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
ATM
Final classification
Uncertain Significance
ATM c.6059G>T · p.Gly2020Val
ATM
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
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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