ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.9021dup (p.Arg3008fs) (rs876660235)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220949 SCV000277484 pathogenic Hereditary cancer-predisposing syndrome 2019-04-30 criteria provided, single submitter clinical testing Structural Evidence;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000237011 SCV000293444 pathogenic not provided 2017-04-21 criteria provided, single submitter clinical testing This duplication of one nucleotide in ATM is denoted c.9021dupA at the cDNA level and p.Arg3008ThrfsX55 (R3008TfsX55) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CTGA[dupA]CGTG. The duplication causes a frameshift, which changes an Arginine to a Threonine at codon 3008, and creates a premature stop codon at position 55 of the new reading frame. Even though this frameshift occurs in the last exon of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 49 amino acids are replaced with 54 incorrect amino acids and impacts the FATC domain (Stracker 2013). ATM Arg3008ThrfsX55 has been observed in the homozygous state in a patient with classic Ataxia Telangiectasia, whose lymphoblastoid cell line exhibited radiosensitivity and absence of ATM protein production (Mitui 2005, Podralska 2014). We consider this variant to be pathogenic.
Invitae RCV000552654 SCV000622878 pathogenic Ataxia-telangiectasia syndrome 2019-10-03 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 63 of the ATM mRNA (c.9021dupA), causing a frameshift at codon 3008. This creates an alternate translational stop signal in the last exon of the ATM mRNA (p.Arg3008Thrfs*55). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acids including the native stop codon and extend the ATM protein by 6 amino acids. This variant has been observed in an individual with ataxia-telangiectasia (PMID: 21778326). ClinVar contains an entry for this variant (Variation ID: 233164). Experimental studies in patient derived lymphoblastoid cells that are compound heterozygous for this frameshift and a missense variant (p.Val2716Ala) demonstrated reduced expression of ATM and RAD51, and down-regulated single-strand annealing and homology-directed double strand break repair activity (PMID: 21778326). A missense substitution at this codon (p.Arg3008Cys) has been determined to be pathogenic (PMID: 18573109, 12552566, 22649200, 15101044). This suggests that the arginine residue is critical for ATM protein function and that other disruptions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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