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LYFE SCIENCES
Project: HERA
NM_000051.4:c.3137T>C
p.Leu1046Pro  ·  ATM
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Classification rationale
1

The ATM c.3137T>C (p.Leu1046Pro) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 overall (AF 1.85893e-06; 3/1613832 alleles; 0 homozygotes), with the highest observed frequency in the South Asian population at 2.19587e-05 (2/91080 alleles; 0 homozygotes).

3

In silico evidence supports a deleterious missense effect, with REVEL 0.854 exceeding the ATM PP3 threshold of 0.7333, while SpliceAI predicts no significant splice impact (maximum delta score 0.01).

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
  • —
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= 1.85893e-06; MAF= 0.00019%, 3/1613832 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19587e-05; MAF= 0.00220%, 2/91080 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 = 0.01).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueL1046
Hotspots ↗