Variant classification summary

NM_006218.2:c.2176G>A

PIK3CA · NP_006209.2:p.(Glu726Lys) · NM_006218.2

GRCh37: chr3:178938934 G>A · GRCh38: chr3:179221146 G>A

Gene: PIK3CA Transcript: NM_006218.2

Final call

VUS

PM2 supporting PP5 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.2

Protein

NP_006209.2:p.(Glu726Lys)

gnomAD AF

ClinVar

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PIK3CA c.2176G>A (p.Glu726Lys, p.E726K) variant has been observed in somatic cancers in COSMIC (COSV55875460, n=150) and has been reported in ClinVar as Pathogenic, including expert-panel review by the ClinGen Brain Malformations Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at Supporting strength under the Brain Malformations VCEP population rule.

3

Published PIK3CA disease-mechanism and functional literature was identified, but the retrieved materials do not provide enough variant-specific assay detail to assign PS3 or BS3 for p.Glu726Lys without direct full-text review.

4

In silico data show no predicted splice disruption by SpliceAI (max delta score 0.02), with REVEL 0.442 and BayesDel 0.266518; however, PP3 is not applicable for PIK3CA gain-of-function variants in this VCEP framework and BP4 is restricted to non-missense splicing-context variants.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 2, 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 evidence was identified showing that this missense change creates the same amino acid substitution as a previously established pathogenic variant through a different nucleotide change.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS2	Not assessed	Published PIK3CA overgrowth literature supports that de novo and postzygotic mutations occur in this disease spectrum, but the retrieved materials do not provide case-level parental testing and multi-tissue allele-fraction data for p.Glu726Lys needed to assign PS2 under the Brain Malformations VCEP rules.	PMID:24497998 PMID:22729224 cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3	Not assessed	Functional literature relevant to PIK3CA was identified, but the retrieved materials do not provide assay-level results, validation details, or VCEP-compatible evidence strength for p.Glu726Lys, so PS3 cannot be assigned from the available record.	PMID:29533785 PMID:22729224 oncokb cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS4	Not assessed	This variant has been reported in affected individuals and is absent from population databases, but the retrieved materials do not provide the case-level phenotype categories and point totals required to score PS4 under the Brain Malformations VCEP point system.	clinvar PMID:22729224 PMID:24497998 cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
PM1	Not met	The p.Glu726Lys substitution is outside the PIK3CA Table 4 approved PM1 functional-domain intervals (amino acids 322-483 and 797-1068), so PM1_Supporting is not met under the Brain Malformations VCEP specification.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the Brain Malformations VCEP PM2 threshold of at most one person in population databases and supports PM2 at Supporting strength.	gnomad_v2 gnomad_v4 cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM5	Not assessed	No validated evidence was identified in the retrieved materials showing a different pathogenic missense change at the same codon that would support PM5 for p.Glu726Lys.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2	Not assessed	The Brain Malformations VCEP allows PP2 for PIK3CA when the missense constraint z-score exceeds 3.09, but the retrieved materials do not provide the gene-level z-score needed to determine whether this threshold is met.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1	Not met	This variant is absent from gnomAD and therefore far below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%, so BA1 is not met.	gnomad_v2 gnomad_v4 cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS1	Not met	This variant is absent from gnomAD and therefore below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%, so BS1 is not met.	gnomad_v2 gnomad_v4 cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS2	Not met	No evidence was identified for at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected family members carrying this variant, so BS2 is not met.	gnomad_v2 gnomad_v4 cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS3	Not met	No well-established functional study in the retrieved materials showed normal or benign function for p.Glu726Lys, so BS3 is not met.	PMID:29533785 PMID:22729224 oncokb cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	No evidence was identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 cannot be assessed from the available materials.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP4	N/A	This is a missense variant. Under the Brain Malformations VCEP specification, BP4 is limited to synonymous, intronic noncanonical splice-site, and UTR variants evaluated for predicted lack of splicing impact.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 spliceai
BP5	Not assessed	No alternate molecular diagnosis was identified that would explain the phenotype independently of this variant, so BP5 cannot be assigned from the available materials.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7	N/A	This is a missense variant rather than a synonymous, intronic, or UTR variant, so BP7 is not applicable under the Brain Malformations VCEP specification.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PVS1	N/A	PVS1 is not applicable for PIK3CA in the Brain Malformations VCEP framework because the disease mechanism is gain of function, and this missense variant is not a null-variant type.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 pvs1_variant_assessment
PP1	N/A	PP1 is not applicable in the Brain Malformations VCEP specification for this gene-disease context.	cspec
PP3	N/A	PP3 is not applicable for PIK3CA gain-of-function missense variants in the Brain Malformations VCEP framework. Although SpliceAI predicts no significant splice impact (max delta score 0.02), REVEL is 0.442, and BayesDel is 0.266518, the VCEP does not use traditional pathogenicity prediction algorithms for this gain-of-function mechanism.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 spliceai revel bayesdel
PP4	N/A	PP4 is not applicable in the Brain Malformations VCEP specification because phenotype specificity is incorporated into the PS4 point-based framework.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5	Met	Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Pathogenic.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 clinvar
BP1	N/A	BP1 is not applicable for PIK3CA in this gain-of-function disease context.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3	N/A	BP3 is not applicable in the Brain Malformations VCEP specification for this gene-disease context.	cspec
BP6	N/A	BP6 is not applicable in the Brain Malformations VCEP specification.	cspec
BS4	N/A	BS4 is not applicable in this VCEP framework because these disorders are typically driven by de novo, germline mosaic, or postzygotic mutations rather than informative multigenerational segregation patterns.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM3	N/A	PM3 is not applicable in the Brain Malformations VCEP specification for this gene-disease context.	cspec
PM4	N/A	PM4 is not applicable in the Brain Malformations VCEP specification for this gene-disease context.	cspec
PM6	N/A	PM6 is not applicable in the Brain Malformations VCEP specification.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.