Submissions for variant NM_000251.3(MSH2):c.2152C>T (p.Gln718Ter)

dbSNP: rs587779139

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076411	SCV000107440	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000214955	SCV000276621	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	clinical testing	The p.Q718* pathogenic mutation (also known as c.2152C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2152. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This mutation has been identified in multiple hereditary non-polyposis colorectal cancer (HNPCC)//Lynch syndrome families to date, most of them of Portuguese descent (Isidro G et al. Hum. Mutat., 2000 Jan;15:116; Lage PA et al. Cancer, 2004 Jul;101:172-7; Ewald J et al. Br J Surg, 2007 Aug;94:1020-7; Valentin MD et al. Fam. Cancer, 2011 Dec;10:641-7; Monteiro Santos EM et al. BMC Cancer, 2012 Feb;12:64; Rossi BM et al. BMC Cancer. 2017 Sep;17(1):623; Schneider NM et al. Cancer Med. 2018 May;7(5):2078-88). It has also been reported in three families with early-onset and/or familial prostate cancer, along with other more typical Lynch-associated tumors (Maia S et al. Fam. Cancer, 2016 Jan;15:111-21). Of note, this alteration is designated as p.Gln718* and p.Gln718Ter 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	RCV000627699	SCV000548243	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln718*) 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: 10612836, 11910346, 15222003, 21681552, 26289772, 26437257). ClinVar contains an entry for this variant (Variation ID: 90909). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506389	SCV000601458	pathogenic	not provided	2016-08-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000076411	SCV000837850	pathogenic	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000076411	SCV000914305	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000214955	SCV001345240	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 13 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 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001804826	SCV002512770	pathogenic	Lynch syndrome 1	2021-11-08	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate
Myriad Genetics, Inc.	RCV001804826	SCV004188000	pathogenic	Lynch syndrome 1	2023-08-07	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.
Baylor Genetics	RCV001804826	SCV004196941	pathogenic	Lynch syndrome 1	2021-04-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353948	SCV000592540	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Gln718X variant has been previously reported in the literature in 10 of 416 proband chromosomes in individuals meeting various criteria for Lynch syndrome or early onset colorectal cancer (Ewald 2007, Isido 1999, Lage 2004, Terdiman 2002, Santos 2012) and an MSH2 deficient tumour was demonstrated by IHC for this variant in at least one study (Ewald 2007). The variant was also identified by the MMRV (memorial university database), and the InSight colorectal cancer database. The p.Gln718X variant leads to a premature stop codon at position 718, which is predicted to lead to a truncated or absent protein and loss of function. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease for Lynch syndrome. In summary, based on the above information, this variant is classified as pathogenic.
GeneReviews	RCV001804826	SCV002054067	not provided	Lynch syndrome 1		no assertion provided	literature only