NM_000051.4:c.5164del (p.Leu1722TrpfsTer2) is a frameshift deletion in ATM creating a premature termination codon at amino acid 1723, well upstream of the most C-terminal pathogenic residue p.Arg3047. Loss of function is an established disease mechanism for ATM, and this null variant is predicted to undergo nonsense-mediated decay, satisfying PVS1 at Very_Strong strength per the ClinGen HBOP VCEP v1.5.0 ATM PVS1 decision tree.1 This variant is absent from gnomAD v2.1 and v4.1 population databases (0 alleles observed), meeting the ATM VCEP v1.5.0 threshold of <=0.001% for PM2_Supporting.2 The variant creates a premature termination codon at codon 1723, upstream of p.Arg3047, satisfying the ATM VCEP v1.5.0 criterion for PM5_Supporting, which applies to frameshifting or truncating variants with PTCs upstream of this boundary.3 Applying the ClinGen HBOP VCEP v1.5.0 ACMG/AMP combination rules: 1 Very_Strong (PVS1) + 2 Supporting (PM2, PM5) satisfies Rule 4, resulting in a classification of Pathogenic.4
ATM
Final classification
Pathogenic
ATM c.5164del · p.Leu1722TrpfsTer2
ATM
NM_000051.4:c.5164del (p.Leu1722TrpfsTer2) is a frameshift deletion in ATM creating a premature termination codon at amino acid 1723, well upstream of the most C-terminal pathogenic residue p.Arg3047. Loss of function is an established disease mechanism for ATM, and this null variant is predicted to undergo nonsense-mediated decay, satisfying PVS1 at Very_Strong strength per the ClinGen HBOP VCEP v1.5.0 ATM PVS1 decision tree.
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, PM2 supporting, PM5 supporting; maps to Pathogenic.
Classification rationale
PVS1PM2PM5
Pathogenic
ATM c.5164del
PVS1 + PM2 + PM5
→
Pathogenic
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 7 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_000051.4:c.5164del is a frameshift deletion resulting in a premature termination codon at p.(Leu1722TrpfsTer2), well upstream of the most C-terminal pathogenic residue p.Arg3047. Under the ATM HBOP VCEP v1.5.0 PVS1 decision tree (adapted from PMID:30192042), this null variant in exon 34 of 63 is predicted to undergo nonsense-mediated decay and meets criteria for PVS1 at Very_Strong strength. Loss of function is an established disease mechanism for ATM in both autosomal recessive ataxia-telangiectasia and autosomal dominant cancer predisposition.
Frameshift deletion c.5164del creates PTC at codon 1723well upstream of p.Arg3047PTC located in exon 34 of 63 coding exons
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes), satisfying the ATM VCEP v1.5.0 threshold of <=0.001% for PM2_Supporting. Absence from large population databases supports pathogenicity.
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)VCEP threshold for PM2_Supporting: frequency <=0.001% in gnomAD v4
✓
PM5
supporting
Pathogenic
Under the ATM VCEP v1.5.0, PM5_Supporting is applied to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This variant creates a PTC at codon 1723, which is well upstream of p.Arg3047 (the most C-terminal pathogenic residue per the VCEP).
Frameshift c.5164del creates PTC at p.Leu1722TrpfsTer2 (aa1723)PTC is upstream of p.Arg3047the VCEP-defined C-terminal pathogenic boundary
Assessed · not applied
Pathogenic
PS3
No variant-specific functional evidence was identified for NM_000051.4:c.5164del.
PS4
The ATM VCEP v1.5.0 specifies PS4 requires case-control studies with p<=0.05 and OR>=2 (or lower 95% CI >=1.5).
PP1
The ATM VCEP v1.5.0 specifies PP1 for autosomal recessive ataxia-telangiectasia segregation (>=1 affected relative for Supporting).
Benign
BA1
The ATM VCEP v1.5.0 defines BA1 as Grpmax Filtering AF >0.5% in gnomAD v4.
BS1
The ATM VCEP v1.5.0 defines BS1 as Grpmax Filtering AF >0.05% in gnomAD v4.
BS3
No variant-specific functional evidence demonstrating rescue of ATM-specific features or radiosensitivity was identified for NM_000051.4:c.5164del.
BP2
The ATM VCEP v1.5.0 specifies BP2 for co-occurrence of the variant in trans with a known pathogenic variant in unaffected (non-A-T) individuals, using a point system per the ATM PM3/BP2 table.
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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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