ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8988-1G>C (rs730881386)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159756 SCV000209773 pathogenic not provided 2016-09-23 criteria provided, single submitter clinical testing The c.8988-1G>C variant in the ATM gene has been reported previously in association with ataxia-telangiectasia (Teraoka et al., 1999). This splice site mutation destroys the canonical splice acceptor site in intron 62. It is predicted to cause abnormal gene splicing due to the activation of a cryptic acceptor splice site, leading to the truncation of 13 nucleotides (Teraoka et al., 1999). The c.8988-1G>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.8988-1G>C as a pathogenic variant.
Ambry Genetics RCV000563949 SCV000667817 pathogenic Hereditary cancer-predisposing syndrome 2018-04-05 criteria provided, single submitter clinical testing The c.8988-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 62 of the ATM gene. This mutation has been detected in both the homozygous and compound heterozygous state with another ATM mutation in multiple individuals with a diagnosis of ataxia-telangiectasia (A-T) (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Carranza D et al. Neuromolecular Med. 2017 Mar;19:161-174). This mutation was found to abolish <span style="font-family:arial,sans-serif; font-size:10pt">the native acceptor site in coding intron 61 and activate a cryptic splice site resulting in a frameshift deletion of 13 nucleotides (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31). A colony survival assay showed intermediate radiosensitivity of cells that harbor this mutation, and a Western blot analyses looking at the expression of ATM in nuclear lysates of long-term primary T cells showed absence of the protein in cells that harbor this mutation (Carranza D et al. Neuromolecular Med. 2017 Mar;19:161-174). Of note, this alteration is also designated as IVS64-1G>C in published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Invitae RCV000627869 SCV000748753 pathogenic Ataxia-telangiectasia syndrome 2020-10-09 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). This variant has been reported as heterozygous in an individual affected with ataxia-telangiectasia, without finding the second allele in ATM (PMID: 10330348). This variant is also known as IVS64-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 181987). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). An experimental study has shown that this sequence change causes the loss of 13 nucleotides from exon 63 as a result of alternative splicing, causing a frameshift at codon 2996 (p.Ser2996Argfs*6) (PMID: 10330348). A different truncation (p.Arg3047*) that lies downstream of this variant has been determined to be pathogenic (PMID: 19431188, 8755918, 19691550, 18560558, 10980530, 26628246). This suggests that deletion of this region of the ATM protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000627869 SCV000798694 pathogenic Ataxia-telangiectasia syndrome 2018-03-20 criteria provided, single submitter clinical testing
GeneKor MSA RCV000563949 SCV000821705 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This variation occurs 1 base before exon 63 of the ATM gene in a position is highly conserved in the human and other genomes which is crucial for mRNA processing. This mutation is expected to result in incorrect splicing and removal of the entire exon in the resulting protein. This variant has been described in the international literature in association with ataxia-telangiectasia (Am J Hum Genet. 1999, 64:1617-31). The mutation database ClinVar contains an entry for this variant (Variation ID: 181987).
Color Health, Inc RCV000563949 SCV001350511 pathogenic Hereditary cancer-predisposing syndrome 2020-09-10 criteria provided, single submitter clinical testing This variant causes a G>C nucleotide substitution at the -1 position of intron 62 splice acceptor site of the ATM gene. This variant is also known as IVS62-1G>C and IVS64-1G>C in the literature. A functional study has shown that this variant causes the deletion of 13 bases from the start of exon 63, resulting in frameshift disrupting the C-terminus of the TP53 binding domain and the FATC domain (PMID: 10330348). This variant has been reported in individuals affected with ataxia telangiectasia in homozygous state (PMID: 27664052) and in compound heterozygous state with a pathogenic c.8146G>T (p.V2716F) variant (PMID: 30338439). This variant has also been reported in another individual affected with ataxia telangiectasia with an unknown second mutation (PMID: 10330348). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

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