ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7517_7520delGAGA (rs587781905)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130244 SCV000185088 pathogenic Hereditary cancer-predisposing syndrome 2018-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000236845 SCV000292954 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing This deletion of four nucleotides in ATM is denoted c.7517_7520delGAGA at the cDNA level and p.Arg2506ThrfsX3 (R2506TfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAGA[delGAGA]CGGA. The deletion causes a frameshift, which changes an Arginine to a Threonine at codon 2506, 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.7517_7520delGAGA, previously reported as ATM 7517del4, has been observed in numerous patients with classic ataxia-telangiectasia in both the homozygous and compound heterozygous state and is considered an Italian pathogenic founder variant (Gilad 1996, Coutinho 2004, Cavalieri 2006, Magliozzi 2006, Chessa 2009, Demuth 2011). We consider this variant to be pathogenic.
Counsyl RCV000258095 SCV000485200 pathogenic Ataxia-telangiectasia syndrome 2015-12-23 criteria provided, single submitter clinical testing
Invitae RCV000258095 SCV000546740 pathogenic Ataxia-telangiectasia syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg2506Thrfs*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 reported in individuals affected with ataxia-telangiectasia (PMID: 8845835, 19691550, 17124347, 16941484, 21965147, 12815592). This variant is also known as 7517del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 141647). Loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000258095 SCV000598151 pathogenic Ataxia-telangiectasia syndrome 2016-09-12 criteria provided, single submitter clinical testing This heterozygous variant in the ATM gene (autosomal recessive transmission), inherited from the father, was present in a female patient who also harbours a second variant in the same gene inherited by the mother (compound heterozygosity).
Color RCV000130244 SCV000687776 pathogenic Hereditary cancer-predisposing syndrome 2017-06-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000258095 SCV000694356 pathogenic Ataxia-telangiectasia syndrome 2016-02-15 criteria provided, single submitter clinical testing Variant summary: Variant results in a frameshift mutation altering the 3050 amino acid long ATM beginning at position 2506 and leading to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Mutation taster predicts the variant to be disease causing. It is absent from the large and broad cohorts of the ExAC project but while it was reported in several ATM patients in either compound heterozygosity or homozygosity indicating pathogenicity. The reported patients are predominantly of Italian origin and the variant is considered to be one of the most common Italian AT mutation (Cavalieri_Hum Mutat_2006, Chessa_Human_Genetics_2009). Furthermore, a clinical laboratory classifies variant as "Pathogenic" via ClinVar (without evidence to independently evaluate). Truncating mutations are known mechanisms of AT and truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.8264_8268delATAAG/p.Tyr2755fs), and considering the additional supporting information, the variant shows strong indications for pathogenicity, and therefore, it is classified as pathogenic.
GeneReviews RCV000258095 SCV000328284 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only

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