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.1 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.2 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.3 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.4
Final classification
VUS
PP2PM2
PIK3CA
c.93A>G
p.Ile31Met
This variant
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.
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PP2 supporting (+1) + PM2 supporting (+1) = 2 points, which maps to VUS.
Classification rationale
PP2PM2
VUS
PIK3CA c.93A>G
PP2 + PM2
→
VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_006218.2 · variants mapped to exon structure
PIK3CA
NM_006218.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
review
Pathogenic
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.
Variant absent from gnomAD v2.1.Variant absent from gnomAD v4.1.
PP2
supporting
review
Pathogenic
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.
PIK3CA missense z-score 5.5986 from gnomAD constraint data.VCEP PP2 threshold >3.09.
Assessed · not applied
· 10 not met · 2 not assessed
Pathogenic
PS1
No previously established pathogenic PIK3CA variant with the same amino acid change at p.Ile31 was identified.
PS2
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.
PS3
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.
PS4
Although PM2 is met, no report-ready affected-individual phenotype point assignments were identified for this variant under the Brain Malformations VCEP PS4 framework.
PM1
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.
PM5
No different missense change at codon 31 was identified as an established pathogenic PIK3CA variant in the reviewed evidence.
Benign
BA1
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%.
BS1
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%.
BS2
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.
BS3
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.
BP2
No evidence was identified showing this variant in cis or in trans with a known pathogenic PIK3CA variant, so BP2 is not met.
BP5
No alternate molecular basis for the phenotype was identified in the reviewed evidence, so BP5 is not met.
N/A · 14
PVS1 · PM3 · PM4 · PM6 · PP1 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain Significance by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.286. BayesDel score = -0.0727233.
Functional
Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55898376, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links