ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8814_8824del (p.Met2938fs) (rs758814126)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000408957 SCV000486255 likely pathogenic Ataxia-telangiectasia syndrome 2016-04-28 criteria provided, single submitter clinical testing
GeneDx RCV000483094 SCV000568342 likely pathogenic not provided 2016-03-30 criteria provided, single submitter clinical testing This deletion of 11 nucleotides in ATM is denoted c.8814_8824del11 at the cDNA level and p.Met2938IlefsX14 (M2938IfsX14) at the protein level. The surrounding sequence is TGAT[del11]AGGA. The deletion causes a frameshift, which changes a Methionine to an Isoleucine at codon 2938, and creates a premature stop codon at position 14 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. ATM c.8814_8824del11 has been observed in at least three patients with Ataxia-Telangiectasia (Gilad 1998, Sandoval 1999, Cavalieri 2008). Based on the currently available evidence, we consider this deletion to be a likely pathogenic variant.
Invitae RCV000408957 SCV000622856 pathogenic Ataxia-telangiectasia syndrome 2020-01-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met2938Ilefs*14) in the ATM gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) affected with ataxia-telangiectasia (PMID: 9497252, 23454770, 9887333, 17910737). This variant is also known as 8814del11 in the literature. ClinVar contains an entry for this variant (Variation ID: 370841). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000571341 SCV000668079 pathogenic Hereditary cancer-predisposing syndrome 2017-03-14 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000571341 SCV000682520 pathogenic Hereditary cancer-predisposing syndrome 2020-02-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000408957 SCV001426788 pathogenic Ataxia-telangiectasia syndrome 2020-07-12 criteria provided, single submitter clinical testing Variant summary: ATM c.8814_8824del11 (p.Met2938IlefsX14) 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. The variant allele was found at a frequency of 8e-06 in 251404 control chromosomes. c.8814_8824del11 has been reported in the literature in individuals affected with Ataxia-Telangiectasia (e.g. Gilad_1998, Sandoval_1999, Cavalieri_2008). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating ATM protein function in patient cells with this mutation in compound heterozygosity with a second pathogenic mutation. These studies report reduced ATM protein levels and reduced ATM-dependent activities in patient-derived cell lines, however the contributions of the individual variants to the observed phenotypes were not studied (e.g. Gilad_1998, Delia_2000, Prodosmo_2013). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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