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 (3 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) | 0.01 | -8 bp |
| Donor Loss (DL) | 0.0 | 85 bp |
| Acceptor Gain (AG) | 0.02 | 383 bp |
| Donor Gain (DG) | 0.0 | 449 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines for PVS1: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows that c.8996A>T is a missense change and does not introduce a stop codon or affect canonical splice sites. Therefore, this criterion is not applied because it does not meet the definition of a null variant.
PS1 (Not Applied)
According to VCEP guidelines for PS1: "Strong Strength: 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 shows no other variant resulting in the same amino acid change (D2999V) has been reported as pathogenic. Therefore, PS1 is not applied because the requirement of the same amino acid change as a known pathogenic variant is not met.
PS2 (Not Applied)
According to standard ACMG guidelines for PS2: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence shows no de novo data are available for this variant. Therefore, PS2 is not applied because de novo occurrence has not been demonstrated.
PS3 (Not Applied)
According to VCEP guidelines for PS3: "Moderate Strength: Moderate Use when a variant fails to rescue both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.". The evidence shows no functional studies of the D2999V variant. Therefore, PS3 is not applied because there is no functional data demonstrating an impact.
PS4 (Not Applied)
According to VCEP guidelines for PS4: "Strong Strength: Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).". The evidence shows no case-control or proband data. Therefore, PS4 is not applied due to lack of statistical or case-level evidence.
PM1 (Not Applied)
According to standard ACMG guidelines for PM1: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.". The evidence shows D2999V lies outside the ATM kinase domain or any known mutational hotspot. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines for PM2: "Supporting Strength: Supporting Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply.". The evidence shows c.8996A>T is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength because the variant is extremely rare or absent in population databases.
PM3 (Not Applied)
According to VCEP guidelines for PM3: "Supporting Strength: Supporting Use ATM PM3/BP2 table.". The evidence shows no data demonstrating occurrence in trans with a pathogenic variant in recessive inheritance. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to VCEP guidelines for PM4: "Moderate Strength: Use for stop-loss variants.". The evidence shows this is a missense change, not a stop-loss or in-frame indel. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines for PM5: "Supporting Strength: Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047...". The evidence shows D2999V is a missense change and there is no known pathogenic missense at the same residue. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines for PM6: "Assumed de novo, without confirmation of paternity and maternity.". The evidence shows no de novo data. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines for PP1: "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.". The evidence shows no family segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines for PP2: "Missense variant in a gene with a low rate of benign missense variation and where missense is a common mechanism of disease.". The evidence shows ATM disease mechanism is loss of function and missense variants are not the predominant mechanism. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines for PP3: "Supporting Strength: Protein: REVEL >.7333; RNA: At least one well-established in silico predictor shows impact on splicing.". The evidence shows REVEL score 0.18 (<.7333) and SpliceAI score 0.02 indicating no splicing impact. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines for PP4: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.". No phenotype or clinical presentation data are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines for PP5: "Reputable source reports variant as pathogenic.". ClinVar reports this variant as VUS. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines for BA1: "Stand Alone Strength: Filtering Allele Frequency >.5%.". The evidence shows allele frequency 0%. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines for BS1: "Strong Strength: Filtering Allele Frequency >.05%.". The evidence shows allele frequency 0%. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines for BS2: "Observed in a healthy adult individual for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age.". No healthy adult observations are reported. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines for BS3: "Moderate Strength: Use when a variant rescues both an ATM specific feature AND radiosensitivity.". No functional rescue data are available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines for BS4: "Lack of segregation in affected members of a family.". There is no segregation data. Therefore, BS4 is not applied.
BP1 (Supporting)
According to standard ACMG guidelines for BP1: "Missense variant in a gene for which primarily truncating variants cause disease.". The evidence shows ATM disease mechanism is loss of function and this is a missense change. Therefore, BP1 is applied at Supporting strength.
BP2 (Not Applied)
According to VCEP guidelines for BP2: "Supporting Strength: Use ATM PM3/BP2 table.". No evidence of this variant being observed in trans with a pathogenic variant. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines for BP3: "In-frame deletions/insertions in repetitive region without a known function.". This is a missense variant, not an in-frame indel. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines for BP4: "Supporting Strength: Protein Analysis: REVEL score ≤.249; RNA: at least one well-established in silico predictor shows impact on splicing.". The evidence shows REVEL score 0.18 (≤.249) and SpliceAI score 0.02 indicating no splicing impact. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines for BP5: "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 for BP6: "Reputable source reports variant as benign.". No reputable source classifies this as benign. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines for BP7: "Synonymous variant for which splicing prediction algorithms predict no impact on splicing.". This is a missense variant. Therefore, BP7 is not applied.