ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.9139C>T (p.Arg3047Ter) (rs121434219)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000493958 SCV000581447 pathogenic Hereditary cancer-predisposing syndrome 2017-10-10 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)
Color RCV000493958 SCV000682541 likely pathogenic Hereditary cancer-predisposing syndrome 2018-10-10 criteria provided, single submitter clinical testing
Counsyl RCV000199061 SCV000795374 pathogenic Ataxia-telangiectasia syndrome 2017-11-08 criteria provided, single submitter clinical testing
GeneDx RCV000485169 SCV000565861 pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing This variant is denoted ATM c.9139C>T at the cDNA level and p.Arg3047Ter (R3047X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). This variant has been observed in the homozygous state in at least one patient with Ataxia-telangiectasia (A-T) and in trans with ATM pathogenic variants in other patients (Toyoshima 1998, Chessa 2009, Byrd 2012, Liu 2016). ATM protein was shown to be expressed in a cell line from one patient with A-T who carried this variant in trans with another pathogenic variant, consistent with the prediction that Arg3047Ter does not cause nonsense-mediated decay (Byrd 2012). Even though only the ten terminal amino acids are lost, the variant is reported to result in absent kinase activity and deficient activation by oxidation (Barone 2009, Guo 2010). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000199061 SCV000253749 pathogenic Ataxia-telangiectasia syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the ATM gene (p.Arg3047*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 10 amino acids of the ATM protein. This variant has been reported as homozygous or in trans with different pathogenic variants in multiple individuals with ataxia-telangiectasia (PMID: 8755918, 19691550, 18560558, 10980530, 26628246). ClinVar contains an entry for this variant (Variation ID: 3029). Experimental studies have shown that this truncated protein is expressed in cell culture but fails to phosphorylate ATM target proteins (PMID: 19431188). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003168 SCV000023326 pathogenic Ataxia-telangiectasia without immunodeficiency 1998-01-13 no assertion criteria provided literature only

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