Starting
Initialising…
0%
ATM
Final classification
Pathogenic
ATM c.1158del · p.Lys387ArgfsTer3
ATM

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.

Gene
ATM
Transcript
NM_000051.3
HGVS · transcript:coding
NM_000051.3:c.1158del
Consequence
N/A
GRCh38
chr11:108249023 AG>A
GRCh37
chr11:108119750 AG>A
Basis 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. ▾
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

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

PVS1 + PM2 + PM5 + PP5 → Pathogenic
1 clinvar ↗oncokb ↗
2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗
3 cspec ↗vcep_atm_pvs1_1_5pvs1_gene_contextpvs1_variant_assessmentpm5_candidates
Gene diagram · NM_000051.3 · variants mapped to exon structure
ATM NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      —
      Research & evidence
      Population frequency · supports pathogenic
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      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%
      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
      Not observed in any ancestry group.
      gnomAD v4 ↗ gnomAD v2 ↗
      ClinVar screenshot
      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)
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11).
      SpliceAI ↗
      Functional / OncoKB screenshot
      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.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      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.
      COSMIC ↗ Hotspots ↗
      Sources & reference links
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 9 PMIDs not cited in assessment
      27413114 ↗ ATM Mutations in Cancer: Therapeutic Implications. ONCOKB
      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
      15928302 ↗ Cancer risks and mortality in heterozygous ATM mutation carriers. CLINVAR
      19147735 ↗ Rapid flow cytometry-based structural maintenance of chromosomes 1 (SMC1) phosphorylation assay for identification of ataxia-telangiectasia homozygotes and heterozygotes. CLINVAR
      23807571 ↗ Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients. CLINVAR
      25614872 ↗ Ten new ATM alterations in Polish patients with ataxia-telangiectasia. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR