LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_000051.4:c.182T>G
ATM
· NP_000042.3:p.(Phe61Cys)
· NM_000051.4
GRCh37: chr11:108098612 T>G
·
GRCh38: chr11:108227885 T>G
Gene:
ATM
Transcript:
NM_000051.4
Final call
PM2 supporting
BS3 supporting
Variant details
Gene
ATM
Transcript
NM_000051.4
Protein
NP_000042.3:p.(Phe61Cys)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
For ATM, the governing Version 1.6 framework excludes PS2, PM6, and BS4; PP1 is potentially applicable but requires documented affected-relative segregation that is absent from the available case evidence.
2
The exact Table S1 entry is direct functional measurement (DeepATM_predicted=No) and is classified Functional with Medium-high confidence, supporting benign functional evidence rather than pathogenic functional loss.
3
The ATM VCEP-approved calibration file was searched under c.182T>G, p.Phe61Cys, and p.F61C; it contains no variant-specific entry and only calibrates three approved kinase assays and the approved Mitui radiosensitivity assay.
4
BS3 Supporting is recorded provisionally with needs_human_review=true because the direct prime-editing assay is outside the current approved assay set; PS3 is not met because the result is Functional rather than non-functional.
5
The ClinGen HBOP ATM VCEP version 1.6 governs this assessment.
6
PS4 remains not assessed because variant-specific case-control enrichment statistics are absent.
7
PP4, PP5, BP5, and BP6 are excluded or not applicable under the ATM VCEP; no expert-panel ClinVar assertion is present.
8
The variant is missense, so PP3 and BP4 use REVEL only; REVEL 0.62 meets neither the ATM VCEP PP3 threshold (>0.7333) nor the BP4 threshold (<=0.249).
9
BP7 is not applicable because the variant is not synonymous or qualifying deep-intronic.
10
Population evidence supports PM2 at supporting strength because the variant is absent from gnomAD v2.1 and v4.1.
11
BA1 and BS1 are not met because the variant is not observed at their ATM VCEP frequency thresholds.
12
BS2 is not applicable under the ATM VCEP because ATM-related cancer predisposition has incomplete penetrance.
Final determination:
Rule31 in the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.6 v1.6 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Uncertain Significance - Conflicting Evidence.
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 | N/A | Not applicable: c.182T>G is a missense variant, whereas ATM PVS1 covers null variants such as nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion variants. |
cspec
vcep_atm_pvs1_1_5
|
| PS1 | Not assessed | Not assessed: no established p.Phe61Cys comparator was identified, and SpliceAI returned no score to rule out a splice defect. |
vcep_atm_ps1_1_5
cspec
clinvar
spliceai
|
| PS2 | N/A | Not applicable: the ATM Version 1.6 specification explicitly marks PS2 as Not Applicable. |
cspec
|
| PS3 | Not met | Not met: Table S1 directly measured c.182T>G as Functional, not a failure of ATM function, but the assay is outside the VCEP-approved assay set. |
vcep_suppl_tables1_pmid_40580951
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
|
| PS4 | Not assessed | Not assessed: no case-control p-value, odds ratio, relative risk, hazard ratio, or lower 95% confidence interval is available for this variant. |
cspec
|
| PM1 | N/A | Not applicable: the ATM VCEP prohibits PM1 because benign and pathogenic variants share domains and germline hotspots are not well defined. |
cspec
|
| PM2 | Met | Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying the ATM PM2 threshold of ≤0.001%. |
cspec
gnomad_v2
gnomad_v4
|
| PM3 | Not assessed | Not assessed: no affected Ataxia-Telangiectasia proband or qualifying pathogenic allele in trans was documented, so the VCEP PM3 point total is unavailable. |
vcep_atm_pm3_bp2_1_5
|
| PM4 | N/A | Not applicable: p.(Phe61Cys) is a missense substitution, while the ATM VCEP PM4 rule is restricted to stop-loss variants. |
cspec
|
| PM5 | N/A | Not applicable: ATM PM5 is restricted to qualifying truncating or RNA-supported splice variants and explicitly excludes missense changes such as p.Phe61Cys. |
cspec
pm5_candidates
|
| PM6 | N/A | Not applicable: the ATM Version 1.6 specification explicitly marks PM6 as Not Applicable. |
cspec
|
| PP1 | Not assessed | Not assessed: no affected-relative segregation, parental testing, pedigree, or meiosis data are documented for this variant. |
cspec
|
| PP2 | N/A | Not applicable: the ATM VCEP states that ATM lacks a defined low rate of benign missense variation required for PP2. |
cspec
|
| PP3 | Not met | Not met: REVEL 0.62 is below the ATM VCEP PP3 Supporting threshold of >0.7333 for missense variants. |
cspec
revel
vcep_suppl_tables1_pmid_40580951
|
| PP4 | N/A | Not applicable: the ATM VCEP excludes PP4 because cancer phenotypes are nonspecific and ataxia-telangiectasia phenotype evidence is incorporated into PM3/BP2. |
cspec
|
| PP5 | N/A | Not applicable: the ATM VCEP excludes PP5, and no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present. |
cspec
clinvar
|
| BA1 | Not met | Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the ATM VCEP BA1 threshold of >0.5%. |
cspec
gnomad_v2
gnomad_v4
|
| BS1 | Not met | Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the ATM VCEP BS1 threshold of >0.05%. |
cspec
gnomad_v2
gnomad_v4
|
| BS2 | N/A | Not applicable: the ATM VCEP excludes BS2 because ATM-related cancer predisposition has incomplete penetrance. |
cspec
|
| BS3 | Met | Met, provisionally: direct prime-editing classified c.182T>G as Functional with Medium-high confidence, consistent with retained ATM function and BS3 Supporting. |
vcep_suppl_tables1_pmid_40580951
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
|
| BS4 | N/A | Not applicable: the ATM Version 1.6 specification explicitly marks BS4 as Not Applicable. |
cspec
|
| BP1 | N/A | Not applicable: the ATM VCEP excludes BP1 because pathogenic missense variants are known for ATM. |
cspec
|
| BP2 | Not assessed | Not assessed: no unaffected adult carrying the variant with a qualifying pathogenic ATM allele in trans was documented, so the VCEP BP2 point total is unavailable. |
vcep_atm_pm3_bp2_1_5
|
| BP3 | N/A | Not applicable: ATM VCEP marks BP3 as not applicable, and c.182T>G is a missense substitution rather than an in-frame repeat-region indel. |
cspec
|
| BP4 | Not met | Not met: REVEL 0.62 exceeds the ATM VCEP BP4 Supporting threshold of <=0.249 for missense variants. |
cspec
revel
spliceai
vcep_suppl_tables1_pmid_40580951
|
| BP5 | N/A | Not applicable: the governing ATM VCEP marks BP5 as not applicable for this variant assessment. |
cspec
|
| BP6 | N/A | Not applicable: the ATM VCEP excludes BP6, and no exact-variant ClinVar expert-panel Benign or Likely benign classification is present. |
cspec
clinvar
|
| BP7 | N/A | Not applicable: c.182T>G produces the missense change p.Phe61Cys, whereas BP7 is restricted to synonymous or qualifying deep-intronic variants. |
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.