Classification rationale

PM2 VUS

PIK3CA c.1631C>A

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.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at Supporting strength under the Brain Malformations VCEP specification.² This variant lies outside the VCEP-approved PIK3CA PM1 domains at amino acids 322-483 and 797-1068, so PM1 is not met.³ 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.⁴

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1

4 spliceai ↗revelbayesdelvcep_clingen_brainmalform_acmg_specifications_v1_1

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 · 1 applied · 13 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 · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at Supporting strength under the Brain Malformations VCEP specification for a rare control frequency.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.The VCEP specifies PM2 at Supporting strength for variants absent/rare in controls.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS1 No pathogenic variant with the same p.Thr544Asn amino-acid change from a different nucleotide substitution was identified, so PS1 is not applied at this time.

PS2 No confirmed de novo result with parental testing and no demonstrated higher allele fraction in affected tissue relative to another tissue were identified for this variant, so PS2 is not applied.

PS3 No accepted variant-specific functional assay meeting Brain Malformations VCEP requirements was identified for p.Thr544Asn, so PS3 is not applied.

PS4 This variant satisfies PM2 because it is absent from gnomAD v2.1 and v4.1, but no scored series of affected individuals reaching the VCEP PS4_Supporting threshold of 0.5 points was identified, so PS4 is not applied.

PM1 For PIK3CA, the VCEP allows PM1 only at Supporting strength for variants within the approved Table 4 domains at amino acids 322-483 and 797-1068.

PM5 No different missense variant at residue Thr544 established as pathogenic was identified, so PM5 is not applied at this time.

PP2 The Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the gene-level missense constraint z-score is greater than 3.09, but that z-score was not provided here, so PP2 is left unassessed.

Benign

BA1 This variant is absent from gnomAD v2.1 and v4.1 and therefore does not exceed the VCEP BA1 threshold of greater than 0.0926%.

BS1 This variant is absent from gnomAD v2.1 and v4.1 and therefore does not exceed the VCEP BS1 threshold of greater than 0.0185%.

BS2 This variant is absent from gnomAD, and no evidence of at least 3 homozygotes in population data or at least 3 well-phenotyped unaffected family members was identified, so BS2 is not met.

BS3 No well-established functional study showing normal or non-damaging effect for p.Thr544Asn was identified, so BS3 is not applied.

BP2 No observation of this variant in cis or trans with a known pathogenic PIK3CA variant was identified, so BP2 is not applied.

BP5 No alternate molecular diagnosis explaining the phenotype was identified together with this variant, so BP5 is not applied.

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

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain Significance by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).

ClinVar ↗

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 ↗

Functional 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 ↗

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; COSV55880047, n = 7 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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