ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8988-2A>G (rs786202087)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164726 SCV000215398 pathogenic Hereditary cancer-predisposing syndrome 2020-03-13 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 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). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000627859 SCV000748743 likely pathogenic Ataxia-telangiectasia syndrome 2020-09-16 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in the last intron (intron 62) of the ATM gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed to be homozygous or on the opposite chromosome (in trans) from a pathogenic variant in individuals affected with ataxia-telangiectasia (PMID: 27664052, 12815592). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 185326). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site and strengthen a cryptic acceptor site in exon 63, located 13 nucleotides downstream of the natural splice site. Additionally, an experimental study has reported that disruption of this splice site (c.8988-1G>C) results in the loss of 13 nucleotides from exon 63, causing a frameshift at codon 2996 (p.Ser2996Argfs*6) (PMID: 10330348). 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.
Color Health, Inc RCV000164726 SCV001356782 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-08 criteria provided, single submitter clinical testing This variant causes an A>G nucleotide substitution at the canonical -2 position of intron 62 splice acceptor site of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, it is expected to result in an absent or non-functional protein product. This variant has been observed in compound heterozygous state with c.901+1G>A 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). A different variant affecting the same splice acceptor site, c.8988-1G>C, is known to be disease-causing due to its disruptive impact on RNA splicing (Clinvar variation ID: 181987). Loss of ATM function is a known mechanism of disease. 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.

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