ATM c.1219_1221dup, p.Phe407dup
NM_000051.4:c.1219_1221dup
Variant of Uncertain Significance (VUS)
The variant NM_000051.4:c.1219_1221dupTTT (F407dup) in ATM is classified as VUS. Only PM2_supporting (absent from controls) and BP4_supporting (benign computational predictions) apply, which is insufficient to reach a benign or pathogenic classification.
ACMG/AMP Criteria Applied
PM2
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.1219_1221dup
Protein Change
F407dup
Location
Exon 9
(Exon 9 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.1219_1221dup
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 8 submitter reviews in ClinVar
Submitter Breakdown
8 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 (8 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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.1219_1221dupTTT is an in‐frame duplication, not predicted to cause loss of function. Therefore, this criterion is not applied because the variant does not meet the threshold for a null effect.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Use for protein changes as long as splicing is ruled-out for both alterations'. The evidence for this variant shows: F407dup is not the same amino acid change as any previously established pathogenic variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
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 due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Use when a variant fails to rescue both an ATM specific feature AND radiosensitivity for Strong, or only an ATM feature for Supporting'. The evidence for this variant shows: no functional studies exist for F407dup. Therefore, this criterion is not applied due to missing functional rescue data.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Case-control studies; p≤0.05 AND OR≥2 or lower 95% CI≥1.5'. The evidence for this variant shows: no case–control data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or critical and well-established functional domain'. The evidence for this variant shows: F407dup lies outside known ATM functional domains/hot spots. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: Frequency ≤.001% if n=1 in a single subpopulation'. The evidence for this variant shows: absent from gnomAD and other population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent in controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'Use ATM PM3/BP2 table for recessive inheritance'. The evidence for this variant shows: no data on trans configuration with a pathogenic variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Use for stop-loss variants at Moderate strength'. The evidence for this variant shows: F407dup is an in‐frame duplication, not a stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Supporting for frameshift/truncating variants upstream of p.R3047 or splice variants with PTC upstream'. The evidence for this variant shows: F407dup is neither a truncating nor a splice variant with PTC. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co‐segregation with disease in multiple affected family members'. The evidence for this variant shows: no segregation data reported. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation'. The evidence for this variant shows: ATM has both missense and truncating pathogenic variants and is not constrained for missense variation. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting if REVEL>0.7333 or splicing predictor shows impact'. The evidence for this variant shows: SpliceAI score=0.19 (no impact), REVEL unavailable. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic'. The evidence for this variant shows: ClinVar reports uncertain significance. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Filtering Allele Frequency >0.5%'. The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Filtering Allele Frequency >0.05%'. The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult with full penetrance'. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Moderate if variant rescues both ATM features and radiosensitivity, Supporting if either'. The evidence for this variant shows: no functional rescue data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense in gene for which only truncating variants cause disease'. The evidence for this variant shows: ATM missense variants can be pathogenic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Use ATM PM3/BP2 table for variants in cis with a pathogenic variant'. The evidence for this variant shows: no phase data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In‐frame indels in a repetitive region without a known function'. The evidence for this variant shows: region is not repetitive. Therefore, this criterion is not applied.
BP4
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: SpliceAI predicts no impact on splicing; no in silico evidence of deleterious effect. Therefore, this criterion is applied at Supporting strength because computational tools do not predict a functional impact.
BP5
BP5 (Not Applied) Strength Modified
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 such case reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign'. The evidence for this variant shows: ClinVar reports uncertain. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted splice impact'. The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.