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 pathogenic not provided 2019-06-24 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 9450906, 9497252, 9887333, 23454770, 10864201, 17910737, 29625052)
Invitae RCV000408957 SCV000622856 pathogenic Ataxia-telangiectasia syndrome 2019-12-30 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 The c.8814_8824del11 pathogenic mutation, located in coding exon 60 of the ATM gene, results from a deletion of 11 nucleotides at positions 8814 to 8824, causing a translational frameshift with a predicted alternate stop codon (p.M2938Ifs*14). This mutation has been detected in the compound heterozygous state in several ataxia telangiectasia (AT) patients from the literature (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62:551-61; Cavalieri S et al. Ann. Hum. Genet. 2008 Jan;72:10-8). 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.
Color Health, Inc RCV000571341 SCV000682520 pathogenic Hereditary cancer-predisposing syndrome 2020-02-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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