ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1524del (p.Gly509fs) (rs786204737)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169584 SCV000221089 likely pathogenic Ataxia-telangiectasia syndrome 2015-01-27 criteria provided, single submitter literature only
GeneDx RCV000236634 SCV000293432 likely pathogenic not provided 2016-02-29 criteria provided, single submitter clinical testing This deletion of one nucleotide in ATM is denoted c.1524delT at the cDNA level and p.Gly509GlufsX3 (G509EfsX3) at the protein level. The normal sequence, with the base that is deleted in braces, is TACT[T]GGAG. The deletion causes a frameshift which changes a Glycine to a Glutamic Acid at codon 509, and creates a premature stop codon at position 3 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.1524delT, also published as ATM Leu508LeufsX4, has been observed in at least one individual with Ataxia Telangiectasia (Cavalieri 2008). Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Invitae RCV000169584 SCV000622267 pathogenic Ataxia-telangiectasia syndrome 2020-09-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly509Glufs*3) in the ATM 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 on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with ataxia-telangiectasia (PMID: 16941484). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 189158) Loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000573650 SCV000665463 pathogenic Hereditary cancer-predisposing syndrome 2019-04-30 criteria provided, single submitter clinical testing The c.1524delT pathogenic mutation, located in coding exon 9 of the ATM gene, results from a deletion of one nucleotide at position 1524, causing a translational frameshift with a predicted alternate stop codon (p.G509Efs*3). This mutation was detected in conjunction with a second ATM mutation in an Italian individual with ataxia-telangiectasia (Cavalieri S et al, Hum. Mutat. 2006 Oct; 27(10):1061). 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 RCV000573650 SCV001349858 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169584 SCV001448433 pathogenic Ataxia-telangiectasia syndrome 2020-11-11 criteria provided, single submitter clinical testing Variant summary: ATM c.1524delT (p.Gly509GlufsX3) 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 was absent in 251190 control chromosomes (gnomAD). c.1524delT has been reported in the literature in individuals affected with Ataxia-Telangiectasia, breast cancer and ovarian cancer (Cavalieri_2006, Rizzolo_2019, Bochtler_2019, Arvai_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.

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