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 Likely benign (3 clinical laboratories) and as Uncertain significance (1 clinical laboratories) and as 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 | 66 bp |
| Donor Loss (DL) | 0.0 | -31 bp |
| Acceptor Gain (AG) | 0.01 | -99 bp |
| Donor Gain (DG) | 0.01 | 16 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.8518T>C is a synonymous change (p.Lys2840=) with no predicted splice impact. Therefore, this criterion is not applied because the variant does not create a null allele.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: 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: no change in amino acid sequence. Therefore, this criterion is not applied because there is no amino acid change.
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 information on de novo occurrence. Therefore, this criterion is not applied due to lack of de novo data.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Moderate Strength: Use when a variant fails to rescue both an ATM-specific feature AND radiosensitivity. Supporting Strength: Use when a variant fails to rescue an ATM-specific feature only." The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied because functional data are lacking.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 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 or case-series data. 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 functional domain without benign variation." The evidence for this variant shows: synonymous change outside known critical domains. 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, that is sufficiently rare and PM2_supporting would apply." The evidence for this variant shows: absent from gnomAD (MAF=0%, n=0). Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Use ATM PM3/BP2 table for recessive cases." The evidence for this variant shows: no reported trans or cis observations in recessive inheritance. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes (in-frame deletions/insertions) not predicted to cause LOF." The evidence for this variant shows: synonymous change with no length alteration. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Supporting Strength: Use for genomic frameshift and truncating variants with PTC upstream of p.R3047; apply to splice variants as PM5_supporting under specific conditions." The evidence for this variant shows: no truncating or frameshift effect. 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 assumed de novo data. 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 in a gene definitively known to cause the disease." The evidence for this variant shows: no segregation data. 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 where missense is a common mechanism of disease." The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Protein: REVEL >.7333; RNA: At least one well-established in silico predictor shows impact on splicing." The evidence for this variant shows: SpliceAI score=0.01 (no splice impact) and no REVEL data indicating 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 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 without available evidence." The evidence for this variant shows: ClinVar reports conflicting benign/VUS. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Filtering Allele Frequency >.5%." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Filtering Allele Frequency >.05%." The evidence for this variant shows: absent from population databases. 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 dominant disorder." The evidence for this variant shows: no healthy adult observations documented. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Moderate Strength: Use when a variant rescues both an ATM-specific feature AND radiosensitivity. Supporting Strength: Use when a variant rescues either feature." The evidence for this variant shows: no functional assays demonstrating rescue. 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 where only truncating variants cause disease." The evidence for this variant shows: synonymous change. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Use ATM PM3/BP2 table." The evidence for this variant shows: no observed cis/trans configuration. 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 without known function." The evidence for this variant shows: not an in-frame indel. 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: CADD score=0.55, SpliceAI score=0.01, and other in silico predictors supporting no effect. Therefore, this criterion 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." The evidence for this variant shows: no alternate molecular basis 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 without available evidence." The evidence for this variant shows: ClinVar reports conflicting classifications. Therefore, this criterion is not applied.
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Use for synonymous and deep intronic variants defined as further than +7/-40 from splice sites with curator discretion." The evidence for this variant shows: synonymous change at c.8518 with SpliceAI score=0.01 indicating no splice impact. Therefore, this criterion is applied at Supporting strength.