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.1 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.2 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.3 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.4
PIK3CA
Final classification
Likely Pathogenic
PIK3CA c.3140A>G · p.His1047Arg
PIK3CA
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.
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PS3 strong (+4) + PM1 supporting (+1) + PM2 supporting (+1) + PP5 supporting (+1) = 7 points, which maps to Likely Pathogenic.
Classification rationale
PS3PM1PM2PP5
Likely Pathogenic
PIK3CA c.3140A>G
PS3 + PM1 + PM2 + PP5
→
Likely Pathogenic
Gene diagram
· NM_006218.2 · variants mapped to exon structure
PIK3CA
NM_006218.2
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
This 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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
0.0004%
· 1 / 248,274
0 hom
0 hom
European (non-Finnish) 1 / 112,236 |
0.00089% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.455. BayesDel score = 0.247638.
Functional
Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55873195, n = 3817 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
5papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:16322248
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:16432179
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:17376864
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:20593314
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:22370636
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links