Submissions for variant NM_000251.3(MSH2):c.1035G>A (p.Trp345Ter)

dbSNP: rs63750396

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076005	SCV000107016	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variant introducing a premature termination codon
Ambry Genetics	RCV000492045	SCV000580470	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	The p.W345* pathogenic mutation (also known as c.1035G>A), located in coding exon 6 of the MSH2 gene, results from a G to A substitution at nucleotide position 1035. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This alteration has been reported in multiple individuals with personal and/or family histories consistent with Lynch syndrome (Ponz de Leon M et al, Br. J. Cancer 2004 Feb; 90(4):882-7; Tang R, Clin. Genet. 2009 Apr; 75(4):334-45). In addition, an alteration resulting in the same amino acid change and stop codon, p.W345* (c.1034G>A) has been reported in a HNPCC-like family with loss of expression of MSH2 on IHC (Casey G et al, JAMA 2005 Feb; 293(7):799-809). 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	RCV000202230	SCV000779393	pathogenic	not provided	2018-04-23	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1035G>A at the cDNA level and p.Trp345Ter (W345X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with Lynch syndrome (Ponz de Leon 2004, Tang 2009, Vargas-Parra 2017) and is considered pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193248	SCV001361976	pathogenic	Hereditary nonpolyposis colon cancer	2019-06-17	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1035G>A (p.Trp345X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251438 control chromosomes. c.1035G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome or related cancer (Leon_2004, Roberts_2014, Kamiza_2015, Mu_2016, Vargas-Parra_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258035	SCV001434863	pathogenic	Lynch syndrome 1	2019-02-21	criteria provided, single submitter	clinical testing	The c.1035G>A (p.Trp345*) variant in the MSH2 gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple individuals with Lynch associated tumor (PMID 14970868, 15713769, 19419416, 28577310). Microsatellite instability (PMID 14970868) or MSH2 loss (PMID 15713769, 28577310) were observed in some of the tumors. This variant has never been observed in general population databases. Therefore, we classify this c.1035G>A (p.Trp345*) variant in the MSH2 gene as pathogenic.
Invitae	RCV001854313	SCV002236755	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-02-11	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: 90510). This premature translational stop signal has been observed in individual(s) with colorectal cancer (PMID: 14970868, 26053027). 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).
Myriad Genetics, Inc.	RCV001258035	SCV004187948	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202230	SCV000257120	pathogenic	not provided		no assertion criteria provided	research