LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_000051.3:c.8056T>C
ATM
· NP_000042.3:p.(Phe2686Leu)
· NM_000051.3
GRCh37: chr11:108205741 T>C
·
GRCh38: chr11:108335014 T>C
Gene:
ATM
Transcript:
NM_000051.3
Final call
VUS
PM2 supporting
PP3 supporting
Variant details
Gene
ATM
Transcript
NM_000051.3
Protein
NP_000042.3:p.(Phe2686Leu)
gnomAD AF
6.195978809752471e-07 (v4.1)
ClinVar
Uncertain Significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2_supporting is met: the variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-07, 1/1,613,950 alleles), well below the VCEP ATM PM2_supporting threshold of ≤0.001%.
2
PP3 is met: REVEL score of 0.913 exceeds the VCEP ATM PP3 threshold of >0.7333 for missense variants. AlphaMissense is 0.98 and SpliceAI predicts no splicing impact (max delta=0.00).
3
No other pathogenic or benign criteria are met. PVS1, PS1, PS3, PS4, PM5, and PP1 are not applicable or not met. BA1, BS1, BS3, BP2, and BP4 are not met. Remaining criteria (PS2, PM1, PM6, PP2, PP4, PP5, BS2, BS4, BP1, BP5, BP6, BP7) are not applicable per VCEP ATM v1.5.0 specifications.
4
With PM2_supporting and PP3 as the only criteria met (two pathogenic supporting), there is insufficient evidence to classify this variant beyond Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules. No benign criteria are met to trigger conflicting-evidence rules.
Final determination:
No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.5.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.
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 |
|---|---|---|---|
| BP3 | N/A | VCEP HBOP ATM v1.5.0 deems BP3 not applicable. |
|
| PM3 | N/A | Skipped per case instructions; PM3 was excluded from assessment. |
|
| PM4 | N/A | Missense variant; VCEP ATM PM4 applies only to stop-loss variants. |
|
| PVS1 | N/A | Missense variant (p.Phe2686Leu); PVS1 under VCEP ATM v1.5.0 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon deletion). |
|
| PS1 | Not met | No known pathogenic or likely pathogenic missense variant at the same residue (p.Phe2686) with a different amino acid change was identified in ClinVar or VCEP reference datasets. PS1 requires a comparator variant at the same residue with established pathogenicity. |
clinvar
|
| PS2 | N/A | VCEP HBOP ATM v1.5.0 deems PS2 not applicable. |
cspec
|
| PS3 | Not met | No variant-specific experimental functional assay data (kinase activity or radiosensitivity rescue) are available for p.Phe2686Leu. The VCEP-approved Suppl_TableS1 (PMID 40580951) provides computational combined functional scores only; the 'Non-functional' classification derives from in silico predictions (boostDM, EVE, REVEL, AlphaMissense), not from experimental functional assays. VCEP PS3 requires laboratory-based functional evidence demonstrating failure to rescue ATM kinase activity and/or radiosensitivity. |
vcep_suppl_tables1_pmid_40580951
|
| PS4 | Not met | No case-control study demonstrating statistically significant enrichment of this variant in affected individuals. VCEP ATM PS4 requires a case-control study with p-value ≤0.05 AND (OR/RR/HR ≥2 OR lower 95% CI ≥1.5). One proband (AT1083, PMID 31429931) carried this variant in compound heterozygous state with a pathogenic splice variant, but a single case observation does not meet the case-control threshold. |
PMID:31429931
|
| PS5 | N/A | PS5 is not specified in the VCEP HBOP ATM v1.5.0 framework. Under generic ACMG/AMP, no authoritative source has recently and definitively classified this variant as pathogenic with evidence unavailable for independent review. |
cspec
|
| PM1 | N/A | VCEP HBOP ATM v1.5.0 deems PM1 not applicable for ATM. |
cspec
|
| PM2 | Met | This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-07, 1/1,613,950 alleles; highest subpopulation NFE AF=8.48e-07, 1/1,179,832 alleles). This is well below the VCEP ATM PM2_supporting threshold of ≤0.001% (n=1 in a single subpopulation). |
gnomad_v2
gnomad_v4
gnomad_canada
|
| PM5 | N/A | Missense variant. VCEP ATM PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with observed splicing impact where PVS1_VS(RNA) is applied. |
cspec
|
| PM6 | N/A | VCEP HBOP ATM v1.5.0 deems PM6 not applicable. |
cspec
|
| PP1 | Not met | No segregation data available for this variant. VCEP ATM PP1 requires observation in affected relatives for the autosomal recessive condition (1 relative for Supporting, 2 for Moderate, ≥3 for Strong). |
|
| PP2 | N/A | VCEP HBOP ATM v1.5.0 deems PP2 not applicable for ATM. |
cspec
|
| PP3 | Met | REVEL score of 0.913 exceeds the VCEP ATM PP3 threshold of >0.7333 for missense variants. SpliceAI predicts no splicing impact (max delta=0.00), consistent with a purely missense effect. BayesDel score is 0.331. |
revel
spliceai
bayesdel
|
| PP4 | N/A | VCEP HBOP ATM v1.5.0 deems PP4 not applicable for ATM. |
cspec
|
| PP5 | N/A | VCEP HBOP ATM v1.5.0 deems PP5 not applicable for ATM. |
cspec
|
| BA1 | Not met | gnomAD v4.1 overall allele frequency is 6.20e-07 (0.000062%), well below the VCEP ATM BA1 threshold of >0.5% (Grpmax Filtering AF). The variant is absent from gnomAD v2.1 and gnomAD-Canada. |
gnomad_v4
|
| BS1 | Not met | gnomAD v4.1 overall allele frequency is 6.20e-07 (0.000062%), well below the VCEP ATM BS1 threshold of >0.05% (Grpmax Filtering AF). The variant is absent from gnomAD v2.1 and gnomAD-Canada. |
gnomad_v4
|
| BS2 | N/A | VCEP HBOP ATM v1.5.0 deems BS2 not applicable for ATM. |
cspec
|
| BS3 | Not met | No experimental functional data demonstrating rescue of ATM kinase activity or radiosensitivity for p.Phe2686Leu. VCEP BS3 requires variant-specific functional rescue data (both ATM-specific feature AND radiosensitivity for moderate; either for supporting). No such data available. |
|
| BS4 | N/A | VCEP HBOP ATM v1.5.0 deems BS4 not applicable for ATM. |
cspec
|
| BP1 | N/A | VCEP HBOP ATM v1.5.0 deems BP1 not applicable for ATM. |
cspec
|
| BP2 | Not met | No observation of this variant in trans with a pathogenic variant in an unaffected (non-A-T) individual. VCEP ATM BP2 requires co-occurrence data in unaffected individuals with point assignments per the PM3/BP2 table. |
|
| BP4 | Not met | REVEL score of 0.913 far exceeds the VCEP ATM BP4 threshold of ≤0.249 for missense variants. Multiple in silico tools predict a deleterious effect (REVEL 0.913, AlphaMissense 0.98, BayesDel 0.331). Computational evidence does not support a benign interpretation. |
revel
bayesdel
|
| BP5 | N/A | VCEP HBOP ATM v1.5.0 deems BP5 not applicable for ATM. |
cspec
|
| BP6 | N/A | VCEP HBOP ATM v1.5.0 deems BP6 not applicable for ATM. |
cspec
|
| BP7 | N/A | Missense variant (p.Phe2686Leu). VCEP ATM BP7 applies only to synonymous and deep intronic variants (further than +7 at donor or -21 at acceptor sites), or to silent/intronic variants with observed lack of aberrant RNA splicing. This is a coding missense change. |
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.