Submissions for variant NM_000051.4(ATM):c.8988-2A>G

dbSNP: rs786202087

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164726	SCV000215398	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	The c.8988-2A>G pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 62 in the ATM gene. A similar alteration, c.8988-1G>C (also designated as IVS64-1G>C in the published literature), has been identified in two compound heterozygous patients with ataxia-telangiectasia and has been reported to result in the activation of a cryptic acceptor site, leading to a deletion of 13 nucleotides (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31. Mitui M et al. Hum. Mutat. 2003 Jul; 22(1):43-50). 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 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627859	SCV000748743	pathogenic	Ataxia-telangiectasia syndrome	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 62 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with ataxia-telangiectasia (PMID: 12552559, 27664052). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 185326). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a new termination codon (Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000164726	SCV001356782	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-03-09	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 62 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in a disrupted protein product. This variant has been observed in the compound heterozygous state with an additional pathogenic ATM variant in two related individuals affected with ataxia telangiectasia (BioSamples family ID: 1629). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice acceptor site (c.8988-1G>C, c.8988-1G>A) are known to be disease-causing due to its disruptive impact on RNA splicing (ClinVar variation ID: 181987, 219587). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258066	SCV001434897	likely pathogenic	Ataxia-telangiectasia syndrome; Breast cancer, susceptibility to	2018-08-10	criteria provided, single submitter	clinical testing	This c.8988-2A>G variant in the ATM gene is predicted to disrupt a canonical splice donor site and thus alter mRNA splicing. It is absent from general population database. Therefore, this c.8988-2A>G variant is classified as likely pathogenic.
Revvity Omics, Revvity	RCV000627859	SCV002024406	likely pathogenic	Ataxia-telangiectasia syndrome	2019-05-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468720	SCV004210317	likely pathogenic	Familial cancer of breast	2024-03-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003468720	SCV004933095	likely pathogenic	Familial cancer of breast	2024-02-06	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.