NM_006218.2:c.93A>G

PIK3CA · NP_006209.2:p.(Ile31Met) · NM_006218.2

GRCh37: chr3:178916706 A>G · GRCh38: chr3:179198918 A>G

Gene: PIK3CA Transcript: NM_006218.2

Final call

VUS

PP2 supporting PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.2

Protein

NP_006209.2:p.(Ile31Met)

gnomAD AF

ClinVar

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

The PIK3CA c.93A>G (p.Ile31Met) variant has been observed in somatic cancers in COSMIC (COSV55898376, n=2) and has been reported in ClinVar as Uncertain Significance by the ClinGen Brain Malformations Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting PM2 at supporting strength under the Brain Malformations VCEP framework.

The missense change affects codon 31, which is outside the PIK3CA Table 4 kinase-domain intervals used for PM1 and was not identified as a statistically significant hotspot in the retrieved hotspot review.

Computational review showed REVEL 0.286, BayesDel -0.0727233, and SpliceAI max delta 0.06, but the Brain Malformations VCEP does not apply PP3 to PIK3CA gain-of-function missense variants and restricts BP4 to synonymous, intronic, or UTR variants.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 2, 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 met	No previously established pathogenic PIK3CA variant with the same amino acid change at p.Ile31 was identified. Other ClinVar missense substitutions at codon 31 identified in the reviewed evidence are classified as uncertain significance rather than pathogenic, so PS1 is not met.	clinvar
BS4	N/A	BS4 is not applicable in this Brain Malformations VCEP framework because these disorders are typically caused by de novo, germline mosaic, or post-zygotic variants rather than informative multi-generation segregation patterns.	cspec
BS2	Not met	The reviewed evidence does not show at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected heterozygous family members, so BS2 is not met.	cspec gnomad_v2 gnomad_v4
PS2	Not met	No report was identified showing this variant was absent from confirmed parental samples, and no tissue-comparison evidence was identified showing a higher allele fraction in affected tissue than in another tissue. Therefore the VCEP requirements for PS2 are not met.	cspec
PP4	N/A	PP4 is not applicable in this Brain Malformations VCEP framework because phenotype specificity is incorporated into the PS4 point-based system.	cspec
PP3	N/A	Computational review showed REVEL 0.286, BayesDel -0.0727233, and SpliceAI max delta 0.06, but the Brain Malformations VCEP does not apply PP3 to PIK3CA gain-of-function variants because traditional pathogenicity predictors are not considered reliable for this mechanism.	cspec revel bayesdel spliceai
PM1	Not met	The p.Ile31Met change is outside the PIK3CA Table 4 critical domains approved for PM1 under this VCEP, which are amino acids 322-483 and 797-1068. The retrieved hotspot review also did not show a statistically significant hotspot at codon 31, so PM1 is not met.	cspec hotspots
PS4	Not met	Although PM2 is met, no report-ready affected-individual phenotype point assignments were identified for this variant under the Brain Malformations VCEP PS4 framework. Two somatic observations in COSMIC do not establish the minimum case-based evidence needed to reach PS4_Supporting, so PS4 is not met.	cspec gnomad_v2 gnomad_v4
PVS1	N/A	PVS1 is not applicable for PIK3CA in this Brain Malformations VCEP framework because the relevant disease mechanism is gain of function rather than loss of function. This missense variant also does not fall into a generic null-variant category.	cspec pvs1_variant_assessment
PP5	N/A	PP5 is not used in this Brain Malformations VCEP framework.	cspec
BP7	N/A	BP7 is restricted to synonymous, intronic, or certain non-coding variants, and this is a missense variant. Therefore BP7 is not applicable.	cspec
BP5	Not met	No alternate molecular basis for the phenotype was identified in the reviewed evidence, so BP5 is not met.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, but this Brain Malformations VCEP applies BP4 only to synonymous, intronic, or UTR variants evaluated for splicing. Because this is a missense variant, BP4 is not applicable.	cspec spliceai
BP3	N/A	BP3 is not applicable in this Brain Malformations VCEP framework.	cspec
BP2	Not met	No evidence was identified showing this variant in cis or in trans with a known pathogenic PIK3CA variant, so BP2 is not met.	cspec
BP1	N/A	BP1 is not applicable for PIK3CA in this Brain Malformations VCEP framework because the disease mechanism is gain of function rather than the pattern addressed by BP1.	cspec
BS3	Not assessed	Curated literature links for possible functional review were identified, but no independently confirmed exact-variant functional study showing a normal or benign effect was established from the reviewed evidence. Therefore BS3 was not assessed.	oncokb PMID:26627007 PMID:28528867 PMID:29533785
BA1	Not met	This variant was absent from gnomAD v2.1 and gnomAD v4.1, which is below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%. Therefore BA1 is not met.	cspec gnomad_v2 gnomad_v4
PP2	Met	The Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the missense constraint z-score is greater than 3.09. Live gnomAD constraint review identified a PIK3CA missense z-score of 5.60, which is above this threshold, so PP2 is met at supporting strength.	cspec gnomad_v2
PP1	N/A	PP1 is not applicable in this Brain Malformations VCEP framework.	cspec
PM5	Not met	No different missense change at codon 31 was identified as an established pathogenic PIK3CA variant in the reviewed evidence. Other codon 31 ClinVar substitutions identified in the review are classified as uncertain significance, so PM5 is not met.	clinvar
PM4	N/A	PM4 is not applicable in this Brain Malformations VCEP framework.	cspec
PM3	N/A	PM3 is not applicable in this Brain Malformations VCEP framework.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with the Brain Malformations VCEP PM2 rule for variants absent or rare in controls. Under this VCEP, PM2 is capped at supporting strength, so PM2 is met at supporting strength.	cspec gnomad_v2 gnomad_v4
PS3	Not assessed	Curated literature links for possible functional review were identified, but no independently confirmed exact-variant validated functional study showing an abnormal gain-of-function effect was established from the reviewed evidence. Therefore PS3 was not assessed.	oncokb PMID:26627007 PMID:28528867 PMID:29533785
BP6	N/A	BP6 is not applicable in this Brain Malformations VCEP framework.	cspec
BS1	Not met	This variant was absent from gnomAD v2.1 and gnomAD v4.1, which is below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%. Therefore BS1 is not met.	cspec gnomad_v2 gnomad_v4
PM6	N/A	PM6 is not applicable in this Brain Malformations VCEP framework.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.