NM_006218.4:c.397G>A (p.Asp133Asn) in PIK3CA is absent from gnomAD population databases (v2.1, v4.1), meeting PM2 at supporting strength per the ClinGen Brain Malformations VCEP v1.1.1 PIK3CA has a high missense constraint z-score exceeding the BMVCEP threshold of 3.09, consistent with a gene where missense variants are a common disease mechanism, meeting PP2 at supporting strength.2 PVS1 is not applicable because the disease mechanism for PIK3CA-related brain malformations is gain of function, as specified by the BMVCEP v1.1.3 Residue Asp133 falls outside all Table 4 approved functional domains for PIK3CA (ABD 31-108, Ras-binding 173-292, kinase 322-483, kinase 797-1068); PM1 is not met.4 No functional data, no de novo reports, no phenotype cases, no ClinVar entries, and no literature citations were identified for this variant. PS1, PS2, PS3, PS4, and PM5 are not met.5 Applying the BMVCEP Tavtigian point framework (PMID:32720330): PM2_Supporting (+1) + PP2_Supporting (+1) = 2 points total. Score of 2 falls within the VUS range (0-5).6 No benign criteria are met: BA1 and BS1 population frequency thresholds are not exceeded; BS2 requires homozygotes or well-phenotyped heterozygotes not observed; BS3 lacks functional studies showing no effect; BP2, BP5 lack supporting evidence.7
PIK3CA
Final classification
VUS
PIK3CA c.397G>A · p.Asp133Asn
PIK3CA
NM_006218.4:c.397G>A (p.Asp133Asn) in PIK3CA is absent from gnomAD population databases (v2.1, v4.1), meeting PM2 at supporting strength per the ClinGen Brain Malformations VCEP v1.1.
ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 v1.1 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP2 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM2PP2
VUS
PIK3CA c.397G>A
PM2 + PP2
→
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
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes). Under the BMVCEP, PM2 is awarded at supporting strength for variants absent or rare (≤1) in population controls.
Absent from gnomAD v2.1 and v4.1 population databases.
✓
PP2
supporting
Pathogenic
PIK3CA has a high gnomAD missense constraint z-score well above the BMVCEP threshold of 3.09, indicating a low rate of benign missense variation. This variant is a missense change in a gene where missense variants are a common disease mechanism. PP2 applies specifically to PIK3CA, MTOR, and AKT3 per the VCEP.
PIK3CA missense z-score exceeds 3.09 threshold in gnomADconsistent with significant missense constraint. BMVCEP explicitly names PIK3CA as eligible for PP2.
Assessed · not applied
Pathogenic
PS1
No same amino acid change has been previously established as pathogenic per BMVCEP criteria independent of this point.
PS2
No de novo occurrence data is available for this variant.
PS3
No functional assay data is available for this specific variant (p.Asp133Asn).
PS4
PS4 requires PM2 first (which is met) and phenotype points per Table 2A/2B of the BMVCEP.
PM1
Residue Asp133 falls outside all approved Table 4 functional domains for PIK3CA.
PM5
No pathogenic missense variants have been established at residue Asp133.
Benign
BA1
This variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%).
BS1
This variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%).
BS2
No homozygotes are present in gnomAD for this variant, and no well-phenotyped heterozygous family members have been identified.
BS3
No well-established in vitro or in vivo functional studies show no damaging effect on protein function for this variant.
BP2
No evidence that this variant has been observed in cis or trans with a known pathogenic variant in PIK3CA.
BP5
No evidence that this variant has been found in a case with an alternate molecular basis for disease in a different gene.
N/A · 11
PVS1 · PM6 · PP1 · PP3 · PP4 · PP5 · BS4 · BP1 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
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 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.19. BayesDel score = -0.494007.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links