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 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.
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