Back
LYFE SCIENCES
Project: HERA
NM_000051.4:c.2222A>G
p.Tyr741Cys  ·  ATM
Starting
Initialising…
0%
Legacy Engine
Ready
View Legacy →
Classification rationale
1

The ATM c.2222A>G (p.Tyr741Cys) variant has been observed once in somatic cancer in COSMIC and has been reported in ClinVar with conflicting germline classifications, including uncertain significance and likely benign submissions.

clinvar ↗
2

This variant is present in population databases at low frequency, including gnomAD v4.1 at 0.00217% overall (35/1,611,122 alleles) with a highest observed subpopulation frequency of 0.00447% in East Asian individuals, which is above the ATM PM2_Supporting threshold of <=0.001% and below the BS1 and BA1 thresholds.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

Computational evidence is mixed: SpliceAI predicts possible splice impact with a maximum delta score of 0.29, supporting ATM PP3_Supporting, whereas REVEL is low at 0.153 and BayesDel is negative at -0.288378, which argues against a damaging missense effect but does not resolve the predicted splice concern.

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
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
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= 1.41539e-05; MAF= 0.00142%, 4/282608 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000100492; MAF= 0.01005%, 2/19902 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.1724e-05; MAF= 0.00217%, 35/1611122 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 4.47007e-05; MAF= 0.00447%, 2/44742 alleles, homozygotes = 0); grpmax FAF= 1.965e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (3 clinical laboratories).
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 possible splice impact for this variant (max delta score = 0.29). REVEL score = 0.153. BayesDel score = -0.288378.
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; COSV105123853, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueY741
Hotspots ↗