Submissions for variant NM_000251.3(MSH2):c.1120C>T (p.Gln374Ter)

dbSNP: rs63750558

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076043	SCV000107056	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing a premature termination codon
Ambry Genetics	RCV000162405	SCV000212737	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-14	criteria provided, single submitter	clinical testing	The p.Q374* pathogenic mutation (also known as c.1120C>T), located in coding exon 7 of the MSH2 gene, results from a C to T substitution at nucleotide position 1120. This changes the amino acid from a glutamine to a stop codon within coding exon 7. In a study of 1,721 German probands suspected of HNPCC, this mutation was detected in one family (Mangold E et al. Int J Cancer, 2005 Sep;116:692-702). This mutation has also been reported in a Japanese patient diagnosed with a cardiac angiosarcoma at age 38 (Sunami K et al. Cancer Sci, 2019 Apr;110:1480-1490). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076043	SCV001338280	pathogenic	Lynch syndrome	2020-02-07	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1120C>T (p.Gln374X) 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. The variant was absent in 251398 control chromosomes. c.1120C>T has been reported in the literature in individuals affected with Lynch Syndrome (example, Mangold_2005, Lubomierski_2005, Brieger_2011) and as a germline variant in at-least one individual with a cardiac angiosarcoma who later underwent counseling for Lynch synsrome (Sunami_2019). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic citing one overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001385293	SCV001585097	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-19	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 90548). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15849733). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln374*) 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). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800373	SCV002047033	pathogenic	not provided	2021-05-06	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of MSH2 protein synthesis. It has been reported in individuals and families with Lynch syndrome in the published literature (PMID: 21598002 (2011), 16015629 (2005), 15849733 (2005)). Based on the available information, this variant is classified as pathogenic.
GeneDx	RCV001800373	SCV002104482	pathogenic	not provided	2022-03-08	criteria provided, single submitter	clinical testing	Observed in individuals with personal and/or family histories consistent with pathogenic variants in this gene, however, one study identified inconsistent tumor immunohistochemistry (Mangold 2005, Lubomierski 2005, Brieger 2011, Tzortzatos 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15849733, 26177554, 16015629, 21598002, 25525159, 30742731)
Genetics and Molecular Pathology, SA Pathology	RCV002272052	SCV002556630	pathogenic	Lynch syndrome 1	2021-01-11	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Myriad Genetics, Inc.	RCV002272052	SCV004188101	pathogenic	Lynch syndrome 1	2023-07-31	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.