ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5763-2A>G

dbSNP: rs876659489
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569324 SCV000665511 likely pathogenic Hereditary cancer-predisposing syndrome 2016-04-08 criteria provided, single submitter clinical testing The c.5763-2A>G intronic variant results from a A to G substitution two nucleotides upstream from coding exon 37 of the ATM gene. A similar variant, c.5763-2A>T (also designated as c.5762A>T and IVS40-2A→T in the literature), has been previously reported in multiple individuals with ataxia telangiectasia, and has been shown to cause protein truncation and absence of ATM kinase activity through RT-PCR and Western blot analyses (Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71; Broeks et al. Hum. Mutat. 1998;12(5):330-7). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 125000 alleles tested) in our clinical cohort. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site and create a potential alternative splice acceptor site; however, direct evidence is not available. This nucleotide position is highly conserved in available vertebrate species. Alterations that disrupt the canonical splice acceptor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.5763-2A>G variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001865741 SCV002258124 likely pathogenic Ataxia-telangiectasia syndrome 2022-02-21 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with ATM-related conditions. 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: 481234). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 38 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).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.