Submissions for variant NM_000251.3(MSH2):c.1738G>T (p.Glu580Ter)

dbSNP: rs63751411

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076261	SCV000107282	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000483706	SCV000568631	pathogenic	not provided	2017-03-23	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1738G>T at the cDNA level and p.Glu580Ter (E580X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 Glu580Ter has been found to be associated with reduced mRNA expression (Casey 2005). In addition, this variant has been observed in at least one individual with a malignant mixed glioma and several individuals with personal and/or family histories of colon cancer, some of which met Amsterdam or Bethesda Lynch Syndrome criteria and whose corresponding tumors were often microsatellite unstable and/or had abnormal protein staining on immunohistochemistry (Leung 1998, Chen 1999, Mangold 2005, Jasperson 2010, Brieger 2011). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics	RCV000491635	SCV000580455	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-29	criteria provided, single submitter	clinical testing	The p.E580* pathogenic mutation (also known as c.1738G>T), located in coding exon 11 of the MSH2 gene, results from a G to T substitution at nucleotide position 1738. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. This mutation has been identified in multiple individuals diagnosed with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Heinimann K et al. Cancer. 1999 Jun;85(12):2512-8; Jasperson K et al. Fam. Cancer. 2010 Jun;9(2):99-107; Rossi BM et al. BMC Cancer. 2017 Sep 5;17(1):623). Tumor analysis performed on cancer samples from multiple individuals carrying this mutation showed consistent microsatellite instability and absence of MSH2 protein on immunohistochemistry (Leung S et al. Am. J. Pathol. 1998 Oct;153(4):1181-8; Casey G et al. JAMA. 2005 Feb;293(7):799-809; Mangold E et al. J. Pathol. 2005 Dec;207(4):385-95). 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	RCV000552781	SCV000625302	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu580*) 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 variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 90763). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003452854	SCV004187976	pathogenic	Lynch syndrome 1	2023-08-03	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000483706	SCV000691906	pathogenic	not provided		no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785573	SCV000924145	pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249917	SCV001423934	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing