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""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -333 bp |
| Donor Loss (DL) | 0.08 | 38 bp |
| Acceptor Gain (AG) | 0.0 | 162 bp |
| Donor Gain (DG) | 0.03 | -139 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: it is a missense change (F523L) and not a null variant. Therefore, this criterion is not applied because missense variants do not meet loss-of-function criteria in the ATM PVS1 decision tree.
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. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.' The evidence for this variant shows: there is no previously established pathogenic variant with the same amino acid change F523L. Therefore, this criterion is not applied because the same amino acid change has not been reported as pathogenic.
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 (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity for Moderate strength, or only one feature for Supporting strength.' The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied due to absence of functional data.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Strong Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).' The evidence for this variant shows: no case-control or statistical association data are available. Therefore, this criterion is not applied due to lack of association studies.
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.' The evidence for this variant shows: F523L is not known to lie within a hotspot or critical domain defined for ATM. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Frequency ≤.001% if n=1 in a single subpopulation (Supporting Strength).' The evidence for this variant shows: it is absent from gnomAD and other population databases (n=0). Therefore, this criterion is applied at Supporting strength because the variant is extremely rare.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: 'Use ATM PM3/BP2 table for recessive conditions.' The evidence for this variant shows: no data on allelic phase or occurrence in trans with a pathogenic variant. Therefore, this criterion is not applied due to lack of trans observation data.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants.' The evidence for this variant shows: F523L is a missense substitution without length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Supporting use for genomic frameshift and truncating variants with PTC upstream of p.R3047.' The evidence for this variant shows: F523L is missense, not truncating. Therefore, this criterion 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.' The evidence for this variant shows: no de novo information is 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 are available. 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 and pathogenic missense variants common.' The evidence for this variant shows: ATM has both benign and pathogenic missense variants reported. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Protein: REVEL >.7333; RNA: impact on splicing by in silico predictors.' The evidence for this variant shows: REVEL score is 0.08 (below threshold) and SpliceAI indicates no splice impact. 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 or clinical data are 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: not present in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Filtering Allele Frequency >.5% (Stand Alone).' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Filtering Allele Frequency >.05% (Strong).' The evidence for this variant shows: allele frequency is 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 individual for a fully penetrant disorder.' 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: 'Use when a variant rescues both an ATM specific feature AND radiosensitivity for Moderate, or one for Supporting.' 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 of a family.' 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 variant in a gene for which primarily truncating variants cause disease.' The evidence for this variant shows: ATM pathogenic variants include missense substitutions. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: 'Use ATM PM3/BP2 table for recessive conditions.' The evidence for this variant shows: no evidence of in trans occurrence with a pathogenic variant. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in repetitive regions.' The evidence for this variant shows: F523L is not an in-frame indel in a repetitive region. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Protein Analysis: Metapredictor REVEL score ≤.249; RNA: lack of splicing impact.' The evidence for this variant shows: REVEL score is 0.08 and SpliceAI indicates no impact. Therefore, this criterion is applied at Supporting strength because multiple computational tools predict benign effect.
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 data. 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: not present in ClinVar or other sources. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Supporting for synonymous or deep intronic variants with no predicted impact on splicing.' The evidence for this variant shows: it is a missense change, not synonymous. Therefore, this criterion is not applied.