Submissions for variant NM_000251.3(MSH2):c.142G>T (p.Glu48Ter)

dbSNP: rs63750615

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076158	SCV000107174	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506167	SCV000604262	pathogenic	not specified	2016-11-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537461	SCV000625261	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-05-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu48*) 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: 19419416, 20587412, 22371642). Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 90662). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000582377	SCV000691895	pathogenic	not provided	2020-12-31	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Counsyl	RCV000662482	SCV000784980	pathogenic	Lynch syndrome 1	2017-10-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001011543	SCV001171876	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-21	criteria provided, single submitter	clinical testing	The p.E48* pathogenic mutation (also known as c.142G>T), located in coding exon 1 of the MSH2 gene, results from a G to T substitution at nucleotide position 142. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MSH2-related disease (Ambry internal data). This mutation has been identified in numerous Lynch syndrome families to date (Tang R et al. Clin. Genet., 2009 Apr;75:334-45; Berends MJ et al. Int. J. Cancer, 2001 May;92:398-403; Sjursen W et al. J. Med. Genet., 2010 Sep;47:579-85; Zahary MN et al. World J. Gastroenterol., 2012 Feb;18:814-20). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV000582377	SCV002102635	pathogenic	not provided	2022-03-03	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 patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Pino 2009, Tang 2009, Sjursen 2010, Zahary 2012); This variant is associated with the following publications: (PMID: 26053027, 11291077, 19419416, 22371642, 20587412, 19324997, 31615790)
Myriad Genetics, Inc.	RCV000662482	SCV004018413	pathogenic	Lynch syndrome 1	2023-03-23	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	RCV000662482	SCV004194556	pathogenic	Lynch syndrome 1	2023-06-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354006	SCV000592452	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Glu48X variant was identified in two reports, as a truncating mutation in endometrial cancer (Berends 2001), and as resulting in a loss of protein by immunohistochemistry in a patient with Lynch syndrome (Zahary 2012). The variant was also identified in dbSNP (ID: rs63750615) “With pathogenic allele”, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database, and “the ClinVar database (classified as a pathogenic variant by an expert panel). The variant was not found in the following databases: NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae database, COSMIC, “MMR Gene Unclassified Variants Database”, Zhejiang Colon Cancer Database”, GeneInsight COGR database, and UMD. The p.Glu48X variant leads to a premature stop codon at position 48, 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.