Variant classification summary

NM_006218.2:c.1631C>A

PIK3CA · NP_006209.2:p.(Thr544Asn) · NM_006218.2

GRCh37: chr3:178936089 C>A · GRCh38: chr3:179218301 C>A

Gene: PIK3CA Transcript: NM_006218.2

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.2

Protein

NP_006209.2:p.(Thr544Asn)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PIK3CA c.1631C>A (p.Thr544Asn, T544N) variant has been reported in ClinVar and is currently classified as uncertain significance by the ClinGen Brain Malformations Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at Supporting strength under the Brain Malformations VCEP specification.

3

This variant lies outside the VCEP-approved PIK3CA PM1 domains at amino acids 322-483 and 797-1068, so PM1 is not met.

4

SpliceAI predicts no significant splice impact (max delta score 0.00), REVEL is 0.164, and BayesDel is -0.174013; however, the Brain Malformations VCEP does not apply PP3 or BP4 missense computational criteria to gain-of-function PIK3CA variants.

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
PS1	Not assessed	No pathogenic variant with the same p.Thr544Asn amino-acid change from a different nucleotide substitution was identified, so PS1 is not applied at this time.	clinvar vcep_clingen_brainmalform_acmg_specifications_v1_1
BS4	N/A	Under the Brain Malformations VCEP specification, BS4 is not applicable because these disorders are typically caused by de novo, germline mosaic, or post-zygotic variants rather than informative multigenerational segregation patterns.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BS2	Not met	This variant is absent from gnomAD, and no evidence of at least 3 homozygotes in population data or at least 3 well-phenotyped unaffected family members was identified, so BS2 is not met.	gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
PS2	Not assessed	No confirmed de novo result with parental testing and no demonstrated higher allele fraction in affected tissue relative to another tissue were identified for this variant, so PS2 is not applied.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4	N/A	Under the Brain Malformations VCEP specification, PP4 is not used because phenotype specificity is incorporated into PS4.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3	N/A	SpliceAI predicts no significant splice effect for this variant (max delta score 0.00), REVEL is 0.164, and BayesDel is -0.174013; however, the Brain Malformations VCEP does not apply PP3 to gain-of-function PIK3CA missense variants.	spliceai revel bayesdel vcep_clingen_brainmalform_acmg_specifications_v1_1
PM1	Not met	For PIK3CA, the VCEP allows PM1 only at Supporting strength for variants within the approved Table 4 domains at amino acids 322-483 and 797-1068. Thr544 lies outside these intervals, so PM1 is not met.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS4	Not assessed	This variant satisfies PM2 because it is absent from gnomAD v2.1 and v4.1, but no scored series of affected individuals reaching the VCEP PS4_Supporting threshold of 0.5 points was identified, so PS4 is not applied.	gnomad_v2 gnomad_v4 cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PVS1	N/A	PVS1 is not applicable under the Brain Malformations VCEP because the relevant disease mechanism for PIK3CA is gain of function, and this is a missense variant rather than a null variant.	vcep_clingen_brainmalform_acmg_specifications_v1_1 pvs1_gene_context pvs1_variant_assessment
PP5	N/A	PP5 is not used under current ClinGen SVI and Brain Malformations VCEP guidance.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7	N/A	BP7 is limited to synonymous, intronic, or UTR variants with no predicted splice effect and low conservation; this variant is missense, so BP7 is not applicable.	spliceai vcep_clingen_brainmalform_acmg_specifications_v1_1
BP5	Not assessed	No alternate molecular diagnosis explaining the phenotype was identified together with this variant, so BP5 is not applied.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BP4	N/A	SpliceAI predicts no significant splice effect for this variant (max delta score 0.00), but the Brain Malformations VCEP applies BP4 only to synonymous, intronic, or UTR variants evaluated with splicing predictors. Because this is a missense variant, BP4 is not applicable.	spliceai vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3	N/A	BP3 is not applicable under the Brain Malformations VCEP for these genes because the relevant exon regions do not contain repetitive regions without known function.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	No observation of this variant in cis or trans with a known pathogenic PIK3CA variant was identified, so BP2 is not applied.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1	N/A	BP1 is not applicable because loss of function is not the relevant disease mechanism in this PIK3CA VCEP framework.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BS3	Not assessed	No well-established functional study showing normal or non-damaging effect for p.Thr544Asn was identified, so BS3 is not applied.	oncokb vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and therefore does not exceed the VCEP BA1 threshold of greater than 0.0926%.	gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2	Not assessed	The Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the gene-level missense constraint z-score is greater than 3.09, but that z-score was not provided here, so PP2 is left unassessed.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1	N/A	PP1 is not applicable under the Brain Malformations VCEP because disease-causing variants are typically de novo or mosaic rather than supported by informative familial segregation.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PM5	Not assessed	No different missense variant at residue Thr544 established as pathogenic was identified, so PM5 is not applied at this time.	clinvar vcep_clingen_brainmalform_acmg_specifications_v1_1
PM4	N/A	PM4 is not applicable under the Brain Malformations VCEP for this PIK3CA missense variant.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PM3	N/A	PM3 is not applicable because the relevant PIK3CA disorders in this framework are not interpreted as recessive conditions requiring trans observations.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at Supporting strength under the Brain Malformations VCEP specification for a rare control frequency.	gnomad_v2 gnomad_v4 cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3	Not assessed	No accepted variant-specific functional assay meeting Brain Malformations VCEP requirements was identified for p.Thr544Asn, so PS3 is not applied.	oncokb vcep_clingen_brainmalform_acmg_specifications_v1_1
BP6	N/A	BP6 is not used under current ClinGen SVI and Brain Malformations VCEP guidance.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BS1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and therefore does not exceed the VCEP BS1 threshold of greater than 0.0185%.	gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
PM6	N/A	PM6 is not used in this framework because de novo evidence is handled through PS2.	vcep_clingen_brainmalform_acmg_specifications_v1_1

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