ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.9019G>T (p.Glu3007Ter) (rs876660382)

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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 RCV000222768 SCV000277771 pathogenic Hereditary cancer-predisposing syndrome 2017-11-08 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 RCV000255661 SCV000322216 likely pathogenic not provided 2018-08-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.9019G>T at the cDNA level and p.Glu3007Ter (E3007X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through protein truncation. Due to the position of the variant, nonsense mediated decay is not expected to occur, but it is predicted to cause loss of normal protein function through protein truncation as the last 49 amino acids are no longer translated. The disrupted region at the end of the gene is located within the FATC domain (Stracker 2013). This variant has been reported in an individual with Ataxia-telangiectasia and in at least two individuals with breast cancer (Broeks 1998, Tung 2015, Hauke 2018). We consider ATM Glu3007Ter to be a likely pathogenic variant.
Invitae RCV000233073 SCV000283103 pathogenic Ataxia-telangiectasia syndrome 2018-02-22 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the ATM gene (p.Glu3007*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 50 amino acids of the ATM protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with ataxia-telangiectasia (PMID: 9792409), and an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 233403). A different truncation (p.Arg3047*) that lies downstream of this variant has been determined to be pathogenic (PMID: 8755918, 19691550, 18560558, 10980530, 26628246, 19431188). This suggests that deletion of this region of the ATM protein is causative of disease.. For these reasons, this variant has been classified as Pathogenic.

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