ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3078-1G>A (rs750663117)

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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 RCV000219914 SCV000275071 pathogenic Hereditary cancer-predisposing syndrome 2017-12-08 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Counsyl RCV000410565 SCV000486113 likely pathogenic Ataxia-telangiectasia syndrome 2016-03-31 criteria provided, single submitter clinical testing
GeneDx RCV000482905 SCV000568319 pathogenic not provided 2017-08-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.3078-1G>A or IVS20-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 20 of the ATM gene. This variant destroys a canonical splice acceptor site and has been shown to cause abnormal gene splicing. Also defined as IVS22-1G>A using alternate nomenclature, this variant was reported in the compound heterozygous state in an individual with ataxia-telangiectasia and RT-PCR analysis demonstrated that this variant causes skipping of the subsequent exon (Izatt 1999). This disruption would be predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000410565 SCV000622387 pathogenic Ataxia-telangiectasia syndrome 2019-11-29 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 20 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs750663117, ExAC 0.002%). This variant has been observed in an individual affected with ataxia-telangiectasia (PMID: 10234507). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 231277). Experimental studies have shown that this sequence change can result in the out-of-frame skipping of exon 21 (PMID: 10234507). Due to alternative exon numbering, exon 21 is also known as exon 23 in the literature. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Color RCV000219914 SCV000687450 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-15 criteria provided, single submitter clinical testing

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