The ATM c.8052_8055del (p.Gln2684HisfsTer8; p.Q2684Hfs*8) variant has not been observed in somatic cancers in COSMIC and is reported in ClinVar as pathogenic.1 This variant is absent from gnomAD v2.1 and v4.1, which is below the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4 and does not meet the BS1 (>0.05%) or BA1 (>0.5%) population thresholds.2 This 4-bp deletion causes a frameshift in exon 55 with a premature stop codon, and under the ATM VCEP framework that supports PVS1 at very strong strength; because the predicted stop is upstream of p.Arg3047, it also meets the ATM-specific truncation-based PM5 rule.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, and the ATM PP3/BP4 computational rules are not applied to this exonic frameshift variant class.4
ATM
Final classification
Pathogenic
ATM c.8052_8055del · p.Gln2684HisfsTer8
ATM
The ATM c.8052_8055del (p.Gln2684HisfsTer8; p.Q2684Hfs*8) variant has not been observed in somatic cancers in COSMIC and is reported in ClinVar as pathogenic.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM5 supporting, PM2 supporting; maps to Pathogenic.
Classification rationale
PVS1PM5PM2
Pathogenic
ATM c.8052_8055del
PVS1 + PM5 + PM2
→
Pathogenic
3
cspec ↗vcep_atm_pvs1_1_5pvs1_variant_assessmentpm5_candidates
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 3 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 · supports pathogenic
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 Pathogenic (3 clinical laboratories). (ClinVarID = 827424)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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