Submissions for variant NM_000251.3(MSH2):c.340G>T (p.Glu114Ter)

dbSNP: rs878853815

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001034685	SCV000284166	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu114*) 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 clinical features of MSH2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 237395). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000228392	SCV000919697	likely pathogenic	Lynch syndrome	2018-03-30	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.340G>T (p.Glu114X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.387_388delTC, p.Gln130fsX2; c.528_529delTG, p.Cys176X; c.704_705delAA, p.Lys235fsX20). The variant was absent in 121212 control chromosomes (ExAC). To our knowledge, no occurrence of c.340G>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission for a clinical diagnostic laboratory (evaluation after 2014) and a reputable database cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985808	SCV001134362	pathogenic	not provided	2019-01-09	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Ambry Genetics	RCV001020232	SCV001181685	pathogenic	Hereditary cancer-predisposing syndrome	2018-07-30	criteria provided, single submitter	clinical testing	The p.E114* pathogenic mutation (also known as c.340G>T), located in coding exon 2 of the MSH2 gene, results from a G to T substitution at nucleotide position 340. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. 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.	RCV003454701	SCV004188147	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.