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LYFE SCIENCES
Project: HERA
NM_006218.4:c.1132T>C
p.Cys378Arg  ·  PIK3CA
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Classification rationale
1

The PIK3CA c.1132T>C (p.Cys378Arg) variant has been reported in ClinVar with an overall Pathogenic classification, and curated somatic oncology resources also list this variant in cancer-associated context.

clinvar ↗ oncokb ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, including 0/1519490 alleles and 0 homozygotes in gnomAD v4.1, which supports rarity in population controls.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Curated functional literature links and a published PIK3CA study support a gain-of-function disease mechanism for mutant PIK3CA, but variant-specific assay evidence meeting Brain Malformations VCEP PS3 requirements was not established for p.Cys378Arg.

oncokb ↗ PMID:17363507 ↗ cspec ↗
4

The variant lies in a Brain Malformations VCEP-approved PIK3CA functional domain, a different missense change at the same residue has been reported as pathogenic, and SpliceAI predicts no splice effect; REVEL and BayesDel scores are also elevated, although PP3 is not applied by this VCEP for gain-of-function missense variants.

cspec ↗ clinvar ↗ spliceai ↗
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
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1519490 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73306 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 917489)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-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 = 0.00). REVEL score = 0.817. BayesDel score = 0.273988.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55882697, n = 16 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueC378
Hotspots ↗