Submissions for variant NM_000251.3(MSH2):c.1030C>T (p.Gln344Ter)

dbSNP: rs63750245

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030234	SCV000107014	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variant introducing a premature termination codon
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030234	SCV000052901	pathogenic	Lynch syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759091	SCV000888193	pathogenic	not provided	2023-08-22	criteria provided, single submitter	clinical testing	The MSH2 c.1030C>T (p.Gln344*) variant causes the premature termination of MSH2 protein synthesis. This variant has been reported in the published literature in individuals and families affected with Lynch syndrome (PMIDs: 27468915 (2017), 18618713 (2008), 15571801 (2004), 12655568 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV001009753	SCV001169856	pathogenic	Hereditary cancer-predisposing syndrome	2018-03-09	criteria provided, single submitter	clinical testing	The p.Q344* pathogenic mutation (also known as c.1030C>T), located in coding exon 6 of the MSH2 gene, results from a C to T substitution at nucleotide position 1030. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This mutation has been described in individuals with early-onset colorectal cancer who met Amsterdam criteria (Bartosova Z et al. Hum. Mutat. 2003 Apr;21:449; Rey JM et al. Cancer Genet. Cytogenet. 2004 Dec;155:149-51; Ziada-Bouchaar H et al. Fam. Cancer. 2017 01;16:57-66). 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	RCV001224622	SCV001396834	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-09-06	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: 36561). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12655568, 15571801, 27468915). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln344*) 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).
Color Diagnostics, LLC DBA Color Health	RCV001009753	SCV001733947	pathogenic	Hereditary cancer-predisposing syndrome	2020-06-30	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 6 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Lynch syndrome (PMID: 12655568, 15571801, 18618713, 27468915). 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.
Myriad Genetics, Inc.	RCV003450651	SCV004188960	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.