PIK3CA c.371C>A, p.(Pro124Gln)

Rule

Brain Malformations VCEP: PM2_Supporting for absent or rare population frequency.

Evidence considered

• gnomAD v2.1 absent
• gnomAD v4.1 absent

Sources

Rule

Brain Malformations VCEP: PS4 requires PM2 first and then phenotype points reaching Supporting, Moderate, Strong, or Very Strong thresholds.

Evidence considered

• Absent from gnomAD v2.1
• Absent from gnomAD v4.1
• somatic cancer knowledgebase observation without VCEP phenotype-point evidence

Still missing

• No overgrowth or brain-malformation case series with VCEP phenotype points were identified for this exact variant.

Sources

Rule

Brain Malformations VCEP: PM1_Supporting for variants in approved Table 4 domains.

Evidence considered

• Approved PM1 domains for PIK3CA are aa 322-483 and aa 797-1068
• variant affects residue 124
• Cancer Hotspots review did not identify a significant hotspot row for residue 124

Sources

Rule

Brain Malformations VCEP: BA1 if allele frequency >0.0926%.

Evidence considered

• Absent from gnomAD v2.1
• Absent from gnomAD v4.1
• BA1 threshold >0.0926%

Sources

Rule

Brain Malformations VCEP: BS1 if allele frequency >0.0185%.

Evidence considered

• Absent from gnomAD v2.1
• Absent from gnomAD v4.1
• BS1 threshold >0.0185%

Sources

Rule

Brain Malformations VCEP: BS2 if at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected heterozygotes are present.

Evidence considered

• Variant absent from gnomAD
• no unaffected family-carrier evidence identified

Still missing

• No unaffected-carrier dataset was identified for this exact variant.

Sources

Rule

PS1 applies when the same amino acid change is already established as pathogenic.

Evidence considered

• ClinVar query returned no result for this variant
• no reviewed comparator source established PS1 eligibility

Still missing

• A validated same-amino-acid pathogenic comparator was not identified in the reviewed sources.

Sources

Rule

Brain Malformations VCEP: PS2_Strong requires both absent-from-parents and tissue-distribution evidence; PS2_Moderate requires one of these specified evidence patterns.

Evidence considered

• VCEP requires parental and/or tissue mosaic evidence for PS2
• ClinVar query returned no result for this variant

Still missing

• No confirmed maternity/paternity data were identified for this exact variant.
• No affected-tissue versus other-tissue allele fraction data were identified for this exact variant.

Sources

Rule

Brain Malformations VCEP: apply PS3 only with acceptable functional assays meeting SVI/VCEP quality requirements.

Evidence considered

• OncoKB flagged variant-specific curated literature
• PMID:22430209 was reviewed at abstract level only in available materials
• VCEP requires established functional assay standards

Still missing

• Direct assay readouts for p.Pro124Gln were not extracted from the cited study in the reviewed materials.
• Assay validation details required for VCEP PS3 strength assignment were not available in the reviewed materials.

Sources

Rule

PM5 applies to a novel missense change at a residue where a different pathogenic missense change has been established.

Evidence considered

• Framework uses classic same-residue missense PM5 logic
• reviewed candidate artifact did not provide usable confirmed comparators

Still missing

• No expert-panel or otherwise established pathogenic same-residue comparator was identified for codon 124 in the reviewed materials.

Sources

Rule

Brain Malformations VCEP: PP2_Supporting if missense constraint z-score > 3.09 for PIK3CA.

Evidence considered

• VCEP-specific PP2 rule requires z-score > 3.09
• required constraint value not present in reviewed materials

Still missing

• Gene-level missense constraint z-score was not provided in the reviewed materials.

Sources

Rule

Brain Malformations VCEP: apply BS3 only with acceptable functional assays supporting no damaging effect.

Evidence considered

• Curated literature was identified for functional review
• no directly confirmed benign functional readout was available in reviewed materials

Still missing

• Direct assay-level evidence showing normal or non-damaging function for p.Pro124Gln was not extracted from the cited literature.

Sources

Rule

Brain Malformations VCEP: BP2 for observation in cis or trans with a known pathogenic variant in the same gene.

Evidence considered

• No cis/trans comparator data identified

Still missing

• No phase data with another pathogenic PIK3CA variant were identified.

Sources

Rule

BP5 applies when a variant is found in a case with an alternate molecular basis for disease.

Evidence considered

• No alternate-cause evidence identified

Still missing

• No alternate molecular diagnosis data were identified.

Sources