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LYFE SCIENCES
Project: HERA
NM_000051.4:c.6733G>A
p.Glu2245Lys  ·  ATM
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Classification rationale
1

The ATM NM_000051.4:c.6733G>A (p.(Glu2245Lys), p.(E2245K)) variant has been observed in somatic cancers in COSMIC (COSV99589774, n=2) and has been reported in ClinVar as a variant of uncertain significance by 2 clinical laboratories.

clinvar ↗ oncokb ↗
2

This variant is extremely rare in population databases, with gnomAD v4.1 showing 1/1613632 alleles overall (AF 6.1972e-07; 0.00006%) and a highest observed subpopulation frequency of 1/1179898 in European non-Finnish individuals (AF 8.4753e-07; 0.00008%), which is below the ATM PM2_Supporting threshold of <=0.001%; it is also absent from gnomAD v2.1 and gnomAD-Canada.

gnomad_v4 ↗ gnomad_v2 ↗ gnomad_canada ↗ cspec ↗
3

In a supplementary ATM functional resource, p.(Glu2245Lys) was classified as Functional with high confidence, but the currently available summary does not provide the criterion-aligned rescue assay detail required to apply ATM BS3.

cspec ↗
4

Computational evidence supports a benign interpretation, with REVEL 0.076 below the ATM BP4 threshold of <=0.249, SpliceAI max delta 0.02 below the BP4 threshold of <=0.1 and below the PP3 threshold of >=0.2, and BayesDel -0.479783 in a benign direction.

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
  • —
Gaps remaining
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Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.1972e-07; MAF= 0.00006%, 1/1613632 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47531e-07; MAF= 0.00008%, 1/1179898 alleles, homozygotes = 0).
gnomAD CanadaAbsent from gnomAD-Canada v1.0.
gnomAD v2 ↗ gnomAD v4 ↗ gnomAD 🇨🇦 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1484028)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.076. BayesDel score = -0.479783.
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; COSV99589774, n = 2 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE2245
Hotspots ↗