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PIK3CA
Final classification
VUS
PM1PM2
PIK3CA
c.1214C>A
p.Ser405Tyr
missense · exon 7
Gene context NCBI Gene ↗ OncoKB ↗

PIK3CA encodes the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), an enzyme that converts the membrane lipid PIP2 into PIP3, thereby activating signaling cascades such as the AKT-mTOR pathway that promote cell survival, proliferation, growth, and motility. It is among the most commonly mutated genes in cancer, and aberrant activation of PI3K signaling is a driving event in tumor development, with the gene implicated in cancers including cervical cancer. Because this pathway is central to tumor growth, it is a major target of cancer therapies, although drug-induced pathway activation can also contribute to treatment resistance.

This variant

PIK3CA encodes the PI3K p110α catalytic subunit that activates the AKT-mTOR pathway, making it a common cancer driver and therapy target. This p.Ser405Tyr change falls within the kinase domain, but as a VUS the available evidence does not establish whether it alters PI3K signaling or contributes to cancer.

Transcript
NM_006218.4
HGVS · transcript:coding
NM_006218.4:c.1214C>A
GRCh38
chr3:179209663 C>A
GRCh37
chr3:178927451 C>A
Basis Met criteria PM1 and PM2 (both Supporting) fall below any pathogenic or likely pathogenic combination threshold, and no benign criterion is met, yielding a VUS. ▾
Met criteria PM1 and PM2 (both Supporting) fall below any pathogenic or likely pathogenic combination threshold, and no benign criterion is met, yielding a VUS.
Classification rationale
PM1PM2 VUS
PIK3CA c.1214C>A missense · exon 7

PM1 (Supporting): residue 405 falls within the PIK3CA kinase domain (residues 322-483). PM2 (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Final classification: VUS — two supporting pathogenic criteria do not reach any pathogenic or likely pathogenic combination threshold under the applied ACMG/AMP 2015 combination rules.

PM1 + PM2 → VUS
Gene diagram · NM_006218.4 · variants mapped to exon structure
PIK3CA NM_006218.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PM1 supporting Pathogenic
Met (Supporting): residue 405 falls within the PIK3CA kinase domain (residues 322-483).
The authoritative PIK3CA domain table lists kinase domains at residues 322-483 and 797-1068, the Kinase Ras-binding domain at 173-292, and the adaptor binding domain at 31-108.The normalized variant consequence is NP_006209.2:p.(Ser405Tyr), placing the affected residue at 405.Residue 405 is within the approved PIK3CA kinase-domain interval 322-483.
cspec ↗
✓
PM2 supporting Pathogenic
Met (Supporting): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
The governing ClinGen Brain Malformations VCEP specifies PM2 as Supporting for a variant absent/rare in an ethnically matched control cohort population sample, with one person maximum.The exact variant NM_006218.4:c.1214C>A is reported as absent from gnomAD v2.1.The exact variant NM_006218.4:c.1214C>A is reported as absent from gnomAD v4.1.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 3 not met · 9 not assessed
Pathogenic
PS1 Not assessed: no pathogenic p.Ser405Tyr comparator was available, so this criterion could not be evaluated.
PS2 Not assessed: no proband or parental genotype data, tissue allele fractions, or confirmation of maternity and paternity were available.
PS3 Not assessed: no variant-specific functional assay evidence for p.Ser405Tyr was available.
PS4 Not assessed: no affected-individual, phenotype, case-control, or variant-specific literature data were provided.
PM5 Not assessed: no pathogenic missense variant at residue 405 was identified for comparison.
PP2 Not assessed: the required PIK3CA missense-constraint z-score (>3.09) was not available.
Benign
BA1 Not met: the variant is absent from population databases, so no allele frequency exceeds the BA1 threshold of 0.0926%.
BS1 Not met: the variant is absent from population databases, so no allele frequency exceeds the BS1 threshold of 0.0185%.
BS2 Not met: the required three homozygotes or qualifying family observations were absent.
BS3 Not assessed: no variant-specific benign functional assay evidence was available.
BP2 Not assessed: no data showed this variant in cis or trans with a known pathogenic PIK3CA variant.
BP5 Not assessed: no alternate molecular diagnosis explaining the phenotype was identified.
N/A · 14 PVS1 · PM3 · PM4 · PM6 · PP1 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3373455)
ClinVar ↗
SpliceAI screenshot
In silico
REVEL score = 0.827. BayesDel score = 0.337221.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
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.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots