NM_006218.2:c.3140A>G

PIK3CA · NP_006209.2:p.(His1047Arg) · NM_006218.2

GRCh37: chr3:178952085 A>G · GRCh38: chr3:179234297 A>G

Gene: PIK3CA Transcript: NM_006218.2

Final call

Likely Pathogenic

PS3 strong PM1 supporting PM2 supporting PP5 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.2

Protein

NP_006209.2:p.(His1047Arg)

gnomAD AF

ClinVar

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The PIK3CA c.3140A>G (p.His1047Arg) variant has been observed in somatic cancers and is reported in ClinVar, including a Pathogenic expert-panel classification by the ClinGen Brain Malformations Variant Curation Expert Panel.

This variant is absent from gnomAD v4.1 and is present once in gnomAD v2.1 (1/248274 alleles; AF 0.00040%), which is below the VCEP PM2 range and well below the BS1 (>0.0185%) and BA1 (>0.0926%) population thresholds.

Published functional studies showed increased PI3K activity, growth factor-independent and anchorage-independent proliferation, Akt-pathway activation, and tumor formation relative to wild type, consistent with a gain-of-function effect.

SpliceAI predicts no significant splice impact (max delta score 0.04), and REVEL and BayesDel scores are 0.455 and 0.247638, respectively; however, this VCEP does not use PP3 or BP4 for PIK3CA gain-of-function missense variants.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 7, which maps to Likely Pathogenic 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
PVS1	N/A	PVS1 is not applicable for this missense variant because the Brain Malformations VCEP specifies that PIK3CA-related disease is driven by gain of function rather than loss of function, and this variant is not a null-variant type in the generic PVS1 framework.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No independently verified evidence was identified in the available sources showing a different nucleotide change that produces the same p.His1047Arg amino acid substitution and is already established as pathogenic under this framework.	cspec clinvar
PS2	Not assessed	No case-level evidence was identified showing confirmed maternity and paternity with absence of the variant in both parents, or tissue-comparison data demonstrating a higher allele fraction in affected tissue than in another tissue, so PS2 cannot be applied from the available evidence.	cspec
PS3	Met	Multiple published functional studies showed that p.His1047Arg increases PI3K pathway activity and produces abnormal gain-of-function behavior relative to wild type. Cell-based assays showed higher PI3K activity, growth factor-independent proliferation, anchorage-independent growth, and resistance to anoikis, and in vivo models showed Akt-pathway activation and tumor formation, supporting an abnormal activating effect.	PMID:16322248 PMID:16432179 PMID:17376864 PMID:20593314 PMID:22370636 cspec
PS4	Not assessed	This variant has been reported in affected individuals and in somatic cancers, but the available materials do not provide a verified Brain Malformations VCEP Table 2A phenotype-point tally for independent cases of this exact variant. Because PS4 in this framework is point based and requires PM2 first plus case-level point assignment, PS4 cannot be fully adjudicated from the available evidence alone.	cspec clinvar
PM1	Met	This missense variant affects residue 1047, which lies within the PIK3CA kinase-domain interval 797-1068 listed by the Brain Malformations VCEP as an approved PM1 domain. Under this framework, domain membership is sufficient for PM1_Supporting and does not require separate hotspot recurrence evidence.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Met	This variant is absent from gnomAD v4.1 and is present once in gnomAD v2.1 at 1/248274 alleles (AF 0.00040%), with no homozygotes. This meets the VCEP PM2 requirement for absent or very rare population occurrence, which is limited to Supporting strength for this gene group.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in this VCEP framework for PIK3CA-related gain-of-function disease.	cspec
PM4	N/A	PM4 is not applicable in this VCEP framework, and this variant is a missense substitution rather than a protein length-changing variant.	cspec
PM5	Not assessed	No independently verified evidence was identified in the available sources showing a different pathogenic missense change at the same residue that can be counted under PM5 for this framework.	cspec clinvar
PM6	N/A	PM6 is not applicable in this VCEP framework for PIK3CA-related disease.	cspec
PP1	N/A	PP1 is not applicable in this VCEP framework because these disorders are typically de novo, germline mosaic, or post-zygotic rather than segregation-based Mendelian presentations suitable for PP1 scoring.	cspec
PP2	Not assessed	The VCEP allows PP2 for PIK3CA if the missense constraint z-score is greater than 3.09, but no verified z-score value was provided in the available evidence files, so PP2 cannot be applied from the current record.	cspec
PP3	N/A	PP3 is not applicable for this PIK3CA gain-of-function missense variant under the Brain Malformations VCEP. Computational results were reviewed: SpliceAI max delta score was 0.04, REVEL was 0.455, and BayesDel was 0.247638, but this framework does not use PP3 for PIK3CA gain-of-function missense interpretation.	cspec spliceai revel bayesdel
PP4	N/A	PP4 is not applicable in this VCEP because phenotype specificity is incorporated into PS4 rather than scored separately.	cspec
PP5	Met	Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	Population frequency does not meet the BA1 threshold. The variant is absent from gnomAD v4.1 and is present once in gnomAD v2.1 at 0.00040%, which is far below the VCEP BA1 threshold of greater than 0.0926%.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Population frequency does not meet the BS1 threshold. The variant is absent from gnomAD v4.1 and is present once in gnomAD v2.1 at 0.00040%, which is far below the VCEP BS1 threshold of greater than 0.0185%.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	BS2 is not met because no homozygotes were observed in gnomAD, and no evidence was identified for at least 3 heterozygous occurrences in well-phenotyped unaffected family members. The available population data show 0 homozygotes.	gnomad_v2 gnomad_v4 cspec
BS3	Not met	Available functional evidence does not support a normal or benign effect. Instead, published studies showed increased PI3K signaling, transformation-associated phenotypes, and oncogenic activity, which argues against BS3.	PMID:16322248 PMID:16432179 PMID:17376864 PMID:20593314 cspec
BS4	N/A	BS4 is not applicable in this VCEP framework.	cspec
BP1	N/A	BP1 is not applicable for PIK3CA in this VCEP because the disease mechanism is gain of function rather than a context in which truncating variants would predominate over missense variants.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	No evidence was identified showing this variant in cis or in trans with another established pathogenic PIK3CA variant, so BP2 cannot be assessed from the available data.	cspec
BP3	N/A	BP3 is not applicable in this VCEP framework.	cspec
BP4	N/A	BP4 is not applicable for this missense variant under the Brain Malformations VCEP because BP4 is restricted to synonymous, intronic, or UTR variants with no predicted splice effect. SpliceAI showed a max delta score of 0.04, but this does not make BP4 applicable to a missense variant in this framework.	cspec spliceai
BP5	Not assessed	No alternate molecular diagnosis or other established explanation for the phenotype was identified in the available evidence, so BP5 cannot be applied.	cspec
BP6	N/A	BP6 is not applicable in this VCEP framework.	cspec
BP7	N/A	BP7 is not applicable because this is a missense variant rather than a synonymous, intronic, or UTR change.	cspec

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