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LYFE SCIENCES
Project: HERA
NM_006218.2:c.3140A>G
p.His1047Arg  ·  PIK3CA
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Classification rationale
1

The PIK3CA c.3140A>G (p.His1047Arg) variant has been observed in somatic cancers and is reported in ClinVar, including a Pathogenic expert-panel classification by the ClinGen Brain Malformations Variant Curation Expert Panel.

clinvar ↗ PMID:16322248 ↗ PMID:16432179 ↗
2

This variant is absent from gnomAD v4.1 and is present once in gnomAD v2.1 (1/248274 alleles; AF 0.00040%), which is below the VCEP PM2 range and well below the BS1 (>0.0185%) and BA1 (>0.0926%) population thresholds.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Published functional studies showed increased PI3K activity, growth factor-independent and anchorage-independent proliferation, Akt-pathway activation, and tumor formation relative to wild type, consistent with a gain-of-function effect.

PMID:16322248 ↗ PMID:16432179 ↗ PMID:17376864 ↗ PMID:20593314 ↗ PMID:22370636 ↗
4

SpliceAI predicts no significant splice impact (max delta score 0.04), and REVEL and BayesDel scores are 0.455 and 0.247638, respectively; however, this VCEP does not use PP3 or BP4 for PIK3CA gain-of-function missense 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
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 4.02781e-06; MAF= 0.00040%, 1/248274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.9098e-06; MAF= 0.00089%, 1/112236 alleles, homozygotes = 0).
gnomAD v4.1Absent from gnomAD v4.1.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (25 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Pathogenic by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.455. BayesDel score = 0.247638.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55873195, n = 3817 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueH1047
Hotspots ↗