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 (5 clinical laboratories) and as Likely benign (1 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) | 0.0 | -359 bp |
| Donor Loss (DL) | 0.0 | -92 bp |
| Acceptor Gain (AG) | 0.0 | 201 bp |
| Donor Gain (DG) | 0.0 | -265 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 shows the variant is a missense change (NM_000051.4:c.2636T>C; I879T), not a predicted loss-of-function. Therefore, this criterion is not applied because the variant type does not meet the loss-of-function requirement.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Strong: Use for protein changes as long as splicing is ruled-out for both alterations'. The evidence shows no known pathogenic variant with the same amino acid 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). No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 (Moderate) is: 'Use when a variant fails to rescue both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity'. No functional studies are available for this variant. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 (Strong) is: 'Case-control studies; p-value ≤ .05 AND OR ≥ 2 or lower 95% CI ≥ 1.5'. No case-control or case series data exist for this variant. 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 and well-established functional domain without benign variation'. I879 is not within a known hotspot or critical domain. Therefore, PM1 is not applied.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2_supporting is: 'Frequency ≤ 0.001% if n = 1 in a single subpopulation'. The allele frequency is 0.00159% with n = 4 in gnomAD, exceeding the threshold. Therefore, PM2 is not applied.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: 'Use ATM PM3/BP2 table for evidence of variants in trans for recessive disorders'. No evidence of this variant in trans with a pathogenic ATM variant is available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 (Moderate) is: 'Use for stop-loss variants'. This variant is missense, not stop-loss. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5_supporting is: 'Use for frameshift and truncating variants with PTC upstream of p.R3047'. This is a missense variant. Therefore, PM5 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'. No such evidence is available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Cosegregation 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 a low rate of benign missense variation'. ATM has both benign and pathogenic missense variants reported. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'REVEL > 0.7333 or splicing impact'. The REVEL score for this variant is 0.06 and SpliceAI predicts no splice effect. 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 or family history 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 submissions are conflicting (VUS and Likely benign). Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 (Stand Alone) is: 'Allele frequency > 0.5%'. The allele frequency is 0.00159%, below the threshold. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 (Strong) is: 'Filtering allele frequency > 0.05%'. The allele frequency is 0.00159%, below the threshold. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a fully penetrant dominant disorder'. No such observations are reported. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 (Moderate/Supporting) is: 'Variant rescues both or either ATM-specific functional features'. No rescue data are available. 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 evidence is available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only truncating variants cause disease'. ATM has documented pathogenic missense variants. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: 'Use ATM PM3/BP2 table for in trans observations'. No such data exist. 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 a known function'. Not applicable to this missense variant. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4_supporting is: 'Protein analysis: REVEL ≤ 0.249; RNA: no splice impact'. The REVEL score is 0.06 and SpliceAI predicts no splice effect. Therefore, BP4 is applied at Supporting strength.
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'. No alternate diagnosis is reported. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign'. ClinVar submissions are conflicting; no consensus. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 (Supporting) is: 'Use for synonymous and deep intronic variants'. This is a missense variant. Therefore, BP7 is not applied.