ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8850+4A>C (rs587782335)

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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 RCV000131263 SCV000186228 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000212091 SCV000209665 uncertain significance not provided 2018-04-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.8850+4A>C or IVS61+4A>C and consists of an A>C nucleotide substitution at the +4 position of intron 61 of the ATM gene. Using alternate nomenclature, this variant would be defined as IVS63+4A>C. In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM c.8850+4A>C was observed at an allele frequency of 0.005% (6/111608) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether ATM c.8850+4A>C is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227772 SCV000283087 uncertain significance Ataxia-telangiectasia syndrome 2018-10-16 criteria provided, single submitter clinical testing This sequence change falls in intron 61 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 (rs587782335, ExAC 0.008%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 142250). 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.
Counsyl RCV000227772 SCV000790694 uncertain significance Ataxia-telangiectasia syndrome 2017-04-05 criteria provided, single submitter clinical testing

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