Classification rationale

PM2 VUS

PIK3CA c.371C>A

The PIK3CA c.371C>A (p.Pro124Gln; p.P124Q) variant has been observed in somatic cancer knowledgebases and is absent from ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at Supporting strength under the Brain Malformations VCEP specification.² Available reviewed functional evidence did not provide directly confirmed assay-level results for p.Pro124Gln that met VCEP requirements for applying either PS3 or BS3 in this pass.³ Computational data show REVEL 0.237, BayesDel 0.018, and SpliceAI max delta 0.05; however, PP3 is not applicable and BP4 is restricted to synonymous, intronic, or UTR splicing contexts in this VCEP.⁴

PM2 → VUS

1 oncokb ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 oncokb ↗PMID:22430209 ↗cspec ↗

4 revelbayesdelspliceai ↗cspec ↗

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_006218.4 · variants mapped to exon structure

PIK3CA NM_006218.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 13 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 · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Under the Brain Malformations VCEP specification, absence or rarity in population controls supports PM2 at Supporting strength.

gnomAD v2.1 absentgnomAD v4.1 absent

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

Assessed · not applied · 5 not met · 8 not assessed

Pathogenic

PS1 No previously established pathogenic variant causing the same amino acid change was identified in the reviewed sources, and no expert-panel same-amino-acid comparator was available for confirmation.

PS2 No case report or database entry was identified with confirmed parental testing and tissue distribution data for this exact variant, so the VCEP de novo or mosaic requirements for PS2 could not be confirmed.

PS3 Curated oncology resources identified functional literature relevant to this variant, but the reviewed materials did not provide directly extractable assay-level results for p.Pro124Gln that could be confirmed against the Brain Malformations VCEP functional requirements, so PS3 was not applied in this pass.

PS4 This variant meets PM2 because it is absent from gnomAD v2.1 and v4.1, but no phenotype-based affected-case point total was identified for this exact variant under the Brain Malformations VCEP scoring framework.

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

PM5 The governing framework uses classic same-residue missense PM5 logic, but no confirmed pathogenic or likely pathogenic same-residue comparator variant was identified in the reviewed materials for codon 124, so PM5 could not be established in this pass.

PP2 The Brain Malformations VCEP allows PP2 for PIK3CA when the gene-level missense constraint z-score is greater than 3.09, but the reviewed case materials did not provide the gene constraint value needed to confirm this criterion in this pass.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%, so BA1 is not met.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%, so BS1 is not met.

BS2 No homozygous occurrences in gnomAD and no series of at least three well-phenotyped unaffected carriers were identified, so the Brain Malformations VCEP requirements for BS2 were not met.

BS3 No well-established functional study showing normal or non-damaging effect for p.Pro124Gln was directly confirmed in the reviewed materials, so BS3 was not applied in this pass.

BP2 No data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 could not be assessed.

BP5 No independent molecular diagnosis or alternate cause of disease was identified that would justify BP5 for this variant.

N/A · 14 PVS1 · PM3 · PM4 · PM6 · PP1 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3 · 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.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.237. BayesDel score = 0.018.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

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; COSV55927445, n = 3 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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