Submissions for variant NM_000251.3(MSH2):c.1373T>G (p.Leu458Ter)

dbSNP: rs63750521

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076136	SCV000107151	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000160582	SCV000211175	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Liu et al., 1994; Wahlberg et al., 1997; Ichikawa et al., 1999; Mangold et al., 2004; Mangold et al., 2005); This variant is associated with the following publications: (PMID: 25525159, 17312306, 26681312, 16321766, 11304573, 15235030, 23741719, 26143115, 8062247, 8931714, 10432927, 16216036, 27601186, 9036882, 31615790)
Ambry Genetics	RCV002381387	SCV002696355	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-21	criteria provided, single submitter	clinical testing	The p.L458* pathogenic mutation (also known as c.1373T>G), located in coding exon 8 of the MSH2 gene, results from a T to G substitution at nucleotide position 1373. This changes the amino acid from a leucine to a stop codon within coding exon 8. This mutation has been reported in multiple families with Lynch syndrome, including several meeting Amsterdam criteria and/or exhibiting loss of MSH2 protein expression on IHC (Mangold E et al. J Med Genet, 2004 Jul;41:567-72; Casey G et al. JAMA, 2005 Feb;293:799-809; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835). This mutation has been identified in individuals with features of Muir-Torre (Liu B et al. Cancer Res, 1994 Sep;54:4590-4) and in families with urinary tract cancers (Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199). 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.
Myriad Genetics, Inc.	RCV003452827	SCV004187909	pathogenic	Lynch syndrome 1	2023-08-01	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000076136	SCV000592499	pathogenic	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH2 p.Leu458X variant was identified in 9 or 4078 proband chromosomes from individuals or families with Lynch syndrome or Muir-Torre syndrome (Ichikawa 1999, Liu 1994, Liu 2000, Mangold 2004, Mangold 2005, Mangold 2005, Salahshor 2001, Wahlberg 1997). Analyses of tumours from probands demonstrated microsatellite instability and/or loss of MSH2 by immunohistochemistry staining (Ichikawa 1999, Liu 2000, Mangold 2004, Mangold 2005, Salahshor 2001). The variant was also identified in dbSNP (ID: rs63750521), HGMD, “Mismatch Repair Genes Variant Database”, and the “InSiGHT Colon Cancer Database”. The p.Leu458X variant leads to a premature stop codon at position 458, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.