Submissions for variant NM_000251.3(MSH2):c.1129C>T (p.Gln377Ter)

dbSNP: rs63750267

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076045	SCV000107058	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing a premature termination codon
Color Diagnostics, LLC DBA Color Health	RCV000583364	SCV000689953	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-07	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 7 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 individuals affected with Lynch syndrome (PMID: 16830052, 25110875, 35313100). 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.
Invitae	RCV001232220	SCV001404768	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln377*) 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 clinical features of Lynch syndrome (PMID: 16830052, 30521064). ClinVar contains an entry for this variant (Variation ID: 90550). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000583364	SCV002605983	pathogenic	Hereditary cancer-predisposing syndrome	2017-11-13	criteria provided, single submitter	clinical testing	The p.Q377* pathogenic mutation (also known as c.1129C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1129. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This mutation has been reported in a patient diagnosed with multiple primary colon cancers diagnosed at ages 32y, 39y, 54y, and 62y, with a family history of colon, endometrial, and breast cancers (Zavodna K et al. Neoplasma. 2006;53(4):269-76). 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.	RCV003452804	SCV004188106	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.