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LYFE SCIENCES
Project: HERA
NM_000051.4:c.6059G>T
p.Gly2020Val  ·  ATM
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Classification rationale
1

The ATM c.6059G>T (p.Gly2020Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as a variant of uncertain significance with multiple clinical laboratory submissions.

clinvar ↗ cosmic ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the ATM PM2_Supporting threshold of 0.001% in gnomAD v4.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

An ATM supplementary functional dataset classified this variant as non-functional, but the available evidence does not document the ATM VCEP-required rescue assay endpoints needed to apply PS3 or BS3.

cspec ↗
4

In silico evidence supports a deleterious missense effect because REVEL is 0.753, which is above the ATM PP3 threshold of 0.7333, while SpliceAI predicts no meaningful splice impact with a maximum delta score of 0.02.

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
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories).
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 = 0.02).
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.
ResidueG2020
Hotspots ↗