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 ↗

Gene diagram · NM_006218.2 · variants mapped to exon structure

PIK3CA NM_006218.2

Fetching transcript structure from UCSC…

Applied criteria · 3 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 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