The ATM c.4158dup (p.Lys1387Ter, p.K1387*) variant has been reported in ClinVar and is classified there as pathogenic, including by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel.1 This variant is absent from gnomAD v4.1 and gnomAD v2.1, which supports PM2_Supporting and does not meet the BA1 or BS1 population thresholds.2 This variant introduces a premature stop at Lys1387 in ATM, and the ATM HBOP VCEP framework supports full-strength PVS1 for this truncating event; the same gene-specific framework also supports PM5_Supporting because the stop is upstream of the ATM truncation cutoff at p.Arg3047Ter.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which supports BP4 and does not support PP3 under the ATM VCEP splice thresholds.4
Final classification
Pathogenic
PM5PM2PVS1PP5BP4
ATM
c.4158dup
p.Lys1387Ter
This variant
The ATM c.4158dup (p.Lys1387Ter, p.K1387*) variant has been reported in ClinVar and is classified there as pathogenic, including by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PM5 supporting, PM2 supporting, PVS1 very strong, BP4 supporting, PP5 supporting; maps to Pathogenic.
Classification rationale
PM5PM2PVS1PP5
BP4
Pathogenic
ATM c.4158dup
PM5 + PM2 + PVS1 + PP5 + BP4
→
Pathogenic
3
cspec ↗vcep_atm_pvs1_1_5pvs1_gene_contextpvs1_variant_assessmentpm5_candidates
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000051.3 · variants mapped to exon structure
ATM
NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 9 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
This variant creates a premature termination at Lys1387 in the ATM reference transcript NM_000051.3, a transcript for which the ATM HBOP VCEP considers all exons constitutive. The stop occurs in exon 28 with 13 downstream exons remaining, and SpliceAI does not suggest an alternative splice-mediated rescue mechanism (max delta score 0.02), so full-strength PVS1 is supported under the ATM VCEP PVS1 framework.
Protein consequence p.(Lys1387Ter)ATM loss of function is an established disease mechanism in this VCEP frameworkVariant lies in exon 28 with multiple downstream exons
PM2
supporting
Pathogenic
This variant is absent from gnomAD v4.1 and gnomAD v2.1, which is below the ATM PM2_Supporting threshold of 0.001% in gnomAD v4.
Absent from gnomAD v4.1Absent from gnomAD v2.1ATM PM2_Supporting threshold ≤0.001%
PM5
supporting
Pathogenic
This truncating variant introduces a premature stop at Lys1387, which is upstream of the ATM HBOP VCEP truncation cutoff at p.Arg3047Ter, so the ATM gene-specific PM5_Supporting rule is met.
Protein consequence p.(Lys1387Ter)ATM PM5 uses truncation-cutoff logic rather than classic same-residue missense logicLys1387Ter is upstream of Arg3047Ter
BP4
supporting
Benign
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the ATM BP4 splice threshold of 0.1. This supports the expected truncating interpretation rather than an alternative splice-mediated effect.
SpliceAI max delta 0.02ATM BP4 splice threshold ≤0.1
Assessed · not applied
· 3 not met · 6 not assessed
Pathogenic
PS3
No reviewed variant-specific assay showed failure to rescue ATM-specific function or radiosensitivity for this variant under the ATM VCEP functional framework, so PS3 was not assigned.
PS4
The available evidence confirms ClinVar reporting, but no reviewed case-control dataset provided a p-value of 0.05 or less together with an odds ratio, hazard ratio, or relative risk meeting the ATM PS4 threshold, so PS4 was not assigned.
PM3
No reviewed patient-level evidence established this variant in trans with another pathogenic or likely pathogenic ATM variant with sufficient phenotype and phase detail to assign PM3 under the ATM point-based framework.
PP1
No reviewed segregation data documented this variant tracking with disease in affected relatives in a way that meets the ATM AR-specific PP1 framework, so PP1 was not assigned.
PP3
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the ATM PP3 splice threshold of 0.2.
Benign
BA1
This variant is absent from gnomAD v4.1, which is below the ATM BA1 threshold of greater than 0.5% group maximum filtering allele frequency.
BS1
This variant is absent from gnomAD v4.1, which is below the ATM BS1 threshold of greater than 0.05% group maximum filtering allele frequency.
BS3
No reviewed variant-specific assay showed rescue of ATM-specific function or radiosensitivity for this variant, so BS3 was not assigned.
BP2
No reviewed evidence showed this variant in cis or in an unaffected adult in trans or homozygous with another pathogenic or likely pathogenic ATM variant, so BP2 cannot be assigned from the available data.
N/A · 14
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP4 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 3148196)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
30348496 ↗
Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
ONCOKB
30553448 ↗
Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.
ONCOKB
34242744 ↗
Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR