Variant classification summary

NM_006218.4:c.1458C>T

PIK3CA · NP_006209.2:p.(Phe486=) · NM_006218.4

GRCh37: chr3:178928272 C>T · GRCh38: chr3:179210484 C>T

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Phe486=)

gnomAD AF

1.1773731194562767e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006218.4:c.1458C>T is a synonymous variant (p.Phe486=) in PIK3CA exon 9. Under the ClinGen Brain Malformations VCEP v1.1, PVS1, PP1, PP3, PP4, PP5, PM6, BS4, BP1, and BP6 are not applicable.

2

PS1, PS5, and PM5 are not applicable because the variant is synonymous and produces no amino acid change.

3

The variant is present in gnomAD v2.1 (2/249,396 alleles; 0.0008%) and v4.1 (19/1,613,762 alleles; 0.00118%), exceeding the VCEP PM2_Supporting threshold of ≤1 allele. The allele frequency does not reach BA1 (>0.0926%) or BS1 (>0.0185%) thresholds. Zero homozygotes are observed (BS2 not met).

4

Residue 486 lies outside both PIK3CA critical functional domains defined by the VCEP Table 4 (AA 322-483 and AA 797-1068); PM1_Supporting is not met.

5

No functional studies, de novo occurrences, brain malformation case reports, or co-segregation data were identified for this variant. ClinVar classifies it as Likely benign (3 clinical laboratories, single submitter, no expert panel review).

6

BP4 and BP7 remain unassessed due to missing splicing prediction (varSEAK, MaxEntScan) and conservation (PhyloP) data. SpliceAI predicts no splice impact (max delta 0.01).

7

No reviewable publications contained variant-specific evidence. All ClinVar-associated PMIDs are guideline or policy documents that do not mention NM_006218.4:c.1458C>T.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of 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	VCEP declares PVS1 not applicable for PIK3CA; the disease mechanism is gain of function, and loss of function has not been established as a disease mechanism for brain malformations.	cspec
PS1	N/A	This variant is synonymous (p.Phe486=) and does not result in an amino acid change; PS1 requires the same amino acid change as a previously established pathogenic variant.	cspec
PS2	Not met	No de novo occurrence has been reported for this variant. VCEP PS2 requires confirmed de novo status with or without tissue mosaicism evidence; no such data are available in the case record.	cspec
PS3	Not met	No well-established in vitro or in vivo functional studies are available for this variant. OncoKB classifies the variant as Unknown Oncogenic Effect with no curated PMIDs. No functional data were identified in the reviewed literature.	oncokb
PS4	Not met	VCEP PS4 requires PM2 first. PM2 is not met (variant exceeds the ≤1 allele threshold in gnomAD). Additionally, no brain malformation phenotype cases have been reported in the literature for this variant. The variant is classified as Likely benign in ClinVar by three clinical laboratories.	cspec clinvar gnomad_v2 gnomad_v4
PS5	N/A	This variant is synonymous (p.Phe486=) and does not result in an amino acid change. PS5 is not defined in the Brain Malformations VCEP and would require a missense change at a residue with known pathogenic variation.	cspec
PM1	Not met	VCEP PM1_Supporting requires location within a Table 4 critical functional domain. PIK3CA domains are kinase domain AA 322-483 and AA 797-1068. Residue 486 lies outside both approved domains (3 residues beyond the N-terminal kinase lobe boundary at 483).	cspec
PM2	Not met	VCEP PM2_Supporting requires ≤1 allele in ethnically matched control populations. This variant is present in gnomAD v2.1 with 2 alleles (AF 0.0008%) and gnomAD v4.1 with 19 alleles (AF 0.00118%), exceeding the VCEP threshold.	cspec gnomad_v2 gnomad_v4
PM5	N/A	PM5 applies to missense changes at an amino acid residue where a different pathogenic missense change has been seen. This variant is synonymous (p.Phe486=) with no amino acid change; PM5 is not applicable.	cspec pm5_candidates
PM6	N/A	VCEP declares PM6 not applicable; PM6 is addressed by PS2 in this framework.	cspec
PP1	N/A	VCEP declares PP1 not applicable because disease-causing variants in brain malformation disorders are germline mosaic, de novo, or mosaic, making co-segregation analysis infeasible.	cspec
PP2	Not met	VCEP PP2 requires a missense constraint z-score > 3.09 in gnomAD. This variant is synonymous, not missense. Additionally, no missense z-score data was retrieved for this case.	cspec
PP3	N/A	VCEP declares PP3 not applicable.	cspec
PP4	N/A	VCEP declares PP4 not applicable; phenotype specificity is accounted for under PS4 in this framework.	cspec
PP5	N/A	VCEP declares PP5 not applicable.	cspec
BA1	Not met	VCEP BA1 threshold is allele frequency > 0.0926%. The highest observed population frequency is 0.00177% (gnomAD v2.1 European non-Finnish) and 0.00160% (gnomAD v4.1 remaining individuals), both well below the BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	VCEP BS1 threshold is allele frequency > 0.0185%. The highest observed population frequency is 0.00177% (gnomAD v2.1), below the BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not met	VCEP BS2 requires ≥3 homozygotes in gnomAD or ≥3 well-phenotyped heterozygous family members. Zero homozygotes are observed; no family data are available.	cspec gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a benign effect for this variant. No functional data were identified in the reviewed literature.	oncokb
BS4	N/A	VCEP declares BS4 not applicable because disease-causing variants are de novo, germline mosaic, or post-zygotic.	cspec
BP1	N/A	VCEP declares BP1 not applicable for PIK3CA; the disease mechanism is gain of function, not loss of function.	cspec
BP2	Not met	No evidence of this variant observed in cis or trans with a known pathogenic variant in PIK3CA.	cspec
BP4	Not assessed	VCEP BP4 is applicable to synonymous variants but requires 2 of 3 splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact. Only SpliceAI data is available (max delta score = 0.01, no impact predicted). varSEAK and MaxEntScan data are not available; the 2-of-3 requirement cannot be satisfied.	cspec spliceai
BP5	Not met	No alternate molecular basis for disease has been identified that would explain the phenotype independently of this variant.	cspec
BP6	N/A	VCEP declares BP6 not applicable.	cspec
BP7	Not assessed	VCEP BP7 is applicable to synonymous variants and requires non-conservation (PhyloP score < 0.1 or absence across vertebrates). SpliceAI predicts no splice impact (max delta 0.01), satisfying the splicing component. However, PhyloP conservation data was not retrieved for this variant; the nucleotide conservation requirement cannot be evaluated.	cspec spliceai
BP3	N/A	Variant is a substitution, not an in-frame deletion/insertion.
PM3	N/A	Brain malformations are not recessive disorders; VCEP declares PM3 not applicable.
PM4	N/A	Variant is a single-nucleotide substitution, not an in-frame deletion/insertion or stop-loss.

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