Variant classification summary

NM_006218.3:c.277C>T

PIK3CA · NP_006209.2:p.(Arg93Trp) · NM_006218.3

GRCh37: chr3:178916890 C>T · GRCh38: chr3:179199102 C>T

Gene: PIK3CA Transcript: NM_006218.3

Final call

VUS

PS3 moderate PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.3

Protein

NP_006209.2:p.(Arg93Trp)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Moderate): two independent cell-based assays showed increased phospho-AKT signaling and lipid kinase activity relative to wild type, indicating an activating effect.

2

PM2 (Supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

3

Overall classification VUS: 1 Moderate + 1 Supporting falls below the ACMG/AMP 2015 threshold for likely pathogenic or likely benign.

Final determination: Generic ACMG/AMP 2015 combination rules require at minimum 1 PS + 1 PM (or equivalent) for Likely Pathogenic; 1 Moderate + 1 Supporting alone does not meet any pathogenic, likely pathogenic, benign, or likely benign combination, so the variant is Uncertain Significance.

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	Not applicable: this is a missense substitution, so no null-variant mechanism such as nonsense-mediated decay or truncation applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no alternate nucleotide change producing the same p.Arg93Trp amino acid change with a prior pathogenic classification was identified.
PS2	Not assessed	Not assessed: no parental sequencing, allele-fraction, or tissue data were available to confirm a de novo origin.	cspec clinvar
PS3	Met	Met (Moderate): two independent cell-based assays showed increased phospho-AKT signaling and lipid kinase activity relative to wild type, indicating an activating effect.	PMID:21266528 PMID:22949682 cspec
PS4	Not assessed	Not assessed: no cerebral-malformation case-series or enrichment data were available; somatic cancer occurrence is not phenotype-specific evidence in this context.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM1	Not met	Not met: residue Arg93 lies outside the VCEP-approved critical kinase domains (amino acids 322-483 and 797-1068).	cspec
PM2	Met	Met (Supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population cohorts.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: disease-causing variants are heterozygous, whereas PM3 requires a pathogenic variant in trans.	cspec
PM4	N/A	Not applicable: missense substitution with no change in protein length for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different, previously established pathogenic missense change at residue Arg93 was available for comparison.	pm5_candidates
PM6	N/A	Not applicable: the VCEP handles de novo evidence through PS2 instead of PM6.	cspec
PP1	N/A	Not applicable: the VCEP does not use familial segregation evidence for these typically mosaic or de novo variants.	cspec
PP2	Not assessed	Not assessed: no gnomAD/ExAC missense constraint z-score was available to test against the required >3.09 threshold.
PP3	N/A	Not applicable: the governing VCEP categorically withdraws PP3 for this gain-of-function gene set.	cspec
PP4	N/A	Not applicable: phenotype specificity is accounted for under PS4.	cspec
PP5	N/A	Not applicable: the exact ClinVar record has zero expert-panel submissions, so the required gate is not satisfied.	cspec clinvar
BA1	Not met	Not met: absent from population databases, with no allele frequency exceeding the >0.0926% threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: no observed allele frequency exceeding the >0.0185% benign threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: fewer than 3 homozygotes in population databases and no well-phenotyped heterozygous family members were documented.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	Not met: both functional studies show an activating effect, the opposite of the benign/neutral effect BS3 requires.	PMID:21266528 PMID:22949682
BS4	N/A	Not applicable: the VCEP does not use absence of familial segregation as benign evidence for these variants.	cspec
BP1	N/A	Not applicable: the disease mechanism is gain-of-function, so BP1's loss-of-function premise does not apply.	cspec
BP2	Not assessed	Not assessed: no phase-resolved evidence places this variant in cis or trans with a known pathogenic PIK3CA variant.	cspec
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: BP4 applies only to synonymous, intronic, and UTR variants; this is a missense substitution.	cspec
BP5	Not assessed	Not assessed: no independently established alternate molecular basis for the disease was documented.
BP6	N/A	Not applicable: the ClinVar record contains no expert-panel benign or likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, but this missense change alters the protein sequence.	generic_acmg_combination_rules

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