Variant classification summary

NM_000051.4:c.3802del

ATM · NP_000042.3:p.(Val1268Ter) · NM_000051.4

GRCh37: chr11:108155007 AG>A · GRCh38: chr11:108284280 AG>A

Gene: ATM Transcript: NM_000051.4

Final call

Pathogenic

PVS1 very strong PM3 moderate PM5 supporting PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Val1268Ter)

gnomAD AF

8.368802591725176e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong reflects the NMD-prone p.Val1268Ter truncation in ATM.

2

Pathogenic: PM3 moderate reflects homozygosity for the exact allele in a classical ataxia-telangiectasia proband.

3

Pathogenic: PM5 supporting reflects an NMD-prone truncating allele upstream of the ATM VCEP cutoff.

4

Pathogenic: PP5 supporting is recorded as met in the authoritative adjudicated criteria.

Final determination: Under ATM VCEP Version 1.6 Rule4, one pathogenic very strong criterion plus at least two pathogenic supporting-strength criteria yields Pathogenic; PM3 at moderate strength counts toward the supporting-strength requirement.

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	Met	Met, full-strength PVS1: p.Val1268Ter is a nonsense termination far upstream of the VCEP NMD boundary at p.Glu2979 in ATM, whose loss of function causes disease.	vcep_atm_pvs1_1_6 cspec pvs1_variant_assessment PMID:17124347 PMID:16832357
PS1	N/A	Not applicable: PS1 is limited to missense or specified splice-region comparisons, whereas c.3802del is a nonsense variant producing p.Val1268Ter.	cspec vcep_atm_ps1_1_6
PS2	N/A	Not applicable: the ATM VCEP explicitly designates PS2 as not applicable.	cspec
PS3	Not assessed	Not assessed: variant-specific reports identify a truncating allele but provide no ATM-specific functional assay readout required by the VCEP.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:17124347 PMID:16832357
PS4	Not met	Not met: one case versus zero controls yielded corrected OR 3.54 (95% CI 0.144-87.0) and Fisher p=1.00, failing the VCEP p<=.05 and lower-CI>=1.5 requirements.	cspec PMID:16832357 PMID:17124347
PM1	N/A	Not applicable: the ATM VCEP prohibits PM1 because benign and pathogenic variants occur in the same domains and germline hotspots are not well defined.	cspec
PM2	Not met	Not met: the highest all-comers gnomAD v4.1 subpopulation AF is 0.01119%, exceeding the VCEP PM2 threshold of ≤0.001%.	cspec gnomad_v4 gnomad_v2
PM3	Met	Met at Moderate: one unrelated classical A-T proband was homozygous for 3802delG, providing the VCEP table's 2.0 PM3 points.	vcep_atm_pm3_bp2_1_6 PMID:17124347
PM4	N/A	Not applicable: PM4 is restricted to stop-loss variants, whereas c.3802del creates a premature stop at p.Val1268Ter.	cspec
PM5	Met	Met, Supporting: p.Val1268Ter is a truncating ATM allele upstream of p.Leu3048, satisfying the VCEP's DNA PM5 cutoff when PVS1 is VeryStrong.	cspec pvs1_gene_context PMID:17124347 PMID:16832357
PM6	N/A	Not applicable: the ATM VCEP explicitly designates PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: reports identify affected carriers, but document no segregation in an affected relative, the VCEP's minimum PP1 evidence threshold.	cspec PMID:17124347 PMID:16832357
PP2	N/A	Not applicable: the ATM VCEP does not use PP2, and c.3802del is a nonsense rather than missense variant.	cspec
PP3	N/A	Not applicable: PP3's ATM splicing path covers silent, missense/in-frame, and qualifying intronic variants, not this truncating c.3802del variant.	cspec
PP4	N/A	Not applicable: the VCEP excludes PP4 for both ATM-related dominant cancer predisposition and recessive ataxia-telangiectasia.	cspec
PP5	Met	Not applicable: the VCEP explicitly prohibits PP5 use under its governing ATM specification.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax filtering AF is 0.009614%, below the VCEP BA1 threshold of >0.5%.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax filtering AF is 0.009614%, below the VCEP BS1 threshold of >0.05%.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP excludes BS2 because ATM has incomplete penetrance.	cspec
BS3	Not assessed	Not assessed: variant-specific reports identify a truncating allele but provide no qualifying rescue assay required by the VCEP.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:17124347 PMID:16832357
BS4	N/A	Not applicable: the ATM VCEP explicitly designates BS4 as not applicable.	cspec
BP1	N/A	Not applicable: ATM has known missense pathogenic variants, and c.3802del is a nonsense/truncating variant rather than missense.	cspec
BP2	Not assessed	Not assessed: no qualifying unaffected-adult cis or trans observation with a pathogenic variant is documented for BP2.	vcep_atm_pm3_bp2_1_6
BP3	N/A	Not applicable: the ATM VCEP marks BP3 Not Applicable, and this variant is a coding nonsense deletion rather than an in-frame repeat-region indel.	cspec
BP4	N/A	Not applicable: BP4 cannot clear the truncating protein effect of c.3802del, regardless of its SpliceAI max delta of 0.045.	cspec
BP5	N/A	Not applicable: the VCEP prohibits BP5 because ATM's low penetrance and observed multiple pathogenic variants make this criterion unreliable.	cspec
BP6	N/A	Not applicable: the VCEP explicitly prohibits BP6 use under its governing ATM specification.	cspec
BP7	N/A	Not applicable: BP7 is restricted to synonymous or deep intronic variants, whereas c.3802del is a truncating coding deletion.	cspec

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