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
Final classification
Pathogenic
PVS1PM5PM2
ATM
c.8052_8055del
p.Gln2684HisfsTer8
This variant
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
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 · 3 applied · 8 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
This 4-bp deletion causes a frameshift, p.Gln2684HisfsTer8 (p.Q2684Hfs*8), in exon 55 of ATM. In the ATM VCEP framework, loss of function is an established disease mechanism, the reference transcript exons are considered constitutive, and this premature stop is well upstream of the transcript end rather than at the extreme 3′ end, supporting PVS1 at very strong strength.
Frameshift consequence p.Gln2684HisfsTer8 / p.Q2684Hfs*8Variant maps to exon 55ATM VCEP includes gene-specific PVS1 guidance
PM2
supporting
Pathogenic
This variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. An observed frequency of 0 is below the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4, so PM2_Supporting is met.
Absent from gnomAD v4.1Absent from gnomAD v2.1
PM5
supporting
Pathogenic
ATM repurposes PM5 for truncating variants with premature termination codons upstream of p.Arg3047. This frameshift introduces a premature stop at p.Gln2691, which is upstream of p.Arg3047, so ATM-specific PM5_Supporting is met; classic same-residue missense comparator logic is not required for this gene-specific rule.
ATM-specific PM5 truncation-cutoff rulePredicted stop upstream of p.Arg3047
Assessed · not applied
· 3 not met · 5 not assessed
Pathogenic
PS3
Available functional publications reviewed in curated sources describe ATM loss-of-function biology or assays of other ATM alterations, but no direct assay of this specific variant was identified showing failure to rescue ATM-specific function and radiosensitivity as required by the ATM framework.
PS4
This variant has been reported in ClinVar and cited literature, but no case-control study or exact-variant enrichment analysis was identified showing p-value ≤0.05 together with an odds ratio, hazard ratio, or relative risk ≥2, or a lower 95% confidence interval ≥1.5.
PM3
No confirmed observation of this variant in trans with a pathogenic or likely pathogenic ATM variant in an affected individual was identified, so PM3 cannot be assigned from the available evidence.
PP1
No segregation data were identified for this variant in affected relatives, so PP1 cannot be assigned.
Benign
BA1
This variant is absent from gnomAD v4.1.
BS1
This variant is absent from gnomAD v4.1.
BS3
No direct assay of this specific variant was identified showing rescue of ATM-specific function or radiosensitivity.
BP2
No evidence was identified showing this variant in trans with a pathogenic ATM variant in an unaffected individual, with phase unknown in an unaffected individual, or as a qualifying homozygous finding under the ATM BP2 framework.
N/A · 17
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP4 · BP5 · BP6 · BP7
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