ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212074 SCV000149162 pathogenic not provided 2018-10-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.7630-2A>C or IVS51-2A>C and consists of an A>C 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). This variant, also denoted as IVS53-2A>C and IVS54-2A>C using alternate exon numbering, has been observed in several individuals with ataxia telangiectasia in the homozygous and compound heterozygous state and has been reported as a founder variant identified in individuals of Polish descent (Telatar 1998, Sandoval 1999, Teraoka 1999, Li 2000, Mitui 2005, Soukupova 2011, Nespoli 2013, Podralska 2014). Furthermore, this variant was studied by Sandoval et al. (1999) in the homozygous state, and was found to cause exon skipping in patient RNA and did not produce any detectable ATM protein. We therefore consider this variant to be pathogenic.
Ambry Genetics RCV000115253 SCV000183992 pathogenic Hereditary cancer-predisposing syndrome 2017-12-22 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,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000206201 SCV000260235 pathogenic Ataxia-telangiectasia syndrome 2018-12-31 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 present in population databases (rs587779866, ExAC 0.003%). This variant has been reported in several individuals affected with ataxia-telangiectasia in both the compound heterozygous and homozygous states (PMID: 9887333, 25374739, 21833744, 9443866). It has also been observed in individuals with breast cancer (PMID: 26681312). This variant is known as IVS51-2A>C and IVS53-2A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 127447). An experimental study using lymphoblastoid cell lines derived from affected individuals showed that this variant results in two aberrant forms of the ATM transcript, one in which exon 52 is skipped and another in which the first 11 nucleotides of exon 52 are skipped (PMID: 9887333). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000206201 SCV000485386 pathogenic Ataxia-telangiectasia syndrome 2015-12-04 criteria provided, single submitter clinical testing
Color RCV000115253 SCV000537667 pathogenic Hereditary cancer-predisposing syndrome 2015-01-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515371 SCV000611168 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212074 SCV000805615 pathogenic not provided 2016-03-25 criteria provided, single submitter clinical testing
GeneKor MSA RCV000115253 SCV000821703 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000206201 SCV000838594 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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