Variant classification summary

NM_006218.3:c.3133G>A

PIK3CA · NP_006209.2:p.(Asp1045Asn) · NM_006218.3

GRCh37: chr3:178952078 G>A · GRCh38: chr3:179234290 G>A

Gene: PIK3CA Transcript: NM_006218.3

Final call

VUS

PM1 supporting PM2 supporting PP2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.3

Protein

NP_006209.2:p.(Asp1045Asn)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The p.Asp1045Asn substitution lies within the PIK3CA C-terminal kinase domain (AA 797-1068), a critical functional domain defined in Table 4 of the Brain Malformations VCEP specification (PM1_Supporting).

2

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases (PM2_Supporting).

3

PIK3CA exhibits strong missense constraint with a gnomAD missense Z-score exceeding 3.09, meeting the VCEP threshold for PP2_Supporting.

4

Under the Brain Malformations VCEP Tavtigian point framework, total points = +3 (PM1_Supporting +1, PM2_Supporting +1, PP2_Supporting +1), which falls within the VUS range (0-5 points). The final classification is Uncertain Significance.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 3, 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
PVS1	N/A	Not applicable under the Brain Malformations VCEP because the disease mechanism for PIK3CA is gain of function; loss of function and haploinsufficiency have not been established as disease mechanisms for brain malformations associated with this gene.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS1	Not met	No other nucleotide change resulting in the same amino acid substitution (p.Asp1045Asn) has been identified as pathogenic in ClinVar or the literature. The variant is reported only as Uncertain significance by a single clinical submitter (ClinVar 3774060).	clinvar
PS2	Not met	No de novo evidence is available. Under the VCEP, PS2 requires confirmed maternity/paternity with variant absent from parental samples (Criteria 1) and differential tissue allelic fraction (Criteria 2) for Strong, or at least one of these criteria for Moderate. No de novo reports exist for this variant.	cspec
PS3	Not met	No variant-specific functional studies were identified. OncoKB classifies this variant as Unknown Oncogenic Effect. No publications with functional data for NM_006218.3:c.3133G>A were found in the literature search.	oncokb
PS4	Not met	Under the VCEP PS4 point-based system, phenotyped cases from literature are required for point assignment. No phenotyped cases were identified in the literature. COSMIC somatic occurrence data (n=13) can contribute only 0.25 points per occurrence category under Table 2A and cannot independently yield PS4 evidence without phenotyped cases. PM2 is met, but no meaningful PS4 points can be assigned without case-level data.	cspec
PS5	Not met	No different amino acid change at the same nucleotide position (c.3133G) has been established as pathogenic. The only variant reported at this nucleotide is c.3133G>A (p.Asp1045Asn), which is classified as VUS in ClinVar.	clinvar
PM1	Met	Residue p.Asp1045 lies within the PIK3CA C-terminal kinase domain (AA 797-1068), which is listed as a critical functional domain in Table 4 of the Brain Malformations VCEP specification. Per VCEP rules, PM1_Supporting is domain-based and does not require hotspot recurrence when the residue falls inside an approved Table 4 domain.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Per VCEP specification, PM2 is applied at Supporting strength for variants absent or rare (≤1) in an ethnically-matched cohort population sample.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No different pathogenic missense variant has been identified at the same amino acid residue (p.Asp1045). The PM5 candidate search found zero comparator variants at this residue in ClinVar. Although the variant is a missense change (p.Asp1045Asn), there is no pathogenic comparator to satisfy PM5.	pm5_candidates clinvar
PM6	N/A	Not applicable under the Brain Malformations VCEP. This criterion is addressed according to PS2 and will not be used separately.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1	N/A	Not applicable under the Brain Malformations VCEP because disease-causing variants in PIK3CA are germline mosaic, de novo, or mosaic rather than inherited in a pattern amenable to co-segregation analysis.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2	Met	PIK3CA is a gene with a low rate of benign missense variation. Per the VCEP specification, PP2 is awarded for PIK3CA because the missense constraint Z-score in gnomAD/ExAC exceeds 3.09, and PIK3CA is explicitly listed as an applicable gene for this criterion.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3	N/A	Not applicable under the Brain Malformations VCEP because PIK3CA variants are gain of function, and traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms. The VCEP states this criterion can be revisited if GOF-specific predictive algorithms become available.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4	N/A	Not applicable under the Brain Malformations VCEP because this criterion is accounted for under PS4.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5	N/A	Not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1	Not met	The VCEP BA1 threshold is allele frequency >0.0926%. This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, falling well below the BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The VCEP BS1 threshold is allele frequency >0.0185%. This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, falling below the BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Under the VCEP, BS2 requires ≥3 homozygotes in gnomAD or ≥3 heterozygous in well-phenotyped family members. This variant is absent from all gnomAD populations and no family member data are available.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing were identified for this variant.	oncokb
BS4	N/A	Not applicable under the Brain Malformations VCEP because disease-causing variants are de novo, germline mosaic, or post-zygotic mutations; lack of segregation analysis does not apply.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1	N/A	Not applicable under the Brain Malformations VCEP because loss of function is not the disease mechanism for PIK3CA brain malformations.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not met	No evidence that this variant has been observed in cis or trans with a known pathogenic variant in PIK3CA.
BP4	N/A	Under the VCEP, BP4 is only applicable for synonymous, intronic (except canonical splice sites), and non-coding UTR variants. This is a missense variant (c.3133G>A, p.Asp1045Asn) and is explicitly excluded from BP4 under the VCEP specification.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP5	Not met	No alternate molecular basis for disease has been identified in a case carrying this variant.
BP6	N/A	Not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7	N/A	Under the VCEP, BP7 is only applicable for synonymous, intronic (except canonical splice sites), and non-coding UTR variants. This is a missense variant (c.3133G>A, p.Asp1045Asn) and does not meet the variant type requirement for BP7.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1

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