ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7630-2A>G (rs587779866)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000493469 SCV000581432 likely pathogenic Hereditary cancer-predisposing syndrome 2017-09-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without splicing assay data in support of pathogenicity,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Counsyl RCV000525719 SCV000796334 likely pathogenic Ataxia-telangiectasia syndrome 2017-12-12 criteria provided, single submitter clinical testing
GeneDx RCV000484828 SCV000570887 pathogenic not provided 2016-07-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.7630-2A>G or IVS51-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 51 of the ATM gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal splicing of exon 52. However, the skipping of exon 52 is predicted to be in-frame. Even though this variant is predicted to result in an in-frame transcript, this single exon deletion would result in the loss of 53 residues, some of which are located within the FAT domain (Stracker 2013). While ATM c.7630-2A>G has not, to our knowledge, been reported in the literature, another variant at this -2 position, ATM c.7630-2A>C, has been reported in several individuals with ataxia telangiectasia in both the homozygous and compound heterozygous state (Telatar 1998, Sandoval 1999, Teraoka 1999, Li 2000, Mitui 2005, Soukupova 2011, Nespoli 2013, Podralska 2014). Additionally, both Sandoval et al. (1999) and Teraoka et al. (1999) report that ATM c.7630-2A>C results in no detectable ATM protein. Based on the currently available information, we consider ATM c.7630-2A>G to be pathogenic.
Invitae RCV000525719 SCV000622764 pathogenic Ataxia-telangiectasia syndrome 2018-12-07 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 51 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 421623). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.7630-2A>C) has been determined to be pathogenic (PMID: 9887333, 25374739, 21833744, 9443866). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic.

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