic mutation (also known as c.1034G>A), located in coding exon 6 of the MSH2 gene, results from a G to A substitution at nucleotide position 1034. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This mutation has been identified in multiple families with Lynch syndrome (Parc Y et al. J. Med. Genet. 2003 Mar;40:208-13; Ponz de Leon M et al. Br. J. Cancer. 2004 Feb;90:882-7; Pedroni M et al. Dis. Markers. 2007;23:179-87), as well as in individuals who did not meet established clinical diagnostic criteria but whose tumors demonstrated microsatellite instability and/or loss of MSH2 expression by immunohistochemistry (IHC) (Casey G et al. JAMA. 2005 Feb;293:799-809; Bécouarn Y et al. Gastroenterol. Clin. Biol. 2005 Jun-Jul;29(6-7):667-75). This alteration has also been reported as an apparently de novo mutation in a proband diagnosed with colorectal cancer at ages 31 and 40, and endometrial cancer at age 47, whose tumor showed loss of MSH2 expression by IHC; both of her parents subsequently tested negative for this mutation (Win AK et al. J. Med. Genet. 2011 Aug;48:530-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003452796	SCV004188018	pathogenic	Lynch syndrome 1	2023-07-31	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	RCV001250028	SCV001423953	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing