The ATM c.4158dup (p.Lys1387Ter, p.K1387*) variant has been reported in ClinVar and is classified there as pathogenic, including by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel.1 This variant is absent from gnomAD v4.1 and gnomAD v2.1, which supports PM2_Supporting and does not meet the BA1 or BS1 population thresholds.2 This variant introduces a premature stop at Lys1387 in ATM, and the ATM HBOP VCEP framework supports full-strength PVS1 for this truncating event; the same gene-specific framework also supports PM5_Supporting because the stop is upstream of the ATM truncation cutoff at p.Arg3047Ter.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which supports BP4 and does not support PP3 under the ATM VCEP splice thresholds.4
ATM
Final classification
Pathogenic
ATM c.4158dup · p.Lys1387Ter
ATM
The ATM c.4158dup (p.Lys1387Ter, p.K1387*) variant has been reported in ClinVar and is classified there as pathogenic, including by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PM5 supporting, PM2 supporting, PVS1 very strong, BP4 supporting, PP5 supporting; maps to Pathogenic.
Classification rationale
PM5PM2PVS1PP5
BP4
Pathogenic
ATM c.4158dup
PM5 + PM2 + PVS1 + PP5 + BP4
→
Pathogenic
3
cspec ↗vcep_atm_pvs1_1_5pvs1_gene_contextpvs1_variant_assessmentpm5_candidates
Gene diagram
· NM_000051.3 · variants mapped to exon structure
ATM
NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 5 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
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) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 3148196)
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 · 9 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
34242744 ↗
Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR