Variant classification summary

NM_006218.4:c.371C>A

PIK3CA · NP_006209.2:p.(Pro124Gln) · NM_006218.4

GRCh37: chr3:178917496 C>A · GRCh38: chr3:179199708 C>A

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Pro124Gln)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PIK3CA c.371C>A (p.Pro124Gln; p.P124Q) variant has been observed in somatic cancer knowledgebases and is absent from ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at Supporting strength under the Brain Malformations VCEP specification.

3

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.

4

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.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 1, which maps to VUS under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Although generic PVS1 scaffolding was reviewed, the Brain Malformations VCEP specifies that PVS1 is not applicable for PIK3CA because the relevant disease mechanism is gain of function, and this variant is a missense substitution rather than a null variant.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 pvs1_variant_assessment
PS1	Not assessed	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.	clinvar cspec
PS2	Not assessed	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.	cspec clinvar
PS3	Not assessed	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.	oncokb PMID:22430209 cspec
PS4	Not met	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. Somatic cancer observations alone do not establish the required phenotype-point threshold for PS4.	gnomad_v2 gnomad_v4 oncokb cspec
PM1	Not met	The Brain Malformations VCEP allows PM1 only at Supporting strength for variants within approved PIK3CA domains at amino acids 322-483 or 797-1068. This variant affects residue 124, which is outside those approved domains, and no statistically significant hotspot evidence was identified for this codon in the reviewed materials.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 hotspots
PM2	Met	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 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in this VCEP framework for this disorder context.	cspec
PM4	N/A	PM4 is not applicable in this VCEP framework for this disorder context.	cspec
PM5	Not assessed	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.	cspec pm5_candidates
PM6	N/A	PM6 is not applicable in this VCEP framework for this disorder context.	cspec
PP1	N/A	PP1 is not applicable in this VCEP framework because these disorders are typically caused by de novo, germline mosaic, or post-zygotic variants rather than informative segregation patterns.	cspec
PP2	Not assessed	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.	cspec
PP3	N/A	PP3 is not applicable in the Brain Malformations VCEP framework for this disorder context, so computational pathogenicity scores were not used to assign this criterion.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable in this VCEP framework for this disorder context.	cspec
PP5	N/A	PP5 is not applicable in this VCEP framework.	cspec
BA1	Not met	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.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	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.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	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.	gnomad_v2 gnomad_v4 cspec
BS3	Not assessed	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.	oncokb PMID:22430209 cspec
BS4	N/A	BS4 is not applicable in this VCEP framework because these disorders are typically caused by de novo, germline mosaic, or post-zygotic variants rather than informative lack-of-segregation patterns.	cspec
BP1	N/A	BP1 is not applicable for PIK3CA in this VCEP because the disease mechanism is gain of function rather than a truncating loss-of-function mechanism.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	No data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 could not be assessed.	cspec
BP3	N/A	BP3 is not applicable in this VCEP framework.	cspec
BP4	N/A	BP4 is restricted by this VCEP to synonymous, intronic, or UTR variants evaluated for splicing. This variant is a missense substitution, so BP4 is not applicable, even though SpliceAI predicts no significant splice impact with a max delta score of 0.05.	cspec spliceai
BP5	Not assessed	No independent molecular diagnosis or alternate cause of disease was identified that would justify BP5 for this variant.	cspec
BP6	N/A	BP6 is not applicable in this VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous, intronic non-canonical splice, or non-coding variants with low conservation. This variant is a missense substitution, so BP7 is not applicable.	cspec

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