ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5006-2A>G

dbSNP: rs2135887733
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001379093 SCV001576827 likely pathogenic Ataxia-telangiectasia syndrome 2023-08-16 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1067747). Disruption of this splice site has been observed in individual(s) with chronic lymphocytic leukemia (PMID: 21933854). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 33 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
Ambry Genetics RCV002341821 SCV002640760 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-16 criteria provided, single submitter clinical testing The c.5006-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 33 in the ATM gene. This nucleotide position is highly 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 a transcript predicted to lead to a protein with an in-frame insertion of 5 amino acids; however, the exact functional impact of the inserted amino acids is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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