Submissions for variant NM_000051.4(ATM):c.8269-1G>A

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003037429	SCV003440468	pathogenic	Ataxia-telangiectasia syndrome	2022-07-30	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 23807571). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 56 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). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003336803	SCV004044382	likely pathogenic	Familial cancer of breast	2023-06-01	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Ambry Genetics	RCV003367961	SCV004053990	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-10	criteria provided, single submitter	clinical testing	The c.8269-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 56 of the ATM gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been confirmed in trans with an ATM pathogenic variant in an individual diagnosed with ataxia telangiectasia (Huang Y et al. Neuromolecular Med, 2013 Sep;15:536-40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.