ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4109+6T>C (rs368606937)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000776097 SCV000910905 likely benign Hereditary cancer-predisposing syndrome 2016-05-03 criteria provided, single submitter clinical testing
GeneDx RCV000588070 SCV000278824 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.4109+6T>C or IVS27+6T>C and consists of a T>C nucleotide substitution at the +6 position of intron 27 of the ATM gene. 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. This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether ATM c.4109+6T>C is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588070 SCV000694273 uncertain significance not provided 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The c.4109+6T>C variant involves the alteration of a non-conserved nucleotide resulting in an intronic change. This variant is located at a position that is not widely known to affect splicing, and 2/5 splicing prediction programs via Alamut predict the loss of a splice donor site, however the significance of these predictions has not been supported with functional studies. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.005% which does not exceed the maximal expected allele frequency for a pathogenic variant in ATM (0.40%). The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. One reputable clinical lab has classified the variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a VUS until additional information becomes available.
Invitae RCV000196920 SCV000254100 uncertain significance Ataxia-telangiectasia syndrome 2018-12-16 criteria provided, single submitter clinical testing This sequence change falls in intron 27 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 (rs368606937, 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: 216212). 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 is not likely to affect RNA splicing, 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.
PreventionGenetics RCV000588070 SCV000805554 likely benign not provided 2018-01-12 criteria provided, single submitter clinical testing

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