ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8418+5_8418+8del (rs730881295)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212083 SCV000209610 pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.8418+5_8418+8delGTGA or IVS57+5_IVS57+8delGTGA and consists of a deletion of four nucleotides at the +5 to +8 position of intron 57 of the ATM gene. The normal sequence, with the bases that are deleted in brackets, is TGgtga[delgtga]cacc, where the capital letters are exonic and lowercase are intronic. RT-PCR analysis in patient cells demonstrated that this variant, previously published as ATM IVS59+5_IVS59+8delGTGA, IVS59+1del4, 8418+1delGTGA, or 8269del150, results in exon skipping (Gilad 1996). This variant has been observed in multiple Ataxia-telangiectasia patients as well as individuals with breast or prostate cancer (Wright 1996, Hacia 1998, Li 2000, Buzin 2003, Pritchard 2016, Pritzlaff 2017). Based on the currently available information, we consider ATM c.8418+5_8418+8delGTGA to be pathogenic.
Ambry Genetics RCV000159624 SCV000215050 pathogenic Hereditary cancer-predisposing syndrome 2017-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation
Invitae RCV000204238 SCV000261443 pathogenic Ataxia-telangiectasia syndrome 2018-12-27 criteria provided, single submitter clinical testing This four nucleotide deletion falls in intron 57 of the ATM mRNA. It does not directly change the encoded amino acid sequence of the ATM protein. This sequence change affects a highly conserved nucleotide near the donor splice site. This variant is present in population databases (rs769139997, ExAC 0.001%). This variant has been reported as compound heterozygous with other ATM variants in several individuals affected with ataxia-telangiectasia (PMID: 9872980, 10817650, 12552559, 28008555), and as heterozygous in individuals affected with breast and prostate cancer (PMID: 26681312, 27433846). This variant is also known as c.8269delta150, 8418+1delGTGA, IVS59+1del4, and IVS59+5_IVS59+8delGTGA in the literature. ClinVar contains an entry for this variant (Variation ID: 181866). Experimental studies have shown that this deletion causes skipping of exon 57 (known as exon 59 in the literature), resulting in a shortened mRNA transcript (PMID: 8808599). For these reasons, this variant has been classified as Pathogenic.
Color RCV000159624 SCV000682483 pathogenic Hereditary cancer-predisposing syndrome 2015-02-02 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000204238 SCV000536753 pathogenic Ataxia-telangiectasia syndrome 2016-04-05 no assertion criteria provided research

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