Submissions for variant NM_000251.3(MSH2):c.2291G>A (p.Trp764Ter)

dbSNP: rs587779143

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076450	SCV000107480	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000491006	SCV000580554	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-27	criteria provided, single submitter	clinical testing	The p.W764* pathogenic mutation (also known as c.2291G>A), located in coding exon 14 of the MSH2 gene, results from a G to A substitution at nucleotide position 2291. This changes the amino acid from a tryptophan to a stop codon within coding exon 14. This mutation has been reported in an individual with early onset colon cancer whose tumor showed absence of MSH2 protein expression (Nagasaka T et al. Cancer Res. 2010 Apr; 70(8):3098-108). This alteration has also been reported in an individual meeting Amsterdam II criteria with early onset colon cancer and hepatocellular carcinoma showing microsatellite instability and loss of MSH2 protein expression (Casper M et al. Scand. J. Gastroenterol. 2013 Mar; 48(3):344-51). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694856	SCV000823318	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp764*) 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 premature translational stop signal has been observed in individual(s) with colorectal cancer and suspected Lynch syndrome (PMID: 20388775, 25980754). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 90948). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003452904	SCV004188032	pathogenic	Lynch syndrome 1	2023-08-08	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.