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LYFE SCIENCES
Project: HERA
NM_006218.2:c.2176G>A
p.Glu726Lys  ·  PIK3CA
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Classification rationale
1

The PIK3CA c.2176G>A (p.Glu726Lys, p.E726K) variant has been observed in somatic cancers in COSMIC (COSV55875460, n=150) and has been reported in ClinVar as Pathogenic, including expert-panel review by the ClinGen Brain Malformations Variant Curation Expert Panel.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at Supporting strength under the Brain Malformations VCEP population rule.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Published PIK3CA disease-mechanism and functional literature was identified, but the retrieved materials do not provide enough variant-specific assay detail to assign PS3 or BS3 for p.Glu726Lys without direct full-text review.

PMID:22729224 ↗ PMID:29533785 ↗ oncokb ↗
4

In silico data show no predicted splice disruption by SpliceAI (max delta score 0.02), with REVEL 0.442 and BayesDel 0.266518; however, PP3 is not applicable for PIK3CA gain-of-function variants in this VCEP framework and BP4 is restricted to non-missense splicing-context variants.

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 (7 clinical laboratories) and as Pathogenic by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Inconclusive
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.442. BayesDel score = 0.266518.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55875460, n = 150 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueE726
Hotspots ↗