ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1235+4_1235+5del (rs770033355)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481339 SCV000567832 uncertain significance not provided 2015-09-03 criteria provided, single submitter clinical testing This variant is denoted ATM c.1235+4_1235+5delAA or IVS9+4_IVS9+5delAA and consists of a deletion of two nucleotides at the +4 to +5 position in intron 9 of the ATM gene. The normal sequence, with the bases that are deleted in braces, is Ggta[delaa]gtgt, where the capital letter is exonic and the lowercase letters are intronic. This deletion is predicted to destroy the nearby natural splice donor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. ATM c.1235+4_1235+5delAA 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. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. The nucleotides that are deleted are conserved in mammals. Based on the currently available information, it is unclear whether ATM c.1235+4_1235+5delAA is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568923 SCV000665551 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000805666 SCV000945632 uncertain significance Ataxia-telangiectasia syndrome 2018-11-19 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs770033355, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 419780). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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