ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3994-1G>T (rs1057516238)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411542 SCV000485338 likely pathogenic Ataxia-telangiectasia syndrome 2015-11-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562309 SCV000667937 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-25 criteria provided, single submitter clinical testing The c.3994-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 26 of the ATM gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Color Health, Inc RCV000562309 SCV000687512 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-11 criteria provided, single submitter clinical testing
Invitae RCV000411542 SCV000947547 likely pathogenic Ataxia-telangiectasia syndrome 2018-08-26 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 26 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 370107). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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