Submissions for variant NM_000251.3(MSH2):c.1285C>T (p.Gln429Ter)

dbSNP: rs63751693

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076112	SCV000107127	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Invitae	RCV000627701	SCV000253798	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln429*) 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 Lynch syndrome (PMID: 7726159, 15849733, 15955785). ClinVar contains an entry for this variant (Variation ID: 90616). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000214917	SCV000278742	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-19	criteria provided, single submitter	clinical testing	The p.Q429* pathogenic mutation (also known as c.1285C>T), located in coding exon 8 of the MSH2 gene, results from a C to T substitution at nucleotide position 1285. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This alteration has been detected in multiple families with HNPCC/Lynch syndrome (Wijnen J et al. Am. J. Hum. Genet., 1995 May;56:1060-6; Wijnen J et al. Am. J. Hum. Genet., 1997 Aug;61:329-35; Gille JJ et al. Br. J. Cancer, 2002 Oct;87:892-7; Wagner A et al. J. Med. Genet., 2002 Nov;39:833-7; Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702). 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV001823109	SCV002073017	pathogenic	Lynch syndrome 1		criteria provided, single submitter	clinical testing	The stop gained p.Q429* in MSH2 (NM_000251.3) has been previously reported in affected patients (Mangold E et al; Wagner A et al; Mueller-Koch Y et al). The variant has been submitted to ClinVar as Pathogenic and has been reviewed by the expert panel. The p.Q429* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function mutations have been reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Human Genetics Bochum, Ruhr University Bochum	RCV001823109	SCV004042776	pathogenic	Lynch syndrome 1	2023-04-14	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PVS1, PS4_SUP, PM2_SUP
Myriad Genetics, Inc.	RCV001823109	SCV004188016	pathogenic	Lynch syndrome 1	2023-08-01	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.
Color Diagnostics, LLC DBA Color Health	RCV000214917	SCV004356675	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-04	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 8 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 individuals affected with Lynch syndrome (PMID: 7726159, 15849733, 15955785, 19706203, 21671081). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353690	SCV000592498	pathogenic	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Gln429X variant was identified in 10 of 4130 proband chromosomes (frequency: 0.002) from individuals or families with HNPCC (Gille 2002, Mangold 2005, Mueller-Koch 2005, Wagner 2002, Wijnen 1995, Wijnen 1997). The variant was also identified in dbSNP (ID: rs63751693) “With pathogenic allele”, Clinvitae database (as pathogenic), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (as pathogenic, reviewed by an expert panel). The variant was not found in the following databases: COSMIC, “MMR Gene Unclassified Variants Database”, Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database and UMD.The p.Gln429X variant leads to a premature stop codon at position 429, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001353690	SCV001741579	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001353690	SCV001955189	pathogenic	not provided		no assertion criteria provided	clinical testing