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.1 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 v4.2 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 BS3.3 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 0.02.4
Final classification
Uncertain Significance
PM2PP3
ATM
c.6059G>T
p.Gly2020Val
This variant
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.
ATM HBOP CSPEC/VCEP criteria-combination framework (cspec_ruleset v1.5.0; Richards et al. 2015 combining rules as instantiated in the retrieved final classification framework).
Classification rationale
PM2PP3
Uncertain Significance
ATM c.6059G>T
PM2 + PP3
→
Uncertain Significance
3
vcep_s_u_p_p_l___t_a_b_l_e_s_1___p_m_i_d___4_0_5_8_0_9_5_1cspec ↗
4
spliceai ↗cspec ↗revel
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 10 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
Supporting
Pathogenic
This variant is absent from gnomAD v4.1 and gnomAD v2.1. A frequency of 0% is below the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4, supporting PM2_Supporting.
gnomAD v4.1: absentgnomAD v2.1: absent
PP3
Supporting
Pathogenic
In silico evidence supports a deleterious effect for this missense variant because the REVEL score is 0.753, which is above the ATM PP3 threshold of >0.7333. SpliceAI predicts no meaningful splice effect with a max delta score of 0.02, supporting interpretation as a missense change rather than a splice-altering variant.
REVEL = 0.753SpliceAI max delta score = 0.02
Assessed · not applied
· 6 not met · 4 not assessed
Pathogenic
PS1
No pathogenic or likely pathogenic ATM variant producing the same amino acid change was identified, and SpliceAI does not suggest a splice effect that would support use of the ATM PS1 splicing table.
PS3
An ATM supplementary functional dataset listed this variant as non-functional, but the available evidence does not document the ATM VCEP-required rescue assay endpoints showing failure to rescue both an ATM-specific feature and radiosensitivity.
PS4
No case-control study or other quantitative enrichment data were identified showing this variant is significantly enriched in affected individuals.
PM3
No evidence was identified showing this variant in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia.
PP1
No segregation data were identified for this variant in affected relatives, so PP1 cannot be assessed from the available evidence.
Benign
BA1
This variant is absent from gnomAD v4.1.
BS1
This variant is absent from gnomAD v4.1.
BS3
No study was identified showing that this variant rescues an ATM-specific functional defect or radiosensitivity.
BP2
No evidence was identified showing this variant in trans with a pathogenic ATM variant in an unaffected individual or other setting that would qualify for BP2 points.
BP4
Benign computational evidence is not supported because the REVEL score is 0.753, which is above the ATM BP4 missense threshold of ≤0.249.
N/A · 16
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links