LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-19
Case ID: NM_000051.3_c.1158del_20260519_104108
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.3:c.1158del

ATM  · NP_000042.3:p.(Lys387ArgfsTer3)  · NM_000051.3
GRCh37: chr11:108119750 AG>A  ·  GRCh38: chr11:108249023 AG>A
Gene: ATM Transcript: NM_000051.3
Final call
Pathogenic
PVS1 very strong PM2 supporting PM5 supporting PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
ATM
Transcript
NM_000051.3
Protein
NP_000042.3:p.(Lys387ArgfsTer3)
gnomAD AF
3.097713020431276e-06 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The ATM NM_000051.3:c.1158del (NP_000042.3:p.(Lys387ArgfsTer3)) variant has been reported in ClinVar as pathogenic with expert panel review, and curated cancer knowledgebase review links this exact variant to cancer-related literature.
2
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 5/1614094 alleles (AF 3.09771e-06; 0.00031%) with no homozygotes, which is below the ATM VCEP PM2_Supporting threshold of 0.001%.
3
This early frameshift introduces a premature stop after residue 389, and the ATM VCEP framework supports loss of function as an established disease mechanism for ATM; because the truncation is far upstream of the ATM-specific p.Arg3047 cutoff, the evidence supports PVS1 and the ATM-specific PM5_Supporting truncation rule.
Final determination: Rule4 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.
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 NM_000051.3:c.1158del causes an early frameshift, NP_000042.3:p.(Lys387ArgfsTer3), with a premature stop after residue 389. The ATM VCEP PVS1 framework states that loss of function is an established disease mechanism for ATM, that NM_000051.3 exons are constitutive, and that caution is mainly needed for extreme 3' variants; this truncation is far upstream of that region and is consistent with a null allele.
cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment
PS1 N/A PS1 is a same-amino-acid or matched splice-event rule. This variant is a frameshift deletion, so PS1 does not apply.
cspec vcep_atm_ps1_1_5
PS2 N/A The ATM VCEP framework does not apply PS2 for this gene-disease context.
cspec
PS3 Not assessed Published functional references were identified, but no retrieved evidence documented a variant-specific ATM rescue assay for c.1158del showing failure to rescue an ATM-specific feature under the ATM VCEP PS3 framework.
oncokb PMID:19147735 PMID:25614872 PMID:27413114 PMID:30348496 PMID:30553448 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4 Not assessed This variant has been reported in affected individuals and is classified as pathogenic in ClinVar, but no case-control study, odds ratio, or other quantitative enrichment data meeting the ATM VCEP PS4 threshold were retrieved.
clinvar PMID:10234507 PMID:15928302 PMID:19147735 PMID:23807571 PMID:25614872
PM1 N/A PM1 is not used in the ATM VCEP framework for this gene-disease context, and this variant is not supported as a hotspot-based event for criterion use.
cspec hotspots
PM2 Met This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 5/1614094 alleles (AF 3.09771e-06, 0.00031%), with highest subpopulation frequency 4.2375e-06 (0.00042%) in European non-Finnish individuals and no homozygotes. These values are below the ATM VCEP PM2_Supporting threshold of 0.001%.
gnomad_v2 gnomad_v4 cspec
PM3 Not assessed Primary literature linked to this variant suggests possible ataxia-telangiectasia case reports, but no retrieved evidence confirmed the exact number of affected probands, the presence of a second pathogenic ATM variant, or phase information required to assign ATM PM3 points.
clinvar PMID:10234507 PMID:15928302 PMID:19147735 PMID:23807571 PMID:25614872 vcep_atm_pm3_bp2_1_5
PM4 N/A Under the ATM VCEP framework, PM4 is reserved for stop-loss variants. This variant is a frameshift deletion, so PM4 does not apply.
cspec
PM5 Met The ATM VCEP repurposes PM5 for truncating variants with premature termination codons upstream of p.Arg3047. This frameshift creates NP_000042.3:p.(Lys387ArgfsTer3), which is far upstream of p.Arg3047, so PM5_Supporting is met under the gene-specific truncation rule.
cspec pm5_candidates
PM6 N/A The ATM VCEP framework does not apply PM6 for this gene-disease context.
cspec
PP1 Not assessed No segregation data were identified that documented this variant tracking with ATM-related disease in the number of affected relatives required by the ATM VCEP PP1 framework.
clinvar PMID:15928302 vcep_atm_pm3_bp2_1_5
PP2 N/A The ATM VCEP framework does not apply PP2 for this gene-disease context.
cspec
PP3 N/A ATM PP3 is specified for missense or non-canonical splicing variants using REVEL or SpliceAI thresholds. This variant is an exonic frameshift deletion, so PP3 is not applied.
cspec
PP4 N/A The ATM VCEP framework does not apply PP4 for this gene-disease context.
cspec
PP5 Met Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.
cspec clinvar
BA1 Not met The gnomAD v4.1 grpmax filtering allele frequency is 1.24e-06 (0.000124%), which is below the ATM BA1 threshold of greater than 0.5%.
gnomad_v4 cspec
BS1 Not met The highest observed gnomAD v4.1 population frequency is 4.2375e-06 (0.00042%), which is below the ATM BS1 threshold of greater than 0.05%.
gnomad_v4 cspec
BS2 N/A The ATM VCEP framework does not apply BS2 for this gene-disease context.
cspec
BS3 Not assessed No variant-specific functional study was retrieved showing that c.1158del rescues ATM-specific function or radiosensitivity, so BS3 cannot be applied from the available evidence.
oncokb PMID:19147735 PMID:25614872 PMID:27413114 PMID:30348496 PMID:30553448 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4 N/A The ATM VCEP framework does not apply BS4 for this gene-disease context.
cspec
BP1 N/A The ATM VCEP framework does not apply BP1 for this gene-disease context.
cspec
BP2 Not assessed No retrieved evidence showed this variant in trans with a pathogenic ATM variant in an unaffected individual or other observation meeting the ATM BP2 point framework.
clinvar PMID:10234507 PMID:15928302 vcep_atm_pm3_bp2_1_5
BP3 N/A The ATM VCEP framework does not apply BP3 for this gene-disease context.
cspec
BP4 N/A ATM BP4 is specified for missense or non-canonical splicing variants using REVEL or SpliceAI thresholds. This variant is an exonic frameshift deletion, so BP4 is not applied.
cspec
BP5 N/A The ATM VCEP framework does not apply BP5 for this gene-disease context.
cspec
BP6 N/A BP6 is not used in current ACMG/AMP-based ATM variant interpretation.
cspec
BP7 N/A ATM BP7 is specified for synonymous or deep intronic variants without splice impact. This variant is a coding frameshift deletion, 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.