NM_006218.2:c.2740G>A

PIK3CA · NP_006209.2:p.(Gly914Arg) · NM_006218.2

GRCh37: chr3:178947865 G>A · GRCh38: chr3:179230077 G>A

Gene: PIK3CA Transcript: NM_006218.2

Final call

VUS

PS2 moderate PM1 supporting PP5 supporting PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.2

Protein

NP_006209.2:p.(Gly914Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The PIK3CA c.2740G>A (p.Gly914Arg) variant has been observed in somatic cancers in COSMIC (9 occurrences) and has been reported in ClinVar with an expert panel pathogenic classification.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls and meeting the Brain Malformations VCEP PM2_Supporting requirement.

In a published functional study of megalencephaly-associated PI3K-pathway variants, mutant lymphoblastoid cell lines showed increased PIP3 and increased downstream S6 and 4E-BP1 phosphorylation, consistent with gain-of-function pathway activation, although an exact p.Gly914Arg-specific validated assay was not identified.

REVEL was 0.871, BayesDel was 0.382681, and SpliceAI predicted no significant splice impact with a maximum delta score of 0.13; however, this VCEP does not apply PP3 to gain-of-function missense variants.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 5, 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 assessed	No previously established pathogenic alternate nucleotide change producing the same p.Gly914Arg amino acid substitution was identified in the reviewed evidence, so PS1 was not assessed.	clinvar
BS4	N/A	BS4 is not applicable in this VCEP because these disorders are typically de novo, germline mosaic, or post-zygotic.	cspec
BS2	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the VCEP BS2 threshold of at least 3 homozygotes in population data, and no well-phenotyped unaffected family carriers were identified.	gnomad_v2 gnomad_v4 cspec
PS2	Met	This variant was reported as de novo in multiple affected individuals with MCAP, including parent-proband trio analysis in the original megalencephaly cohort, which supports PS2_Moderate. The stronger PS2 level was not applied because affected-tissue versus other-tissue allele-fraction data required for PS2_Strong were not established in the reviewed evidence.	PMID:22729224 cspec
PP4	N/A	PP4 is not applicable in this VCEP because phenotype specificity is incorporated into PS4.	cspec
PP3	N/A	PP3 is not applicable in this VCEP for gain-of-function disorders. REVEL was 0.871, BayesDel was 0.382681, and SpliceAI predicted no significant splice effect with a maximum delta score of 0.13, but these scores are not used for PP3 under this gene-specific framework.	cspec revel bayesdel spliceai
PM1	Met	Residue Gly914 lies within the PIK3CA kinase-domain interval 797-1068 listed in Table 4 of the Brain Malformations VCEP specification, so PM1 is met at Supporting strength under the gene-specific domain rule.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS4	Not assessed	This variant was reported in at least five affected individuals with MCAP and is absent from gnomAD v2.1 and v4.1, so case enrichment evidence is present. However, the exact Table 2A phenotype point total needed to assign a PS4 strength under this VCEP was not directly recoverable from the reviewed materials, so PS4 was left for manual point-based adjudication.	PMID:22729224 gnomad_v2 gnomad_v4 cspec
PVS1	N/A	PVS1 is not applicable in this VCEP because the disease mechanism for PIK3CA-related brain malformations is gain of function, and this missense variant is not a null variant category in the generic PVS1 framework.	cspec pvs1_variant_assessment
PP5	Met	Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BP7	N/A	BP7 is not applicable because this is a missense variant rather than a synonymous, intronic, or UTR variant.	cspec
BP5	Not assessed	No alternate molecular diagnosis explaining the phenotype was identified in the reviewed evidence, so BP5 was not assessed.	cspec
BP4	N/A	BP4 is not applicable in this VCEP for missense variants. SpliceAI predicted no significant splice effect with a maximum delta score of 0.13, but the VCEP limits BP4 to synonymous, intronic, and certain non-coding variants.	cspec spliceai
BP3	N/A	BP3 is not applicable in this VCEP.	cspec
BP2	Not assessed	No cis or trans observation with another established pathogenic PIK3CA variant was identified, so BP2 was not assessed.	cspec
BP1	N/A	BP1 is not applicable in this VCEP because the disease mechanism is gain of function rather than truncating loss of function.	cspec
BS3	Not met	No well-established study showed normal function for p.Gly914Arg. Available published pathway assays instead showed increased PI3K-pathway signaling in megalencephaly-associated PIK3CA or PIK3R2 mutant cell lines, which does not support BS3.	PMID:22729224 cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0%, which is below the VCEP BA1 threshold of greater than 0.0926%.	gnomad_v2 gnomad_v4 cspec
PP2	Not assessed	This VCEP allows PP2 for PIK3CA missense variants when the missense constraint z-score is greater than 3.09, but that gene-level constraint value was not provided in the reviewed materials.	cspec
PP1	N/A	PP1 is not applicable in this VCEP.	cspec
PM5	Not assessed	No different established pathogenic missense change at codon Gly914 was identified in the reviewed evidence, so PM5 was not assessed.	clinvar
PM4	N/A	PM4 is not applicable in this VCEP.	cspec
PM3	N/A	PM3 is not applicable in this VCEP.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the VCEP population threshold and supports PM2 at Supporting strength.	gnomad_v2 gnomad_v4 cspec
PS3	Not assessed	Published cell-based studies showed increased PI3K-pathway signaling in megalencephaly-associated mutant lines, but an exact p.Gly914Arg-specific validated functional assay meeting the VCEP PS3 requirements was not identified. In addition, the VCEP states that patient-derived cells alone are insufficient for strong PS3 evidence.	PMID:22729224 cspec
BP6	N/A	BP6 is not applicable in this VCEP.	cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0%, which is below the VCEP BS1 threshold of greater than 0.0185%.	gnomad_v2 gnomad_v4 cspec
PM6	N/A	PM6 is not applicable in this VCEP.	cspec

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