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 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
Population frequency
“
Absent from gnomAD v4.1.
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
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.
Literature · 3 PMIDs triaged · 3 high-priority
3papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
27413114 ↗
functional
ATM Mutations in Cancer: Therapeutic Implications.
Activation of checkpoint arrest and homologous DNA repair are necessary for maintenance of genomic integrity during DNA replication. Germ-line mutations of the ataxia telangiectasia mutated (ATM) gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central ne
BS3PM1PS3
30348496 ↗
functional
Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
The genome instability syndrome, ataxia-telangiectasia (A-T) is caused by null mutations in the ATM gene, that lead to complete loss or inactivation of the gene's product, the ATM protein kinase. ATM is the primary mobilizer of the cellular response to DNA double-strand breaks (DSBs) - a broad signaling network in which many components are ATM targets. The major clinical feature of A-T is cerebell
BS3PM1PS3
30553448 ↗
functional
Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.
Ataxia-telangiectasia mutated (ATM) is a serine-threonine kinase that is integral in the response to DNA double-stranded breaks (DSBs). Cells and tissues lacking ATM are prone to tumor development and enhanced tumor cell migration and invasion. Interestingly, ATM-deficient cells exhibit high levels of oxidative stress; however, the direct mechanism whereby ATM-associated oxidative stress may contr
BS3PM1PS3
Sources & reference links