ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1023del (p.Val342fs) (rs864622340)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206764 SCV000260224 pathogenic Hereditary nonpolyposis colon cancer 2019-11-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val342Leufs*15) 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 not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 220006). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000478573 SCV000570098 pathogenic not provided 2017-09-06 criteria provided, single submitter clinical testing This deletion of one nucleotide in MSH2 is denoted c.1023delT at the cDNA level and p.Val342LeufsX15 (V342LfsX15) at the protein level. The normal sequence, with the base that is deleted in brackets, is GACT[T]GTTA. The deletion causes a frameshift which changes a Valine to a Leucine at codon 342, and creates a premature stop codon at position 15 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Ambry Genetics RCV000491587 SCV000580449 pathogenic Hereditary cancer-predisposing syndrome 2018-12-21 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478573 SCV001134326 pathogenic not provided 2019-04-11 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Integrated Genetics/Laboratory Corporation of America RCV001193997 SCV001363213 likely pathogenic Hereditary nonpolyposis colon cancer 2019-02-05 criteria provided, single submitter clinical testing Variant summary: The variant, MSH2 c.1023delT (p.Val342LeufsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1030C>T (p.Gln344X), c.1221_1222delCT(p.Tyr408fsX8), and c.1226_1227delAG (p.Gln409fsX7)). The variant was absent in 246218 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1023delT in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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