Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 13147 nt | 386–9556 |
| NM_000051.4 | MANE Select | 12915 nt | 151–9321 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe p.H2788Y variant (also known as c.8362C>T), located in coding exon 56 of the ATM gene, results from a C to T substitution at nucleotide position 8362. The histidine at codon 2788 is replaced by tyrosine, an amino acid with similar properties. In an assay testing ATM function, this variant showed a functionally abnormal result (Lee KS et al. Cell, 2025 Sep;188:5081-5099.e27). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
"This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The ATM H2788Y variant has been functionally characterized in a high-throughput cell culture assay, where it failed to rescue the survival and proliferation of ATM-haploid cells upon olaparib treatment. This suggests that the variant leads to a loss of ATM protein function.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -93 bp |
| Donor Loss (DL) | 0.01 | 56 bp |
| Acceptor Gain (AG) | 0.0 | 29 bp |
| Donor Gain (DG) | 0.0 | -33 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines for PVS1: 'Use ATM PVS1 Decision Tree' applies to null variants. The variant is a missense change (H2788Y), not a null variant. Therefore, PVS1 is not applied.
PS1 (Not Applied)
According to VCEP guidelines for PS1: 'Use for protein changes as long as splicing is ruled‐out for both alterations.' There is no known pathogenic variant causing H2788Y via a different nucleotide change. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' No parental data are available. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines for PS3: 'Moderate strength when a variant fails to rescue both an ATM‐specific feature AND radiosensitivity; Supporting strength when a variant fails to rescue an ATM‐specific feature only.' The evidence shows failure to rescue cell survival under olaparib but does not assess ATM‐specific phosphorylation or radiosensitivity. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared to controls.' No case‐control or proband count data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical functional domain without benign variation.' There is no evidence H2788 lies in a defined ATM functional domain. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines for PM2: 'Supporting Frequency ≤0.001% if n=1 in a single subpopulation.' The variant is absent from gnomAD (MAF=0%), meeting this threshold. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines for PM3: 'Use ATM PM3/BP2 table for trans observations in recessive disease.' No phasing or parental genotype data are available to assess trans occurrences. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in‐frame indels or stop‐loss variants.' The variant is missense. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines for PM5: 'Use for novel missense changes at residues with other pathogenic missense variants.' There is no report of a different pathogenic missense at H2788. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity.' No parental data are available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Co‐segregation with disease in multiple affected family members.' No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense variation.' ATM has many reported benign and pathogenic missenses. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines for PP3: 'Supporting when REVEL >0.7333 or RNA predictor shows impact.' The variant has mixed in silico results and SpliceAI score 0.01 indicates no splicing impact; REVEL is unknown/not >0.7333. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' No phenotype data are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic.' ClinVar reports this variant as VUS. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency >5% in controls.' The variant is absent from gnomAD. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP disease‐specific guidelines for BS1: 'Filtering allele frequency >0.05%.' The variant is absent from gnomAD. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy adult controls for a recessive disease.' No healthy individual data are available. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines for BS3: 'Moderate when a variant rescues both an ATM‐specific feature and radiosensitivity; Supporting when it rescues either.' The variant fails functional rescue. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members.' No segregation data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense in a gene where only truncating variants cause disease.' ATM disease is caused by both missense and truncating variants. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines for BP2: 'Use ATM PM3/BP2 table for in cis observations in recessive disease.' No phasing data are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In‐frame indels in repetitive regions without known function.' The variant is missense. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines for BP4: 'Supporting when REVEL ≤0.249 or RNA predictor shows impact.' Mixed computational results and SpliceAI score 0.01 do not meet the REVEL threshold. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in trans with a pathogenic variant for a fully penetrant dominant disorder.' No such data are available. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign.' No such reports exist. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted splicing impact.' The variant is missense. Therefore, BP7 is not applied.