Submissions for variant NM_000251.3(MSH2):c.20del (p.Glu7fs)

dbSNP: rs267607915

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076388	SCV000107415	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
Ambry Genetics	RCV000218615	SCV000275838	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-22	criteria provided, single submitter	clinical testing	The c.20delA pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a deletion of one nucleotide at position 20, causing a translational frameshift with a predicted alternate stop codon (p.E7Gfs*57). This alteration has been previously identified in an individual with multiple primary colon cancers (Julié C et al. Am. J. Gastroenterol. 2008; 103:2825-35). 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, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
GeneDx	RCV000202031	SCV000778970	pathogenic	not provided	2017-10-27	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in MSH2 is denoted c.20delA at the cDNA level and p.Glu7GlyfsX57 (E7GfsX57) at the protein level. The normal sequence, with the base that is deleted in brackets, is AAGG[delA]GACG. The deletion causes a frameshift which changes a Glutamic Acid to a Glycine at codon 7, and creates a premature stop codon at position 57 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.20delA has been observed in at least one family suspected of having Lynch syndrome; and in another individual with a personal history of colorectal cancer, whose tumor studies demonstrated microsatellite instability and absence of MSH2 protein expression on immunohistochemistry (Julie 2008, Bonadona 2011). We consider this variant to be pathogenic.
Invitae	RCV001056824	SCV001221288	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-05-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90886). This premature translational stop signal has been observed in individual(s) with colon cancer (PMID: 18759827). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu7Glyfs*57) 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).
Myriad Genetics, Inc.	RCV003452889	SCV004186784	pathogenic	Lynch syndrome 1	2023-07-26	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202031	SCV000257167	likely pathogenic	not provided		no assertion criteria provided	research