LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_000051.4:c.1440A>C
ATM
· NP_000042.3:p.(Leu480Phe)
· NM_000051.4
GRCh37: chr11:108121632 A>C
·
GRCh38: chr11:108250905 A>C
Gene:
ATM
Transcript:
NM_000051.4
Final call
VUS
Variant details
Gene
ATM
Transcript
NM_000051.4
Protein
NP_000042.3:p.(Leu480Phe)
gnomAD AF
5.8857057890563046e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: no pathogenic or benign criterion is met under the ATM VCEP v1.5 framework, so no criteria-combination rule is satisfied.
Final determination:
No ATM VCEP v1.5 criteria-combination rule is satisfied because no pathogenic or benign criterion was adjudicated as met; the variant therefore remains a VUS.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
| Criterion | Status | Rationale | Evidence used |
|---|---|---|---|
| PVS1 | Not met | Not met: p.Leu480Phe is a missense substitution, not a loss-of-function null variant, and SpliceAI predicts no splice impact (max delta 0.053). |
cspec
vcep_atm_pvs1_1_5
spliceai
PMID:19638463
|
| PS1 | Not met | Not met: L480F reported in one prostate brachytherapy patient (PMID 19638463) is not established pathogenic, so no qualifying same-amino-acid P/LP comparator exists. |
vcep_atm_ps1_1_5
PMID:19638463
spliceai
|
| PS2 | N/A | Not applicable: the ClinGen HBOP ATM VCEP v1.5 specification excludes PS2. |
cspec
|
| PS3 | Not assessed | Not assessed: no variant-specific functional assay result for p.Leu480Phe was available; the sole report is a patient observation, not an engineered assay. |
cspec
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
vcep_suppl_tables1_pmid_40580951
PMID:19638463
|
| PS4 | Not assessed | Not assessed: no qualifying case-control enrichment was available; p.Leu480Phe appeared in 1/21 high- versus 0/20 low-radiotoxicity patients without a significant association. |
cspec
PMID:19638463
|
| PM1 | N/A | Not applicable: the ClinGen HBOP ATM VCEP v1.5 framework excludes PM1. |
cspec
|
| PM2 | Not met | Not met: gnomAD v4.1 frequency 0.00589% (grpmax FAF 0.006641%) exceeds the VCEP's <=0.001% PM2 threshold. |
cspec
gnomad_v4
|
| PM3 | Not assessed | Not assessed: no ataxia-telangiectasia affected-proband observation, in-trans pathogenic variant, or phase information for p.Leu480Phe was available. |
cspec
vcep_atm_pm3_bp2_1_5
PMID:19638463
|
| PM4 | Not met | Not met: p.Leu480Phe is a single amino-acid substitution with no protein-length change, and PM4 is restricted to stop-loss variants. |
cspec
PMID:19638463
|
| PM5 | N/A | Not applicable: the ATM VCEP PM5 rule covers only truncating or qualifying splice variants, not the missense p.Leu480Phe. |
cspec
pm5_candidates
|
| PM6 | N/A | Not applicable: the ClinGen HBOP ATM VCEP v1.5 specification excludes PM6. |
cspec
|
| PP1 | Not assessed | Not assessed: no family segregation or phase data for p.Leu480Phe was available; the single report documents no segregation with an ATM phenotype. |
cspec
PMID:19638463
|
| PP2 | N/A | Not applicable: the ClinGen HBOP ATM VCEP v1.5 framework excludes PP2. |
cspec
|
| PP3 | Not met | Not met: REVEL 0.312 and SpliceAI max delta 0.053 are below the PP3 thresholds of >0.7333 and >=0.2. |
cspec
revel
spliceai
PMID:19638463
|
| PP4 | N/A | Not applicable: the ClinGen HBOP ATM VCEP v1.5 specification excludes PP4. |
cspec
|
| PP5 | N/A | Not applicable: the ATM VCEP v1.5 specification excludes PP5. |
cspec
clinvar
|
| BA1 | Not met | Not met: gnomAD v4.1 grpmax FAF 0.006641% is far below the >0.5% BA1 threshold. |
cspec
gnomad_v4
|
| BS1 | Not met | Not met: gnomAD v4.1 grpmax FAF 0.006641% is below the >0.05% BS1 threshold. |
cspec
gnomad_v4
|
| BS2 | N/A | Not applicable: the ClinGen HBOP ATM VCEP v1.5 specification excludes BS2. |
cspec
|
| BS3 | Not assessed | Not assessed: no variant-specific rescue or ATM phosphorylation result for p.Leu480Phe was available; computational predictions do not substitute for functional data. |
cspec
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
vcep_suppl_tables1_pmid_40580951
PMID:19638463
|
| BS4 | N/A | Not applicable: the ClinGen HBOP ATM VCEP v1.5 specification excludes BS4. |
cspec
|
| BP1 | N/A | Not applicable: the ClinGen HBOP ATM VCEP v1.5 framework excludes BP1. |
cspec
|
| BP2 | Not assessed | Not assessed: no qualifying unaffected carrier with a pathogenic ATM variant in trans, and no phase or homozygosity data, was available. |
cspec
vcep_atm_pm3_bp2_1_5
PMID:19638463
|
| BP3 | N/A | Not applicable: the ATM VCEP v1.5 specification excludes BP3. |
cspec
|
| BP4 | Not met | Not met: REVEL 0.312 exceeds the <=0.249 BP4 threshold, so the clean SpliceAI result (0.053) cannot support BP4 for this missense. |
cspec
revel
spliceai
|
| BP5 | N/A | Not applicable: the ATM VCEP v1.5 specification excludes BP5. |
cspec
|
| BP6 | N/A | Not applicable: the ATM VCEP v1.5 specification excludes BP6. |
cspec
clinvar
|
| BP7 | N/A | Not applicable: p.Leu480Phe is a missense substitution, not synonymous or deep intronic, so BP7 does not apply. |
cspec
|
Disclaimer:
The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.