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PIK3CA
Final classification
VUS
PM1PM2
PIK3CA
c.278G>T
p.Arg93Leu
missense · exon 2
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 p110α catalytic subunit of PI3K, and activating mutations in this gene drive tumor growth through the AKT-mTOR pathway. This missense change (p.Arg93Leu) falls within the adaptor-binding domain and is absent from population databases, yet no functional or clinical evidence establishes its effect on PI3K signaling. The VUS classification reflects that this variant is neither established as pathogenic nor benign.

Transcript
NM_006218.4
HGVS · transcript:coding
NM_006218.4:c.278G>T
GRCh38
chr3:179199103 G>T
GRCh37
chr3:178916891 G>T
Basis PM1 and PM2 are met at Supporting strength, but two supporting criteria do not reach a pathogenic combination threshold and no benign criteria are met, so the variant is classified VUS. ▾
PM1 and PM2 are met at Supporting strength, but two supporting criteria do not reach a pathogenic combination threshold and no benign criteria are met, so the variant is classified VUS.
Classification rationale
PM1PM2 VUS
PIK3CA c.278G>T missense · exon 2

PM1 (Supporting): p.Arg93Leu lies within the approved PI3K adaptor-binding domain (residues 31-108). PM2 (Supporting): the variant is absent from gnomAD v2.1, gnomAD-Canada v1.0, and gnomAD v4.1 (0 of 1,611,098 alleles). Synthesis: PM1 and PM2 at Supporting strength do not meet a pathogenic combination threshold under the generic ACMG/AMP 2015 rules, and no benign criteria apply, yielding a classification of VUS.

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 93 lies within the approved PI3K adaptor-binding domain (residues 31-108).
The governing Brain Malformations VCEP specifies PM1 at Supporting strength for residues affecting critical functional domains in Table 4.The authoritative PIK3CA domain table lists the adaptor binding domain (PI3K ABD) at amino acids 31-108, which contains residue Arg93; the other listed PIK3CA intervals, 173-292, 322-483, and 797-1068, were also checked and do not contain residue 93.The VCEP local guidance states that PM1 is domain-based and does not require hotspot recurrence when the variant falls inside an approved domain.
cspec ↗
✓
PM2 supporting Pathogenic
Met (Supporting): absent from gnomAD v2.1, gnomAD-Canada v1.0, and gnomAD v4.1 (0 of 1,611,098 alleles).
The governing ClinGen Brain Malformations VCEP specifies PM2 at Supporting strength for a variant absent or rare in an ethnically matched control cohort population sample, with at least one qualifying sample.gnomAD v2.1 reports the variant absent.gnomAD v4.1 reports 0 alternate alleles among 1,611,098 total alleles, total AF 0.0, and 0 homozygotes; the African/African American subgroup, reported as the highest observed-frequency subgroup, also has 0 alternate alleles among 74,682 alleles and AF 0.0.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 3 not met · 9 not assessed
Pathogenic
PS1 Not assessed: no ClinVar record or literature documented a previously established pathogenic variant producing the same amino-acid change.
PS2 Not assessed: no proband or parental testing evidence was available to establish a de novo occurrence.
PS3 Not assessed: no variant-specific functional assay evidence was available to demonstrate a damaging effect.
PS4 Not assessed: no affected individuals, phenotype, or case-control data were available to establish enrichment.
PM5 Not assessed: no different pathogenic missense change at residue 93 was documented to serve as a comparator.
PP2 Not assessed: the PIK3CA missense-constraint z-score was not available to test against the >3.09 threshold.
Benign
BA1 Not met: allele frequency 0.0 in gnomAD v4.1, far below the >0.0926% BA1 threshold.
BS1 Not met: allele frequency 0.0 in gnomAD v4.1, below the >0.0185% BS1 threshold.
BS2 Not met: gnomAD v4.1 reports 0 homozygotes versus the 3 required.
BS3 Not assessed: no functional assay evidence was available to show the variant has no damaging effect.
BP2 Not assessed: no family, parental, or phase evidence was available to evaluate a second PIK3CA variant.
BP5 Not assessed: no patient-level workup showing an alternate molecular basis for the phenotype was available.
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
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1611098 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74682 alleles, homozygotes = 0).
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 / 1,611,098
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
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 is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.20). REVEL score = 0.86. BayesDel score = 0.334367.
SpliceAI ↗
Functional / OncoKB screenshot
Functional 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 ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56022812, n = 10 times).
Hotspots
This variant lies 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