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LYFE SCIENCES
Project: HERA
NM_000051.4:c.2930G>A
p.Cys977Tyr  ·  ATM
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Classification rationale
1

The ATM c.2930G>A (p.Cys977Tyr; p.C977Y) variant has been reported in ClinVar, where most submissions classify it as likely pathogenic, although at least one submission classifies it as uncertain significance.

clinvar ↗
2

This variant is very rare in population databases, with gnomAD v4.1 showing an allele frequency of 0.00025% (4/1,609,362 alleles) and gnomAD v2.1 showing 0.00340% (1/29,448 alleles), which is below the ATM PM2_Supporting threshold of 0.001%.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

Computational evidence supports a damaging missense effect, with REVEL 0.778 above the ATM PP3 threshold of 0.7333 and BayesDel 0.318994, while SpliceAI predicts no significant 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
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= 3.39582e-05; MAF= 0.00340%, 1/29448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.9185e-05; MAF= 0.00692%, 1/14454 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.48546e-06; MAF= 0.00025%, 4/1609362 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.39334e-06; MAF= 0.00034%, 4/1178778 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory). (ClinVarID = 233765)
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 = 0.778. BayesDel score = 0.318994.
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; COSV53734070, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueC977
Hotspots ↗