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 sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2020 of the ATM protein (p.Gly2020Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30303537). ClinVar contains an entry for this variant (Variation ID: 955939). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
"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) | 0.02 | 111 bp |
| Donor Loss (DL) | 0.0 | 36 bp |
| Acceptor Gain (AG) | 0.0 | -99 bp |
| Donor Gain (DG) | 0.0 | 61 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength'. The evidence for this variant shows: it is a missense change (G2020V) and does not introduce a stop codon or affect a canonical splice site. Therefore, this criterion is not applied because the variant does not meet null variant criteria.
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. Modification Type: General recommendation'. The evidence for this variant shows: there is no previously established pathogenic variant causing the same amino acid change G2020V. Therefore, this criterion is not applied.
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.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: 'Moderate Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. Modification Type: Gene-specific,Strength'. The evidence for this variant shows: no functional studies have characterized G2020V. Therefore, this criterion is not applied.
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). Modification Type: General recommendation'. The evidence for this variant shows: no case-control or cohort data are available. 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 and well-established functional domain without benign variation'. The evidence for this variant shows: G2020 is not known to lie in a mutational hotspot or critical domain without benign variation. 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 sub population, that is sufficiently rare and PM2_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply'. The evidence for this variant shows: it is absent from gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is extremely rare or absent in controls.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: 'Very Strong Use ATM PM3/BP2 table. Modification Type: Disease-specific,General recommendation,Gene-specific,Strength'. The evidence for this variant shows: no trans or compound heterozygosity data are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: 'Moderate Use for stop-loss variants. Modification Type: General recommendation,Gene-specific'. The evidence for this variant shows: it is a missense variant, not a stop-loss. 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. Apply also to splice variants as PM5_supporting for splice variants...'. The evidence for this variant shows: it is a missense change, not a frameshift or truncating variant. 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 assumption data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Cosegregation 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 that has a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: ATM has known pathogenic missense variants. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Supporting Protein: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing'. The evidence for this variant shows: mixed computational predictions and SpliceAI score of 0.02 indicating no splicing 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 patient phenotype or family history data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation'. The evidence for this variant shows: ClinVar reports VUS. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Filtering Allele Frequency >.5%'. 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: 'Strong Filtering Allele Frequency >.05%'. 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 dominant disorder with full penetrance expected at an early age'. The evidence for this variant shows: no observations in healthy adults. 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 (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. Supporting Strength: Use when a variant rescues EITHER an ATM specific feature OR radiosensitivity'. 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 are known to cause disease'. The evidence for this variant shows: ATM has known pathogenic missense variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: 'Strong Strength: Use ATM PM3/BP2 table. Modification Type: Disease-specific,General recommendation,Gene-specific,Strength'. The evidence for this variant shows: no cis/trans observations with other variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without a known function'. The evidence for this variant shows: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Protein Analysis: Metapredictor REVEL score ≤.249; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing'. The evidence for this variant shows: mixed protein predictions and no splicing impact (SpliceAI 0.02). Therefore, this criterion is not applied.
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, but the evidence is not available for independent evaluation'. The evidence for this variant shows: ClinVar reports VUS. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Supporting Can be considered for BP7_(RNA) with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively. Modification Type: General recommendation'. The evidence for this variant shows: it is a missense change, not synonymous or deep intronic. Therefore, this criterion is not applied.