Submissions for variant NM_000251.3(MSH2):c.1552C>T (p.Gln518Ter)

dbSNP: rs63750780

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076192	SCV000107210	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000657577	SCV000779314	pathogenic	not provided	2015-03-01	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH2 c.1552C>T at the cDNA level and p.Gln518Ter (Q518X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), 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 (Fidalgo 2000, Lage 2004) and is considered pathogenic.
Invitae	RCV000701635	SCV000830446	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln518*) 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 hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 10713887). ClinVar contains an entry for this variant (Variation ID: 90696). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001187045	SCV001353703	pathogenic	Hereditary cancer-predisposing syndrome	2020-05-29	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 28528518). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV001187045	SCV002703825	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-04	criteria provided, single submitter	clinical testing	The p.Q518* pathogenic mutation (also known as c.1552C>T), located in coding exon 10 of the MSH2 gene, results from a C to T substitution at nucleotide position 1552. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This mutation has been reported in Lynch syndrome families and in an individual with ovarian cancer (Fidalgo P et al. Eur. J. Hum. Genet. 2000 Jan;8:49-53; Jaballah-Gabteni A et al. J. Transl. Med. 2019 Jun;17:212; Carter NJ et al. Gynecol. Oncol. 2018 12;151:481-488). 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.	RCV003452840	SCV004188057	pathogenic	Lynch syndrome 1	2023-08-02	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657577	SCV004220953	pathogenic	not provided	2022-09-09	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MSH2 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28528518 (2017)), ovarian cancer (PMID: 30322717 (2018), colon cancer (PMID: 31248416 (2019)), and hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 10713887 (2000)). Based on the available information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000657577	SCV001741587	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000657577	SCV001958636	pathogenic	not provided		no assertion criteria provided	clinical testing