Variant classification summary

NM_006218.4:c.1132T>C

PIK3CA · NP_006209.2:p.(Cys378Arg) · NM_006218.4

GRCh37: chr3:178922363 T>C · GRCh38: chr3:179204575 T>C

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM1 supporting PM2 supporting PM5 moderate

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Cys378Arg)

gnomAD AF

0.0 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PIK3CA c.1132T>C (p.Cys378Arg) variant has been reported in ClinVar with an overall Pathogenic classification, and curated somatic oncology resources also list this variant in cancer-associated context.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, including 0/1519490 alleles and 0 homozygotes in gnomAD v4.1, which supports rarity in population controls.

3

Curated functional literature links and a published PIK3CA study support a gain-of-function disease mechanism for mutant PIK3CA, but variant-specific assay evidence meeting Brain Malformations VCEP PS3 requirements was not established for p.Cys378Arg.

4

The variant lies in a Brain Malformations VCEP-approved PIK3CA functional domain, a different missense change at the same residue has been reported as pathogenic, and SpliceAI predicts no splice effect; REVEL and BayesDel scores are also elevated, although PP3 is not applied by this VCEP for gain-of-function missense variants.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 4, 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
PS1	Not met	No alternate nucleotide change producing the same p.Cys378Arg amino acid substitution was identified in the reviewed ClinVar evidence, and SpliceAI predicts no splice effect that would complicate a protein-based comparison.	clinvar spliceai cspec
PS2	Not assessed	No confirmed de novo or tissue-comparison data were identified to show this variant was absent from parental samples and enriched in affected tissue, so PS2 cannot be applied from the reviewed evidence.	cspec clinvar PMID:31585106 PMID:33105631
PS3	Not assessed	Curated literature links and a published PIK3CA functional study support a gain-of-function disease mechanism for PIK3CA variants, but variant-specific assay details meeting the Brain Malformations VCEP validation requirements were not established for p.Cys378Arg from the reviewed evidence.	oncokb PMID:17363507 cspec
PS4	Not assessed	This variant is rare enough to satisfy the PM2 prerequisite, but the reviewed evidence did not provide a consolidated phenotype-based point total under the Brain Malformations VCEP PS4 scoring system, so PS4 was not applied.	cspec clinvar gnomad_v2 gnomad_v4 PMID:31585106 PMID:33105631
PM1	Met	Residue Cys378 lies within the PIK3CA amino acid 322-483 interval listed by the Brain Malformations VCEP as an approved critical functional domain for PM1_Supporting, so PM1 is met at supporting strength.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0/1519490 alleles and 0 homozygotes in gnomAD v4.1; this is below the VCEP PM2 requirement for absent or rare variation in controls and supports PM2 at supporting strength.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in this Brain Malformations VCEP framework because PIK3CA-related disease is not interpreted as a recessive condition requiring trans observations.	cspec
PM4	N/A	PM4 is not applicable in this Brain Malformations VCEP framework, and this variant is a missense substitution rather than a protein length-changing variant.	cspec
PM5	Met	A different missense change at the same residue, PIK3CA p.Cys378Tyr, is reported in ClinVar as Pathogenic with multiple submitters and no conflicts. Because this variant is also a missense change at codon 378 and SpliceAI predicts no splice impact (max delta score 0.00), classic same-residue PM5 is supported at moderate strength.	clinvar spliceai cspec
PM6	N/A	PM6 is not used in this Brain Malformations VCEP framework because de novo evidence is handled under PS2.	cspec
PP1	N/A	PP1 is not applicable in this Brain Malformations VCEP framework because PIK3CA-related cases are typically mosaic or de novo rather than interpreted through classic familial segregation.	cspec
PP2	Not assessed	The Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the gene-specific missense constraint threshold is exceeded, but a registered case-source record documenting that threshold assessment for this case was not included in the reviewed evidence, so PP2 was left unscored.	cspec
PP3	N/A	PP3 is not applicable in this Brain Malformations VCEP framework for PIK3CA gain-of-function missense variants. REVEL (0.817), BayesDel (0.273988), and SpliceAI (max delta score 0.00) were reviewed but were not used to score PP3 under this rule.	cspec revel bayesdel spliceai
PP4	N/A	PP4 is not applicable in this Brain Malformations VCEP framework because phenotype specificity is incorporated into the PS4 point-based system instead.	cspec
PP5	N/A	PP5 is not used in this Brain Malformations VCEP framework.	cspec
BA1	Not met	This variant does not meet BA1 because it is absent from gnomAD, with 0/1519490 alleles in gnomAD v4.1, which is below the VCEP BA1 threshold of greater than 0.0926%.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant does not meet BS1 because it is absent from gnomAD, with 0/1519490 alleles in gnomAD v4.1, which is below the VCEP BS1 threshold of greater than 0.0185%.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	This variant does not meet BS2 because no homozygotes were observed in gnomAD v4.1, whereas the Brain Malformations VCEP requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected family observations.	gnomad_v4 cspec
BS3	Not assessed	No well-established study demonstrating normal or non-damaging function for p.Cys378Arg was identified, so BS3 was not applied.	oncokb PMID:17363507 cspec
BS4	N/A	BS4 is not applicable in this Brain Malformations VCEP framework.	cspec
BP1	N/A	BP1 is not applicable in this Brain Malformations VCEP framework because PIK3CA-related disease is mediated by gain of function rather than a predominantly truncating loss-of-function mechanism.	cspec
BP2	Not assessed	No phase information was identified showing this variant in cis or trans with another known pathogenic PIK3CA variant, so BP2 was not applied.	cspec clinvar
BP3	N/A	BP3 is not applicable in this Brain Malformations VCEP framework, and this variant is not an in-frame insertion or deletion in a repetitive region.	cspec
BP4	N/A	BP4 is not applicable because this is a missense variant, and the Brain Malformations VCEP restricts BP4 to synonymous, intronic, or UTR variants evaluated for lack of splice impact.	cspec spliceai
BP5	Not assessed	No alternate molecular diagnosis was identified that would explain the phenotype independently of this variant, so BP5 was not applied.	cspec clinvar
BP6	N/A	BP6 is not used in this Brain Malformations VCEP framework.	cspec
BP7	N/A	BP7 is not applicable because this is a missense variant rather than a synonymous or intronic change.	cspec
PVS1	N/A	PVS1 is not applicable in the Brain Malformations VCEP framework for PIK3CA because the disease mechanism is gain of function, and this variant is a missense substitution rather than a null variant.	cspec pvs1_gene_context pvs1_variant_assessment

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