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LYFE SCIENCES
Project: HERA
NM_000051.3:c.4158dup
p.Lys1387Ter  ·  ATM
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

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.

cspec ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
ClinVar evidence
02
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)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueK1387
Hotspots ↗