Variant classification summary

NM_006218.2:c.2040T>C

PIK3CA · NP_006209.2:p.(Val680=) · NM_006218.2

GRCh37: chr3:178938798 T>C · GRCh38: chr3:179221010 T>C

Gene: PIK3CA Transcript: NM_006218.2

Final call

VUS

BP6 supporting benign

Variant details

Gene

PIK3CA

Transcript

NM_006218.2

Protein

NP_006209.2:p.(Val680=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PIK3CA c.2040T>C (p.Val680=) variant has been reported in ClinVar and is classified as likely benign by the ClinGen Brain Malformations Variant Curation Expert Panel.

2

This variant is present in gnomAD at 0.00080% in v2.1 (2/248908 alleles) and 0.00248% in v4.1 (40/1612688 alleles), which is below the VCEP BS1 threshold of 0.0185% and BA1 threshold of 0.0926% but exceeds the VCEP PM2 one-person maximum.

3

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, although additional VCEP-specified splicing predictors and a conservation score were not identified for BP4 and BP7 assessment.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 0, 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	The Brain Malformations VCEP specifies that PVS1 is not applicable for PIK3CA because the relevant disease mechanism is gain of function rather than loss of function.	cspec
PS1	Not met	This is a synonymous variant, p.(Val680=), and no evidence was identified that it results in the same established pathogenic amino acid change as a previously classified pathogenic variant.	cspec clinvar
PS2	Not assessed	No confirmed de novo evidence was identified for this variant, and no tissue-distribution data were identified showing a higher allele fraction in affected tissue than in another tissue as required by the VCEP framework.	cspec
PS3	Not assessed	No published functional or RNA study was identified showing a damaging effect of this exact synonymous variant under the VCEP/SVI assay standards.	cspec
PS4	Not met	The VCEP requires PM2 before PS4 can be used. This variant exceeds the VCEP PM2 one-person maximum because it is present in gnomAD v2.1 at 2/248908 alleles and in gnomAD v4.1 at 40/1612688 alleles, and no point-based affected-case evidence was identified for this exact variant.	cspec gnomad_v2 gnomad_v4 clinvar
PM1	Not met	The VCEP allows PM1_Supporting for PIK3CA variants in approved Table 4 domains at amino acids 322-483 or 797-1068. This synonymous variant affects codon 680, which is outside those approved domains.	cspec
PM2	Not met	The VCEP applies PM2 only at Supporting strength and limits it to a maximum of one person in controls. This variant is present in gnomAD v2.1 at 2/248908 alleles and in gnomAD v4.1 at 40/1612688 alleles, so PM2 is not met.	cspec gnomad_v2 gnomad_v4
PM5	N/A	The governing PM5 framework for this gene uses classic same-residue missense logic, and this variant is synonymous rather than missense.	pm5_candidates cspec
PP1	N/A	The Brain Malformations VCEP does not apply PP1 for this framework.	cspec
PP2	N/A	The VCEP PP2 rule is intended for missense variants using missense constraint, and this variant is synonymous.	cspec
PP3	N/A	The Brain Malformations VCEP specifies that PP3 is not applicable for these gain-of-function disorders because traditional pathogenicity predictors are not validated for this mechanism.	cspec
PP4	N/A	The Brain Malformations VCEP specifies that PP4 is not applicable because phenotype specificity is incorporated into PS4.	cspec
PP5	N/A	PP5 is not used in this framework.	cspec
BA1	Not met	The VCEP BA1 threshold is >0.0926%. This variant is present in gnomAD v4.1 at 0.00248% and in gnomAD v2.1 at 0.00080%, both well below the BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	The VCEP BS1 threshold is >0.0185%. This variant is present in gnomAD v4.1 at 0.00248% and in gnomAD v2.1 at 0.00080%, both below the BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not met	The VCEP applies BS2 when there are at least 3 homozygotes in population data or at least 3 well-phenotyped unaffected heterozygous family members. This variant has 0 homozygotes in gnomAD v2.1 and 0 homozygotes in gnomAD v4.1, and no qualifying family data were identified.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	No published functional or RNA study was identified showing that this exact variant has no damaging effect under the VCEP/SVI assay standards.	cspec
BS4	N/A	The Brain Malformations VCEP does not apply BS4 in this framework.	cspec
BP1	N/A	The Brain Malformations VCEP does not apply BP1 for PIK3CA because the disease mechanism is gain of function rather than a gene in which truncating variants are typically pathogenic.	cspec
BP2	Not assessed	No observation was identified showing this variant in cis or in trans with a known pathogenic PIK3CA variant.	cspec
BP3	N/A	The Brain Malformations VCEP does not apply BP3 in this framework.	cspec
BP4	Not assessed	This synonymous non-canonical variant has a low SpliceAI score, with a maximum delta score of 0.01, which is consistent with no significant splice effect. However, the VCEP requires no-impact predictions from 2 of 3 specified splicing tools, and only SpliceAI evidence was identified.	cspec spliceai
BP5	Not assessed	No evidence was identified that this variant was found in an individual with an alternate molecular explanation for the phenotype.	cspec
BP6	Met	Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Likely benign.	cspec clinvar
BP7	Not assessed	This is a synonymous variant outside the canonical splice consensus, but BP7 requires a non-conserved nucleotide with PhyloP <0.1. No conservation score was identified to confirm that requirement.	cspec spliceai
PM3	N/A	The Brain Malformations VCEP does not apply PM3 in this framework.	cspec
PM4	N/A	The Brain Malformations VCEP does not apply PM4 in this framework.	cspec
PM6	N/A	The Brain Malformations VCEP does not apply PM6 in this framework.	cspec

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