Submissions for variant NM_000251.3(MSH2):c.1009C>T (p.Gln337Ter)

dbSNP: rs63750778

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075997	SCV000107007	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variant introducing a premature termination codon
Eurofins Ntd Llc (ga)	RCV000153512	SCV000203033	pathogenic	not provided	2014-04-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000215536	SCV000274746	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-07	criteria provided, single submitter	clinical testing	The p.Q337* pathogenic mutation (also known as c.1009C>T), located in coding exon 6 of the MSH2 gene, results from a C to T substitution at nucleotide position 1009. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This mutation has been identified in several families with HNPCC/Lynch or Muir-Torre syndrome and whose tumors demonstrated microsatellite instability and/or deficient MSH2 expression (Scott RJ et al. Am. J. Hum. Genet. 2001 Jan; 68(1):118-127; Southey MC et al. Am. J. Surg. Pathol. 2001 Jul; 25(7):936-41; Ward R et al. J. Cancer Res. Clin. Oncol. 2002 Aug; 128(8):403-11; Chubb D et al. Nat Commun. 2016 06;7:11883). 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.
Invitae	RCV001215910	SCV001387678	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-27	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: 90502). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndorme (PMID: 11112663, 12200596). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln337*) 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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000153512	SCV002047022	pathogenic	not provided	2021-05-03	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MSH2 protein synthesis, and is described in online databases as being pathogenic (ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/), InSiGHT (http://insight-database.org)). In addition, it has been reported in individuals and families affected with Lynch syndrome-associated cancers in the published literature (PMID: 11112663 (2001), 11420466 (2001), 12200596 (2002)). Based on the available information, this variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004537286	SCV004107613	pathogenic	MSH2-related disorder	2023-06-01	criteria provided, single submitter	clinical testing	The MSH2 c.1009C>T variant is predicted to result in premature protein termination (p.Gln337*). This variant was reported in an individual with non-polyposis colorectal cancer and individuals with Muir-Torre syndrome (Table 1, Scott et al. 2001. PubMed ID: 11112663; Southey et al 2001. PubMed ID: 11420466; Table 1, Ward et al. 2002. PubMed ID: 12200596). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in MSH2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV003452794	SCV004188050	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.