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
OpenThis alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
"This variant has been reported in ClinVar as Uncertain significance (2 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) | 0.03 | 381 bp |
| Donor Loss (DL) | 0.0 | 447 bp |
| Acceptor Gain (AG) | 0.01 | -10 bp |
| Donor Gain (DG) | 0.0 | 83 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the PVS1 rule is: "Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows that Q3000E is a missense change and does not create a null allele. Therefore, PVS1 is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the PS1 rule is: "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. Modification Type: General recommendation". The evidence shows no previously established pathogenic variant resulting in Q3000E. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the PS2 rule 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, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the PS3 rule is: "Moderate Strength: Moderate Use when a variant fails to rescue both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. Modification Type: Gene-specific,Strength". The evidence shows that no functional studies have been performed for Q3000E. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the PS4 rule is: "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 data. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the PM1 rule is: "Located in a mutational hot spot and/or critical functional domain without benign variation". The evidence shows Q3000 is not in a known mutational hotspot or critical domain. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, the PM2 rule is: "Supporting Strength: Supporting Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply". The evidence for this variant shows it is absent from gnomAD and other population databases. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, the PM3 rule is: "Very Strong Strength: Very Strong Use ATM PM3/BP2 table. Modification Type: Disease-specific,General recommendation,Gene-specific,Strength". The evidence for this variant shows no information on allele phase or recessive inheritance in trans with a pathogenic variant. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the PM4 rule is: "Protein length changes due to in‐frame deletions/insertions in a non-repeat region". The evidence shows Q3000E does not change protein length. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the PM5 rule is: "Supporting Strength: Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047...". The evidence shows Q3000E is a missense change with no other pathogenic missense at the same residue. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the PM6 rule is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows no de novo data. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the PP1 rule is: "Co-segregation with disease in multiple affected family members". The evidence shows no segregation data. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the PP2 rule is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence shows ATM has both LOF and missense pathogenic variants and tolerance to some missense. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the PP3 rule is: "Supporting Strength: Supporting Protein: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing". The evidence shows benign or mixed computational predictions and SpliceAI score 0.03. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the PP4 rule is: "Patient’s phenotype or family history is highly specific for a gene". The evidence shows no phenotype information. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the PP5 rule is: "Reputable source recently reports variant as pathogenic without available evidence". The evidence shows ClinVar entries are VUS or Likely Benign, not Pathogenic. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the BA1 rule is: "Stand Alone Strength: Stand Alone Filtering Allele Frequency >.5%". The evidence shows allele frequency is 0%. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the BS1 rule is: "Strong Strength: Strong Filtering Allele Frequency >.05%". The evidence shows allele frequency is 0%. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the BS2 rule is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age". The evidence shows no such observations. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the BS3 rule is: "Moderate Strength: Moderate Use when a variant rescues both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity". The evidence shows no functional rescue data. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the BS4 rule is: "Lack of segregation in affected members". The evidence shows no segregation data. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the BP1 rule is: "Missense variant in a gene for which primarily truncating variants are known to cause disease". The evidence shows missense variants in ATM can be pathogenic. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the BP2 rule is: "Strong Strength: Strong Use ATM PM3/BP2 table. Modification Type: Disease-specific,General recommendation,Gene-specific,Strength". The evidence shows no evidence of this variant in trans with a pathogenic variant. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the BP3 rule is: "In-frame deletions/insertions in a repetitive region without a known function". The evidence shows Q3000E is not an in-frame indel. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines, the BP4 rule is: "Supporting Strength: Supporting Protein Analysis: Metapredictor REVEL score ≤.249 RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing NOTE: Splice analysis needs to be considered for all variant types...". The evidence shows multiple benign computational predictions and SpliceAI score 0.03. Therefore, BP4 is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines, the BP5 rule is: "Variant found in a case with an alternate molecular basis for disease". The evidence shows no alternate molecular diagnosis. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the BP6 rule is: "Reputable source reports variant as benign without available evidence". The evidence shows no such expert benign assertion. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the BP7 rule is: "Synonymous variant for which splicing prediction algorithms predict no impact". The evidence shows Q3000E is a missense change. Therefore, BP7 is not applied.