Submissions for variant NM_000251.3(MSH2):c.2525_2526del (p.Glu842fs)

dbSNP: rs587779148

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076495	SCV000107524	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Counsyl	RCV000410241	SCV000489727	pathogenic	Lynch syndrome 1	2016-11-11	criteria provided, single submitter	clinical testing
Invitae	RCV000524392	SCV000548299	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-07-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu842Valfs*3) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in families affected with Lynch syndrome (PMID: 21681552, 24344984). ClinVar contains an entry for this variant (Variation ID: 90993). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	RCV000076495	SCV000914306	pathogenic	Lynch syndrome	2019-01-30	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001525554	SCV001735707	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-10	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 15 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 21681552, 24344984). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV001525554	SCV002742611	pathogenic	Hereditary cancer-predisposing syndrome	2017-02-09	criteria provided, single submitter	clinical testing	The c.2525_2526delAG pathogenic mutation, located in coding exon 15 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 2525 to 2526, causing a translational frameshift with a predicted alternate stop codon (p.E842Vfs*3). This mutation has been identified in two unrelated Brazilian Lynch syndrome families (Dominguez-Valentin M et al. Hered Cancer Clin Pract. 2013 Dec;11:18). 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.	RCV000410241	SCV004018405	pathogenic	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000410241	SCV004196884	pathogenic	Lynch syndrome 1	2022-11-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000076495	SCV000592551	pathogenic	Lynch syndrome		no assertion criteria provided	clinical testing	The p.Glu842ValfsX3 variant was identified in an individual with Lynch syndrome in a study by Valentin (2011). The variant was also identified in the HGMD, InSiGHT Colon Cancer database and the ClinVar database (submitted by InSiGHT with a pathogenic classification). The p.Glu842ValfsX3 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 842 and leads to a premature stop codon 3 codons downstream. This alteration is then predicted to result in 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.