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LYFE SCIENCES
Project: HERA
NM_006218.2:c.1631C>A
p.Thr544Asn  ·  PIK3CA
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Classification rationale
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.

clinvar ↗
2

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

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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

cspec ↗
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.

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: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.164. BayesDel score = -0.174013.
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; COSV55880047, n = 7 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueT544
Hotspots ↗