PVS1 is met at Very Strong strength: NM_000051.4:c.9041_9042del is a frameshift deletion resulting in a premature termination codon (p.Gln3014ArgfsTer48) upstream of the p.Arg3047 threshold in a gene where loss of function is an established disease mechanism. The PTC is NMD-competent per the ClinGen SVI PVS1 framework and the ATM VCEP PVS1 decision tree.1 PM2 is met at Supporting strength: this variant is absent from gnomAD v4.1 (allele count 0), meeting the ATM VCEP threshold of ≤0.001% allele frequency in gnomAD v4.2 No benign or conflicting evidence was identified: BA1 and BS1 are not met (variant absent from gnomAD); PS3/BS3 functional evidence was sought but no variant-specific functional data were found in the reviewed literature or VCEP reference tables.3 Under the ATM VCEP v1.5.0 final combination rules, Rule 19 is triggered: 1 Very Strong pathogenic criterion (PVS1) + 1 Supporting pathogenic criterion (PM2_Supporting) yields a classification of Likely Pathogenic.4
ATM
Final classification
Likely Pathogenic
ATM c.9041_9042del · p.Gln3014ArgfsTer48
ATM
PVS1 is met at Very Strong strength: NM_000051.4:c.9041_9042del is a frameshift deletion resulting in a premature termination codon (p.Gln3014ArgfsTer48) upstream of the p.Arg3047 threshold in a gene where loss of function is an established disease mechanism. The PTC is NMD-competent per the ClinGen SVI PVS1 framework and the ATM VCEP PVS1 decision tree.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule19 (1 Pathogenic.Very Strong + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM2 supporting; maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
ATM c.9041_9042del
PVS1 + PM2
→
Likely Pathogenic
1
cspec ↗pvs1_generic_framework ↗vcep_atm_pvs1_1_5
4
cspec ↗final_classification_framework
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 8 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
This frameshift deletion (c.9041_9042del) introduces a premature termination codon at p.Gln3014ArgfsTer48 in exon 63 of ATM. Loss of function is an established disease mechanism for ATM, and this null variant is predicted to undergo nonsense-mediated decay (PTC is not in the last exon and is >55 nt upstream of the final exon-exon junction). The truncation occurs upstream of the p.Arg3047 critical C-terminal threshold defined by the ATM VCEP v1.5.0 PVS1 decision tree, supporting PVS1 at Very Strong strength.
Frameshift deletion creating premature termination codon at position 3061ATM loss-of-function is established disease mechanism for Ataxia-Telangiectasia and hereditary breast/ovarian/pancreatic cancerPTC is NMD-competent per ClinGen SVI PVS1 framework (not in terminal exon
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v4.1 (allele count 0). Per ATM VCEP v1.5.0, a frequency ≤0.001% in gnomAD v4 qualifies for PM2_Supporting. The variant is also absent from gnomAD v2.1 and gnomAD-Canada.
Absent from gnomAD v4.1 (0 alleles0 homozygotes)Absent from gnomAD v2.1
Assessed · not applied
Pathogenic
PS3
No variant-specific functional evidence was identified for NM_000051.4:c.9041_9042del.
PS4
No case-control studies or systematic case observation data were identified for this specific variant.
PM5
The ATM VCEP PM5 rule states: 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.' The premature termination codon created by this variant is at position 3061 (p.Gln3014ArgfsTer48), which is downstream of the p.Arg3047 threshold.
PP1
No cosegregation data were identified for this variant.
Benign
BA1
Per ATM VCEP v1.5.0, BA1 requires Grpmax Filtering AF >0.5% in gnomAD v4.
BS1
Per ATM VCEP v1.5.0, BS1 requires Grpmax Filtering AF >0.05% in gnomAD v4.
BS3
No variant-specific functional evidence demonstrating rescue of ATM function was identified.
BP2
No data were identified regarding observation of this variant in cis or trans with other pathogenic ATM variants.
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.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
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.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Triaged references · 3 PMIDs not cited in assessment
30348496 ↗
Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
ONCOKB
30553448 ↗
Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.
ONCOKB