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LYFE SCIENCES
Project: HERA
NM_006218.2:c.93A>G
p.Ile31Met  ·  PIK3CA
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

cspec ↗ hotspots ↗
4

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.

cspec ↗ spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain Significance by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.286. BayesDel score = -0.0727233.
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueI31
Hotspots ↗