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
PIK3CA
Final classification
VUS
PIK3CA c.93A>G · p.Ile31Met
PIK3CA
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
Gene diagram
· NM_006218.2 · variants mapped to exon structure
PIK3CA
NM_006218.2
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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