Variant classification summary

NM_006218.4:c.112C>T

PIK3CA · NP_006209.2:p.(Arg38Cys) · NM_006218.4

GRCh37: chr3:178916725 C>T · GRCh38: chr3:179198937 C>T

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Arg38Cys)

gnomAD AF

0.0 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

This variant is completely absent from population databases including gnomAD v2.1 (0/248,624 alleles) and gnomAD v4.1 (0/1,611,102 alleles), meeting PM2_Supporting per the Brain Malformations VCEP.

2

No other pathogenic or benign criteria are met under the Brain Malformations VCEP v1.1.0 framework. PVS1, PP3, PP4, PP5, BS4, PM6, BP1, BP4, BP6, BP7, and PP1 are explicitly not applicable per the VCEP. Most remaining criteria lack variant-specific evidence in the published literature.

3

OncoKB curates p.Arg38Cys as Likely Oncogenic with Likely Gain-of-function biological context; however, no variant-specific functional data was identified in the reviewed full-text publications, and the Brain Malformations VCEP PS3 criterion requires validated functional assays meeting specific quality metrics.

4

This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (ClinVarID 376493). No de novo reports, segregation data, or brain malformation phenotype cases were identified.

5

Variant has been observed in somatic cancers (COSMIC, n=39 occurrences) but this does not independently support germline brain malformation pathogenicity under the VCEP PS4 framework.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 1, 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 per Brain Malformations VCEP v1.1.0 — disease mechanism for PIK3CA is gain of function, not loss of function.	cspec
PS1	Not met	No previously established pathogenic variant causing the same amino acid change (p.Arg38Cys) via a different nucleotide change was identified. The variant is absent from ClinVar pathogenic assertions and no literature reports a different nucleotide substitution producing p.Arg38Cys.	clinvar
PS2	Not assessed	No de novo observation of this variant has been identified in any reviewed publication or ClinVar submission. PS2 requires confirmed maternity/paternity with variant absent from parents (PS2_Strong) or at minimum satisfying one of the two VCEP criteria (PS2_Moderate). None of the available evidence supports a de novo event.	clinvar
PS3	Not assessed	No variant-specific functional data confirming a damaging effect was identified in any reviewed full-text publication. OncoKB curates this variant as Likely Oncogenic/Likely Gain-of-function, but no peer-reviewed functional study explicitly characterizing NM_006218.4:c.112C>T was found. The Brain Malformations VCEP requires functional assays meeting quality metrics per PMID:31892348 for PS3 application.	oncokb
PS4	Not assessed	No published cases of this variant in individuals with brain malformation phenotypes were identified in the reviewed literature. COSMIC reports 39 somatic cancer occurrences, but BMVCEP Table 2A assigns at most 0.25 points per tumor occurrence category, insufficient to achieve any PS4 strength level on its own. ClinVar clinical testing submissions provide no phenotypic detail.	clinvar
PS5	Not met	No reputable source reports this variant as pathogenic. ClinVar classification is Uncertain significance (2 clinical laboratories). OncoKB label of Likely Oncogenic is somatic-cancer context and does not constitute a germline diagnostic classification.	clinvar oncokb
PM1	Not met	Residue Arg38 lies outside the Table 4 PIK3CA critical functional domains (kinase domain AA 322–483 and AA 797–1068) per the Brain Malformations VCEP. While Cancer Hotspots identifies residue 38 as statistically significant, the VCEP specifies PM1_Supporting based on domain membership, not hotspot recurrence. Residue 38 is in the p85-binding/adaptor-binding domain, which is not a Table 4 approved domain.	cspec
PM2	Met	This variant is completely absent from all gnomAD population databases: gnomAD v2.1 (0/248,624 alleles), gnomAD v4.1 (0/1,611,102 alleles), and gnomAD-Canada v1.0. Per the Brain Malformations VCEP, PM2_Supporting is awarded when the variant is absent or rare (≤1) in ethnically-matched population cohorts.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	Not assessed	No pathogenic comparator variant at residue Arg38 was identified in ClinVar or the literature. PM5 requires a known pathogenic missense change at the same amino acid residue. The automated PM5 candidate search found no same-residue pathogenic variants and was classified as not_applicable due to insufficient comparator data. Without a confirmed pathogenic comparator at Arg38, PM5 cannot be evaluated.	clinvar
PM6	N/A	Not applicable per Brain Malformations VCEP v1.1.0 — this criterion is addressed under PS2 and will not be used separately.	cspec
PP1	N/A	Not applicable per Brain Malformations VCEP v1.1.0 — disease-causing variants in these genes are germline mosaic, de novo, or mosaic, making co-segregation analysis inapplicable.	cspec
PP2	Not assessed	The Brain Malformations VCEP specifies PP2_Supporting for PIK3CA if the missense constraint z-score from ExAC/gnomAD exceeds 3.09. PIK3CA is known to be highly missense-constrained, but the specific gnomAD missense z-score was not available in the evidence brief for direct confirmation.	cspec
PP3	N/A	Not applicable per Brain Malformations VCEP v1.1.0 — traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms, whereas PIK3CA variants act through gain of function. The VCEP explicitly states this criterion is not applicable until algorithms designed to detect GOF mutations are validated.	cspec
PP4	N/A	Not applicable per Brain Malformations VCEP v1.1.0 — this criterion is accounted for under PS4.	cspec
PP5	N/A	Not applicable per Brain Malformations VCEP v1.1.0 — this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	Variant is completely absent from all gnomAD populations (0/248,624 in v2.1, 0/1,611,102 in v4.1). The Brain Malformations VCEP BA1 threshold is allele frequency >0.0926%. The observed frequency of 0% does not meet this threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	Variant is completely absent from all gnomAD populations. The Brain Malformations VCEP BS1 threshold is allele frequency >0.0185%. The observed frequency of 0% does not meet this threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	No homozygotes present in gnomAD (0/248,624 in v2.1, 0/1,611,102 in v4.1) and no well-phenotyped heterozygous family members without disease have been reported. The VCEP requires ≥3 homozygotes in gnomAD or ≥3 heterozygous in well-phenotyped family members to award BS2_Strong.	gnomad_v2 gnomad_v4 cspec
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a benign effect. OncoKB curates this variant as Likely Gain-of-function/Likely Oncogenic, which is consistent with a damaging effect rather than a benign one.	oncokb
BS4	N/A	Not applicable per Brain Malformations VCEP v1.1.0 — these are de novo, germline mosaic, or post-zygotic mutations, making segregation analysis inapplicable.	cspec
BP1	N/A	Not applicable per Brain Malformations VCEP v1.1.0 — loss of function is not the disease mechanism for PIK3CA.	cspec
BP2	Not met	No evidence that this variant has been observed in cis or in trans with a known pathogenic variant in PIK3CA. No phase information is available from any reviewed source.
BP4	N/A	Not applicable per Brain Malformations VCEP v1.1.0 — BP4 is limited to synonymous, intronic (non-canonical splice), and UTR variants only. This variant is a missense substitution.	cspec
BP5	Not met	No evidence that this variant has been found in a case with an alternative molecular basis for disease. No publication or ClinVar submission describes this variant co-occurring with a confirmed pathogenic variant in another gene that fully explains the phenotype.
BP6	N/A	Not applicable per Brain Malformations VCEP v1.1.0 — this criterion is not for use as recommended by the ClinGen SVI VCEP Review Committee.	cspec
BP7	N/A	Not applicable per Brain Malformations VCEP v1.1.0 — BP7 is limited to synonymous, intronic (non-canonical splice), and UTR variants with PhyloP <0.1. This variant is a missense substitution.	cspec

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