Classification rationale

BA1BS1BP6 Benign

PIK3CA c.2198A>G

The PIK3CA c.2198A>G (p.Lys733Arg) variant has been reported in ClinVar as Benign, including an expert-panel benign classification from the ClinGen Brain Malformations Variant Curation Expert Panel.¹ This variant is present in population databases at a frequency above the Brain Malformations VCEP benign thresholds, with East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1, exceeding both the BS1 threshold of 0.0185% and the BA1 threshold of 0.0926%.² In silico review does not support a splice-disrupting effect, with SpliceAI max delta score 0.12; REVEL was 0.269 and BayesDel was -0.264459, although PP3 and BP4 are not applicable to this missense gain-of-function interpretation under the Brain Malformations VCEP.³

BA1 + BS1 + BP6 → Benign

1 clinvar ↗cspec ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗revelbayesdelcspec ↗

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 · 3 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 · 3

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

This variant exceeds the Brain Malformations VCEP BA1 threshold of 0.0926%. The highest observed population frequency is East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1, both above the BA1 threshold.

gnomAD East Asian frequencyVCEP BA1 threshold

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BS1 strong Benign

This variant exceeds the Brain Malformations VCEP BS1 threshold of 0.0185%. The highest observed population frequency is East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1, both above the BS1 threshold.

gnomAD East Asian frequencyVCEP BS1 threshold

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP6 supporting Benign

Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Benign.

VCEP BP6 applicability statementClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 8 not assessed

Pathogenic

PS1 No evidence was identified showing that this exact amino acid change has been established as pathogenic through a different nucleotide change at the same codon.

PS2 No confirmed de novo or tissue-mosaic evidence was identified for this variant, so the Brain Malformations VCEP requirements for PS2 were not met from the available data.

PS3 No validated functional study for p.Lys733Arg demonstrating an abnormal gain-of-function effect at a level specified by the Brain Malformations VCEP was identified.

PS4 This variant does not meet PM2 because it is present in gnomAD above the VCEP rarity threshold, including East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1; under the Brain Malformations VCEP, PS4 phenotype points can only be used if PM2 is met.

PM1 The Brain Malformations VCEP allows PM1 at Supporting strength for PIK3CA variants in approved Table 4 domains at amino acids 322-483 or 797-1068.

PM2 This variant is not absent or rare enough for PM2 because it is present in gnomAD, with East Asian AF 0.56428% in v2.1 and 0.25756% in v4.1, which are well above the VCEP one-person rarity allowance for PM2_Supporting.

PM5 No reviewed evidence was identified showing a different missense change at Lys733 that is already established as pathogenic for this disease context.

PP2 The Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the missense constraint z-score is greater than 3.09, but no z-score evidence was provided in the reviewed materials.

Benign

BS2 BS2 was not met because the Brain Malformations VCEP requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped family members.

BS3 No validated functional study was identified showing that p.Lys733Arg has a normal or benign effect under the Brain Malformations VCEP/SVI functional evidence framework.

BP2 No evidence was identified showing that this variant has been observed in cis or trans with a known pathogenic PIK3CA variant.

BP5 No evidence was identified showing an alternate molecular explanation for the reported phenotype in a person carrying this variant.

N/A · 13 PVS1 · PM3 · PM4 · PM6 · PP1 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3 · BP4 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 8.99951e-05; MAF= 0.00900%, 143/1588976 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.00257559; MAF= 0.25756%, 115/44650 alleles, homozygotes = 2); grpmax FAF= 0.00219327.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000417941; MAF= 0.04179%, 117/279944 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.00564276; MAF= 0.56428%, 110/19494 alleles, homozygotes = 2); grpmax FAF= 0.00484339.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.009% · 143 / 1,588,976
2 hom · FAF 0.22%

East Asian 115 / 44,650	0.26% 2 hom
Remaining individuals 19 / 61,544	0.031%
South Asian 5 / 90,218	0.0055%
Admixed American 2 / 59,822	0.0033%
African/African American 1 / 74,432	0.0013%
European (non-Finnish) 1 / 1,158,294	8.6e-05%

+ 4 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.042% · 117 / 279,944
2 hom · FAF 0.48%

East Asian 110 / 19,494	0.56% 2 hom
Remaining individuals 1 / 7,112	0.014%
South Asian 4 / 30,560	0.013%
Admixed American 2 / 35,228	0.0057%

+ 4 not observed (African/African American, Ashkenazi Jewish, European (Finnish), European (non-Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (1 clinical laboratory) and as Benign by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.269. BayesDel score = -0.264459.

SpliceAI ↗

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

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55938496, n = 5 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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