Submissions for variant NM_000251.3(MSH2):c.181C>T (p.Gln61Ter)

dbSNP: rs63750951

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076295	SCV000107316	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000219541	SCV000274919	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	The p.Q61* pathogenic mutation (also known as c.181C>T), located in coding exon 1 of the MSH2 gene, results from a C to T substitution at nucleotide position 181. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This mutation was first described in an extended family originating from Spain who fulfilled Amsterdam criteria for HNPCC/Lynch syndrome (Sarroca C et al. Cancer Genet Cytogenet. 2003 Apr 1;142(1):13-20). 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.
Color Diagnostics, LLC DBA Color Health	RCV000219541	SCV000537675	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 1 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 or suspected of having Lynch syndrome (PMID: 12660027, 20587412, 21642682). This variant has been identified in 1/232530 chromosomes 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	RCV000524363	SCV000548182	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln61*) 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 present in population databases (rs63750951, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 12660027, 21642682). ClinVar contains an entry for this variant (Variation ID: 90794). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000202086	SCV000567927	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH2 c.181C>T at the cDNA level and p.Gln61Ter (Q61X) 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 multiple individuals and families with Lynch syndrome (Sarroca 2003, Sjursen 2010, Bonadona 2011). We consider MSH2 Gln61Ter to be pathogenic.
Myriad Genetics, Inc.	RCV003452858	SCV004188120	pathogenic	Lynch syndrome 1	2023-07-26	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	RCV000202086	SCV004220961	pathogenic	not provided	2023-08-24	criteria provided, single submitter	clinical testing	The MSH2 c.181C>T (p.Gln61*) variant causes the premature termination of MSH2 protein synthesis. This variant has been reported in the published literature in affected individuals with colorectal cancer (PMID: 20587412 (2010)), Lynch Syndrome (PMIDs: 21642682 (2011) and 27064304 (2016)), as well as in an individual with both colorectal and bladder cancer (PMID: 29345684 (2018)). The frequency of this variant in the general population, 0.000057 (1/17498 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202086	SCV000257153	pathogenic	not provided		no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000076295	SCV000784702	not provided	Lynch syndrome		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202086	SCV001953610	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000202086	SCV001973758	pathogenic	not provided		no assertion criteria provided	clinical testing