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
Open"This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.19 | -151 bp |
| Donor Loss (DL) | 0.17 | 18 bp |
| Acceptor Gain (AG) | 0.06 | 79 bp |
| Donor Gain (DG) | 0.0 | -85 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: 'Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength'. The evidence for this variant shows: c.1219_1221dupTTT is an in‐frame duplication, not predicted to cause loss of function. Therefore, this criterion is not applied because the variant does not meet the threshold for a null effect.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Use for protein changes as long as splicing is ruled-out for both alterations'. The evidence for this variant shows: F407dup is not the same amino acid change as any previously established pathogenic variant. Therefore, this criterion 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'. The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: 'Use when a variant fails to rescue both an ATM specific feature AND radiosensitivity for Strong, or only an ATM feature for Supporting'. The evidence for this variant shows: no functional studies exist for F407dup. Therefore, this criterion is not applied due to missing functional rescue data.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'Case-control studies; p≤0.05 AND OR≥2 or lower 95% CI≥1.5'. The evidence for this variant shows: no case–control data are available. Therefore, this criterion 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 and well-established functional domain'. The evidence for this variant shows: F407dup lies outside known ATM functional domains/hot spots. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: Frequency ≤.001% if n=1 in a single subpopulation'. The evidence for this variant shows: absent from gnomAD and other population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent in controls.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: 'Use ATM PM3/BP2 table for recessive inheritance'. The evidence for this variant shows: no data on trans configuration with a pathogenic variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: 'Use for stop-loss variants at Moderate strength'. The evidence for this variant shows: F407dup is an in‐frame duplication, not a stop-loss. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Supporting for frameshift/truncating variants upstream of p.R3047 or splice variants with PTC upstream'. The evidence for this variant shows: F407dup is neither a truncating nor a splice variant with PTC. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo data available. Therefore, this criterion 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'. The evidence for this variant shows: no segregation data reported. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation'. The evidence for this variant shows: ATM has both missense and truncating pathogenic variants and is not constrained for missense variation. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Supporting if REVEL>0.7333 or splicing predictor shows impact'. The evidence for this variant shows: SpliceAI score=0.19 (no impact), REVEL unavailable. Therefore, this criterion 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'. The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic'. The evidence for this variant shows: ClinVar reports uncertain significance. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Filtering Allele Frequency >0.5%'. The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Filtering Allele Frequency >0.05%'. The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult with full penetrance'. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Moderate if variant rescues both ATM features and radiosensitivity, Supporting if either'. The evidence for this variant shows: no functional rescue data. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense in gene for which only truncating variants cause disease'. The evidence for this variant shows: ATM missense variants can be pathogenic. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: 'Use ATM PM3/BP2 table for variants in cis with a pathogenic variant'. The evidence for this variant shows: no phase data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In‐frame indels in a repetitive region without a known function'. The evidence for this variant shows: region is not repetitive. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows: SpliceAI predicts no impact on splicing; no in silico evidence of deleterious effect. Therefore, this criterion is applied at Supporting strength because computational tools do not predict a functional impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no such case reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign'. The evidence for this variant shows: ClinVar reports uncertain. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted splice impact'. The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.