ATM c.8996A>T, p.Asp2999Val
NM_000051.4:c.8996A>T
COSMIC ID: COSM9990691
Variant of Uncertain Significance (VUS)
This missense ATM variant c.8996A>T (p.Asp2999Val) is classified as a Variant of Uncertain Significance due to one supporting pathogenic criterion (PM2_supporting) and two supporting benign criteria (BP1_supporting and BP4_supporting), with no functional, segregation, or case-control data to resolve its clinical impact.
ACMG/AMP Criteria Applied
PM2
BP1
BP4
Genetic Information
Gene & Transcript Details
Gene
ATM
Transcript
NM_000051.4
MANE Select
Total Exons
63
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 63 exons | Forward |
Variant Details
HGVS Notation
NM_000051.4:c.8996A>T
Protein Change
D2999V
Location
Exon 63
(Exon 63 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 2999 in gene ATM
Alternate Identifiers
COSM9990691
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.8996A>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Uncertain Significance (VUS)
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 2999 in gene ATM
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.178
0.178
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 4.04metasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
PS3 (Not Applied) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
PM5 (Not Applied) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
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
PP2 (Not Applied) Strength Modified
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
PP3 (Not Applied) Strength Modified
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1: "Strong Strength: Filtering Allele Frequency >.05%.". The evidence shows allele frequency 0%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
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
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
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
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
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
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.