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LYFE SCIENCES
Project: HERA
NM_000051.4:c.6200C>A
p.Ala2067Asp  ·  ATM
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Classification rationale
1

The ATM c.6200C>A (p.Ala2067Asp; p.A2067D) variant has been reported in ClinVar with multiple pathogenic and likely pathogenic germline submissions, and variant-specific cancer curation has linked it to literature consistent with loss of ATM function.

clinvar ↗ oncokb ↗ PMID:25077176 ↗
2

This variant is very rare in population databases, with gnomAD v4.1 showing an allele frequency of 3.10452e-06 (5/1610556 alleles), no homozygotes, and grpmax filtering allele frequency 8e-07, which supports rarity for ATM.

gnomad_v4 ↗ cspec ↗
3

In a published functional study, patient-derived and engineered cells showed markedly reduced ATM protein, absent ATM Ser1981 autophosphorylation, and trace-to-absent phosphorylation of downstream ATM targets, supporting a damaging effect on ATM function.

PMID:25077176 ↗ cspec ↗
4

Computational evidence does not meet the ATM PP3 or BP4 missense thresholds: REVEL is 0.435, BayesDel is 0.0616905, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 3.97905e-06; MAF= 0.00040%, 1/251316 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79647e-06; MAF= 0.00088%, 1/113682 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.10452e-06; MAF= 0.00031%, 5/1610556 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6057e-05; MAF= 0.00161%, 1/62278 alleles, homozygotes = 0); grpmax FAF= 8e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (11 clinical laboratories) and as Likely pathogenic (5 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 39749)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.435. BayesDel score = 0.0616905.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53741904, n = 2 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA2067
Hotspots ↗