Submissions for variant NM_000051.4(ATM):c.8988-1G>C

gnomAD frequency: 0.00001  dbSNP: rs730881386

Total submissions: 10

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	2023-12-12	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 alteration occurs at the 3' terminus of the ATM gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 61 amino acids of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration 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 alteration was found to abolish 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000627869	SCV000748753	pathogenic	Ataxia-telangiectasia syndrome	2024-01-03	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 hereditary cancer syndrome and ataxia-telangiectasia (PMID: 10330348, 31159747). This variant is also known as IVS64-1G>C. ClinVar contains an entry for this variant (Variation ID: 181987). 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 (PMID: 10330348; Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the ATM protein in which other variant(s) (p.Arg3047*) have been determined to be pathogenic (PMID: 8755918, 10980530, 18560558, 19431188, 19691550, 26628246). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 Diagnostics, LLC DBA Color Health	RCV000563949	SCV001350511	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-30	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 62 of the ATM gene. This variant is also known as IVS64-1G>C in the literature. An RNA study has reported that this variant causes the deletion of the first 13 nucleotides of exon 63, creating a frameshift and premature translation stop signal in the last coding exon (PMID: 10330348). The mutation transcript is expected to disrupt the C-terminus of the TP53 binding domain and the FATC domain of the ATM protein. This variant has been reported in the homozygous or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 27664052, 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.
Fulgent Genetics, Fulgent Genetics	RCV002492633	SCV002782672	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-01-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467238	SCV004211989	pathogenic	Familial cancer of breast	2023-05-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467238	SCV004931196	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.
Natera, Inc.	RCV000627869	SCV002083199	pathogenic	Ataxia-telangiectasia syndrome	2021-07-26	no assertion criteria provided	clinical testing