ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.20del (p.Glu7fs) (rs267607915)

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Total submissions: 5
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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 2016-06-06 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. 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). 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 2019-04-16 criteria provided, single submitter clinical testing 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 18759827, 28514183). ClinVar contains an entry for this variant (Variation ID: 90886). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000202031 SCV000257167 likely pathogenic not provided no assertion criteria provided research

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