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.1 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%.2 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.3
Final classification
Pathogenic
PVS1PM2PM5PP5
ATM
c.1158del
p.Lys387ArgfsTer3
This variant
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.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PM5 supporting, PP5 supporting; maps to Pathogenic.
Classification rationale
PVS1PM2PM5PP5
Pathogenic
ATM c.1158del
PVS1 + PM2 + PM5 + PP5
→
Pathogenic
3
cspec ↗vcep_atm_pvs1_1_5pvs1_gene_contextpvs1_variant_assessmentpm5_candidates
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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 · 4 applied · 8 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
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.
Early frameshift with stop at codon 389ATM VCEP PVS1 decision treeATM loss-of-function disease mechanism established
PM2
supporting
Pathogenic
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 absencegnomAD v4 total AF 3.09771e-06ATM PM2 threshold <=0.001%
PM5
supporting
Pathogenic
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.
ATM gene-specific PM5 truncation cutoffPremature stop at residue 389
Assessed · not applied
· 2 not met · 6 not assessed
Pathogenic
PS3
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.
PS4
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.
PM3
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.
PP1
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.
Benign
BA1
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%.
BS1
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%.
BS3
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.
BP2
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.
N/A · 16
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · BS2 · BS4 · BP1 · BP3 · BP4 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.09771e-06; MAF= 0.00031%, 5/1614094 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.2375e-06; MAF= 0.00042%, 5/1179942 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,614,094
0 hom · FAF 0.00012%
0 hom · FAF 0.00012%
European (non-Finnish) 5 / 1,179,942 |
0.00042% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
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 (8 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 141887)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11).
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
10234507 ↗
Rapid and efficient ATM mutation detection by fluorescent chemical cleavage of mismatch: identification of four novel mutations.
CLINVAR
19147735 ↗
Rapid flow cytometry-based structural maintenance of chromosomes 1 (SMC1) phosphorylation assay for identification of ataxia-telangiectasia homozygotes and heterozygotes.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR