Submissions for variant NM_000251.3(MSH2):c.2470C>T (p.Gln824Ter)

dbSNP: rs63750623

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076485	SCV000107514	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000491152	SCV000580580	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-02	criteria provided, single submitter	clinical testing	The p.Q824* pathogenic mutation (also known as c.2470C>T), located in coding exon 15 of the MSH2 gene, results from a C to T substitution at nucleotide position 2470. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This variant has been identified as somatic in conjunction with MSH2 copy neutral loss of heterozygosity (CN-LOH) in a tumor that demonstrated high microsatellite instability and loss of MSH2 and MSH6 expression by immunohistochemistry (IHC) (Ambry internal data). This variant has been reported in at least two Italian families with HNPCC, including an individual whose colorectal cancer demonstrated high microsatellite instability with loss of MSH2 and MSH6 expression by IHC (Genuardi M et al. Int. J. Cancer, 1998 Mar;75:835-9; Viel A et al. Community Genet, 1998;1:229-36; Capozzi E et al. Eur. J. Cancer, 1999 Feb;35:289-95; Ponz de Leon M et al. Br. J. Cancer, 2004 Feb;90:882-7). This variant has also been identified in a Spanish proband whose Lynch syndrome-associated tumor demonstrated loss of MSH2 and MSH6 expression by IHC (Pérez-Cabornero L et al. Cancer Prev Res (Phila), 2011 Oct;4:1546-55). Of note, this mutation is also designated as Q824X and p.Gln824X 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.
Invitae	RCV000816151	SCV000956645	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-02-27	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln824*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in individuals affected with Lynch syndrome (PMID: 9506527, 21778331). ClinVar contains an entry for this variant (Variation ID: 90983). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284510	SCV001470343	pathogenic	not provided	2020-07-16	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MSH2 protein synthesis. In addition, it has been reported in individuals affected with Lynch syndrome in the published literature (PMID: 21778331 (2011), 14970868 (2004), 9506527 (1998)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003452914	SCV004187949	pathogenic	Lynch syndrome 1	2023-08-09	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.