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
Final classification
Likely Pathogenic
PS3PM1PM2PP5
PIK3CA
c.3140A>G
p.His1047Arg
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_006218.2 · variants mapped to exon structure
PIK3CA
NM_006218.2
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 11 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
review
Pathogenic
Multiple published functional studies showed that p.His1047Arg increases PI3K pathway activity and produces abnormal gain-of-function behavior relative to wild type. Cell-based assays showed higher PI3K activity, growth factor-independent proliferation, anchorage-independent growth, and resistance to anoikis, and in vivo models showed Akt-pathway activation and tumor formation, supporting an abnormal activating effect.
MCF-10A experiments showed higher PI3K activity and transformed phenotypes for H1047R compared with wild typeIn vivo studies showed Akt-pathway activation and tumor formation for H1047RStructural study reported a conformational change for His1047Arg that increases membrane association and activity
PM1
supporting
review
Pathogenic
This missense variant affects residue 1047, which lies within the PIK3CA kinase-domain interval 797-1068 listed by the Brain Malformations VCEP as an approved PM1 domain. Under this framework, domain membership is sufficient for PM1_Supporting and does not require separate hotspot recurrence evidence.
p.His1047Arg falls within the approved kinase-domain interval 797-1068 for PIK3CA
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v4.1 and is present once in gnomAD v2.1 at 1/248274 alleles (AF 0.00040%), with no homozygotes. This meets the VCEP PM2 requirement for absent or very rare population occurrence, which is limited to Supporting strength for this gene group.
gnomAD v4.1 absentgnomAD v2.1 total AC 1 of 248274 allelesAF 4.027807986337675e-06
Assessed · not applied
· 4 not met · 7 not assessed
Pathogenic
PS1
No independently verified evidence was identified in the available sources showing a different nucleotide change that produces the same p.His1047Arg amino acid substitution and is already established as pathogenic under this framework.
PS2
No case-level evidence was identified showing confirmed maternity and paternity with absence of the variant in both parents, or tissue-comparison data demonstrating a higher allele fraction in affected tissue than in another tissue, so PS2 cannot be applied from the available evidence.
PS4
This variant has been reported in affected individuals and in somatic cancers, but the available materials do not provide a verified Brain Malformations VCEP Table 2A phenotype-point tally for independent cases of this exact variant.
PM5
No independently verified evidence was identified in the available sources showing a different pathogenic missense change at the same residue that can be counted under PM5 for this framework.
PP2
The VCEP allows PP2 for PIK3CA if the missense constraint z-score is greater than 3.09, but no verified z-score value was provided in the available evidence files, so PP2 cannot be applied from the current record.
Benign
BA1
Population frequency does not meet the BA1 threshold.
BS1
Population frequency does not meet the BS1 threshold.
BS2
BS2 is not met because no homozygotes were observed in gnomAD, and no evidence was identified for at least 3 heterozygous occurrences in well-phenotyped unaffected family members.
BS3
Available functional evidence does not support a normal or benign effect.
BP2
No evidence was identified showing this variant in cis or in trans with another established pathogenic PIK3CA variant, so BP2 cannot be assessed from the available data.
BP5
No alternate molecular diagnosis or other established explanation for the phenotype was identified in the available evidence, so BP5 cannot be applied.
N/A · 13
PVS1 · PM3 · PM4 · PM6 · PP1 · PP3 · PP4 · BS4 · BP1 · BP3 · BP4 · BP6 · BP7
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.
Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial ce
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Cancer-specific mutations in PIK3CA are oncogenic in vivo.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Rare cancer-specific mutations in PIK3CA show gain of function.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Structural effects of oncogenic PI3Kα mutations.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Conditional activation of Pik3ca(H1047R) in a knock-in mouse model promotes mamm
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links