Submissions for variant NM_000251.3(MSH2):c.862C>T (p.Gln288Ter)

dbSNP: rs63750097

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076738	SCV000107775	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000484173	SCV000565185	pathogenic	not provided	2017-06-09	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.862C>T at the cDNA level and p.Gln288Ter (Q288X) 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 identified in multiple families with Hereditary Nonpolyposis Colorectal Cancer and in at least 1 individual with Muir-Torre Syndrome, and tumor studies from some of these individuals showed microsatellite instability and loss of MSH2 protein expression (Wijnen 1995, Wijnen 1997, Kruse 1998, Pistorius 2000, Hendriks 2003, Lage 2004, Mangold 2004, Mangold 2005, Overbeek 2007, Dominquez-Valentin 2013). Based on current information, we consider this variant to be pathogenic.
Invitae	RCV000528830	SCV000625475	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-04-12	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: 91233). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 7726159, 12547705, 15235030, 15849733, 28874130). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln288*) 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	RCV001183048	SCV001348703	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-03	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 5 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, 12547705, 15235030, 15849733, 24344984). 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.
Ambry Genetics	RCV001183048	SCV002682471	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-27	criteria provided, single submitter	clinical testing	The p.Q288* pathogenic mutation (also known as c.862C>T), located in coding exon 5 of the MSH2 gene, results from a C to T substitution at nucleotide position 862. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This mutation has been identified in multiple HNPCC/Lynch syndrome families of various ethnicities, including patients whose tumors were MSI-H and demonstrated loss of MSH2 protein expression by IHC (Wijnen J et al. Am. J. Hum. Genet. 1997 Aug;61:329-35; Pistorius SR et al. Int. J Colorectal Dis, 2000 Nov;15:255-63; Hendriks Y et al. Am. J. Pathol. 2003 Feb;162:469-77; Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Rossi BM et al. BMC Cancer 2017 Sep;17:623). This mutation has also been reported in an individual with Muir-Torre phenotype who had colon cancer and multiple sebaceous skin tumors, one of which was shown to be MSI-H and demonstrated loss of MSH2 staining by IHC analysis (Kruse R et al. Am. J. Hum. Genet. 1998 Jul;63(1):63-70; Mangold E et al. J. Med. Genet., 2004 Jul;41:567-72). Of note, this alteration is also designated as p.Gln288*, p.Gln288X, "C to T at 862 (Gln to Stop)," Q288X, and "862CAG>TAG," in published literature. 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.	RCV003452970	SCV004186899	pathogenic	Lynch syndrome 1	2023-07-28	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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000484173	SCV001956871	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000484173	SCV001966792	pathogenic	not provided		no assertion criteria provided	clinical testing