ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8988-1G>C (rs730881386)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563949 SCV000667817 pathogenic Hereditary cancer-predisposing syndrome 2018-04-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Counsyl RCV000627869 SCV000798694 pathogenic Ataxia-telangiectasia syndrome 2018-03-20 criteria provided, single submitter clinical testing
GeneDx RCV000159756 SCV000209773 pathogenic not provided 2016-09-23 criteria provided, single submitter clinical testing The c.8988-1G>C variant in the ATM gene has been reported previously in association with ataxia-telangiectasia (Teraoka et al., 1999). This splice site mutation destroys the canonical splice acceptor site in intron 62. It is predicted to cause abnormal gene splicing due to the activation of a cryptic acceptor splice site, leading to the truncation of 13 nucleotides (Teraoka et al., 1999). The c.8988-1G>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.8988-1G>C as a pathogenic variant.
GeneKor MSA RCV000563949 SCV000821705 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000627869 SCV000748753 pathogenic Ataxia-telangiectasia syndrome 2017-11-22 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 62) of the ATM gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported as heterozygous in an individual affected with ataxia-telangiectasia, without finding the second allele in ATM (PMID: 10330348). This variant is also known as IVS64-1G>C in the literature.  ClinVar contains an entry for this variant (Variation ID: 181987). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). An experimental study has shown that this sequence change causes the loss of 13 nucleotides from exon 63 as a result of alternative splicing, causing a frameshift at codon 2996 (p.Ser2996Argfs*6) (PMID: 10330348). A different truncation (p.Arg3047*) that lies downstream of this variant has been determined to be pathogenic (PMID: 19431188, 8755918, 19691550, 18560558, 10980530, 26628246). 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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