Variant classification summary

NM_006218.2:c.1624G>A

PIK3CA · NP_006209.2:p.(Glu542Lys) · NM_006218.2

GRCh37: chr3:178936082 G>A · GRCh38: chr3:179218294 G>A

Gene: PIK3CA Transcript: NM_006218.2

Final call

VUS

PP5 supporting PM5 moderate PM2 supporting PS3 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.2

Protein

NP_006209.2:p.(Glu542Lys)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PIK3CA c.1624G>A (p.Glu542Lys) variant has been observed in somatic cancers in COSMIC (COSV55873227, n=1958) and has been reported in ClinVar with an expert panel pathogenic classification for brain malformation-related disease.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population reference datasets.

3

In published functional studies, PIK3CA E542K increased oncogenic activity, activated downstream AKT/TOR signaling, and promoted in vivo tumor formation relative to wild type, consistent with a gain-of-function effect.

4

Computational data show no predicted splice effect by SpliceAI (max delta score 0.00), with REVEL 0.439 and BayesDel 0.232897; under this gain-of-function VCEP these in silico results were not used to apply PP3.

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 met	No previously established pathogenic variant producing the same p.(Glu542Lys) amino acid change by a different nucleotide change was identified in the reviewed ClinVar evidence, so PS1 is not met.	clinvar
BS4	N/A	BS4 is not applicable under the Brain Malformations VCEP because these disorders are typically caused by de novo, germline mosaic, or post-zygotic variants rather than informative multigenerational segregation patterns.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS2	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, and no evidence identified at least 3 homozygotes in population databases or at least 3 well-phenotyped unaffected heterozygous relatives required for BS2.	gnomad_v2 gnomad_v4 cspec
PS2	Not assessed	Available evidence does not document confirmed maternity and paternity with absence of the variant in parents, and it does not provide a verified comparison showing the variant present in affected tissue and absent from or at lower allele fraction in another tissue. PS2 cannot be applied from the reviewed evidence.	cspec clinvar
PP4	N/A	PP4 is not applicable under the Brain Malformations VCEP because phenotype specificity is incorporated into the PS4 point-based framework.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3	N/A	PP3 is not applicable under the Brain Malformations VCEP for PIK3CA gain-of-function disorders because conventional missense pathogenicity algorithms are not considered reliable for this mechanism. REVEL was 0.439, BayesDel was 0.232897, and SpliceAI max delta score was 0.00, but these results were not used to apply PP3.	cspec revel bayesdel spliceai
PM1	Not met	The Brain Malformations VCEP limits PM1 for PIK3CA to Table 4 approved domains at amino acids 322-483 and 797-1068. This missense variant affects residue 542, which is outside those approved intervals, so PM1 is not met.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS4	Not assessed	This variant has been reported in affected individuals and is classified as pathogenic in ClinVar by the Brain Malformations expert panel, and it is absent from gnomAD, which supports the PM2 prerequisite. However, the reviewed evidence does not provide a direct Table 2A phenotype-point tally needed to assign a PS4 strength under the Brain Malformations VCEP, so PS4 was not independently applied in this pass.	clinvar gnomad_v2 gnomad_v4 cspec
PVS1	N/A	PVS1 is not applicable for PIK3CA in the Brain Malformations VCEP because the disease mechanism is gain of function rather than loss 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
PP5	Met	Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Pathogenic.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 clinvar
BP7	N/A	BP7 is restricted to synonymous, intronic, or non-coding variants with no predicted splice effect and does not apply to this missense variant.	cspec spliceai
BP5	Not met	No alternate molecular basis for the reported phenotype was identified in the reviewed evidence, so BP5 is not met.	clinvar
BP4	N/A	BP4 is limited by this VCEP to synonymous, intronic, and non-coding variants assessed with splicing predictors and is not applicable to this missense variant, even though SpliceAI predicts no splice effect.	cspec spliceai
BP3	N/A	BP3 is not applicable under the Brain Malformations VCEP for these genes because the relevant exon regions are not repetitive regions without known function.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	No phase data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 cannot be assessed from the reviewed evidence.	cspec clinvar
BP1	N/A	BP1 is not applicable for PIK3CA in this VCEP because disease is not primarily caused by truncating loss-of-function variants.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS3	Not met	Available functional evidence does not show a normal or no-damaging effect. In published functional studies, PIK3CA E542K increased oncogenic activity, activated downstream AKT/TOR signaling, and showed gain-of-function behavior relative to wild type, which argues against BS3.	PMID:16432179 PMID:17376864 PMID:26627007
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%.	gnomad_v2 gnomad_v4 cspec
PP2	Not assessed	This is a missense variant in a gene for which the VCEP allows PP2 when the missense constraint z-score is greater than 3.09, but the reviewed evidence did not provide the gene-level z-score needed to apply PP2 in this pass.	cspec
PP1	N/A	PP1 is not applicable under the Brain Malformations VCEP because disease-causing variants are typically mosaic or de novo rather than supported by informative familial segregation.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM5	Met	Other missense changes affecting the same residue have been reported in ClinVar as pathogenic or likely pathogenic, including p.(Glu542Gln), p.(Glu542Ala), and p.(Glu542Gly). This supports PM5 for a missense change at residue 542.	clinvar
PM4	N/A	PM4 is not applicable under the Brain Malformations VCEP because this variant is not an in-frame insertion/deletion or stop-loss variant.	cspec
PM3	N/A	PM3 is not applicable because PIK3CA-related brain malformation disorders are not evaluated as recessive conditions in this VCEP framework.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the Brain Malformations VCEP requirement for PM2 and supports PM2 at Supporting strength.	gnomad_v2 gnomad_v4 cspec
PS3	Met	In published functional studies, PIK3CA E542K showed gain-of-function behavior relative to wild type, including in vivo tumor formation with increased AKT pathway activation and constitutive activation of AKT/TOR signaling with transforming activity. This supports an abnormal activating effect consistent with the known disease mechanism and meets PS3 at Supporting strength in this pass.	PMID:16432179 PMID:17376864 PMID:26627007 cspec
BP6	N/A	BP6 is not used under current ClinGen recommendations and is marked not applicable by the Brain Malformations VCEP.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%.	gnomad_v2 gnomad_v4 cspec
PM6	N/A	PM6 is not applicable in this VCEP because de novo and mosaic evidence is handled through the PS2 framework instead.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1

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