Classification rationale

PM2 VUS

PIK3CA c.335T>C

The PIK3CA c.335T>C (p.Ile112Thr, p.I112T) variant has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2_Supporting under the Brain Malformations VCEP rule for variants observed in no more than 1 person.² The p.Ile112Thr change affects residue 112, which is outside the PIK3CA Table 4 approved kinase-domain intervals of amino acids 322-483 and 797-1068, so PM1 is not met.³ Computational data show no predicted splice impact by SpliceAI (max delta score 0.00), with REVEL 0.39 and BayesDel 0.238394, but under this VCEP PP3 is not applicable and BP4 is restricted to synonymous, intronic, or UTR variants.⁴

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1

4 spliceai ↗revelbayesdelcspec ↗

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_006218.4 · variants mapped to exon structure

PIK3CA NM_006218.4

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 review Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0 observed individuals across both datasets, which satisfies the Brain Malformations VCEP PM2 threshold of absent or rare in controls with no more than 1 person observed.

gnomAD v2.1: absentgnomAD v4.1: absentPM2 threshold: <=1 observed person

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 5 not met · 8 not assessed

Pathogenic

PS1 No previously established pathogenic variant producing the same amino acid change was identified in the available sources, so PS1 could not be assessed.

PS2 No confirmed de novo result, parental testing, or tissue mosaicism data were identified for this variant, so PS2 could not be assessed.

PS3 No validated functional study was identified showing an abnormal effect of p.Ile112Thr in an assay meeting the Brain Malformations VCEP PS3 requirements, so PS3 could not be assessed.

PS4 This variant meets PM2_Supporting because it is absent from gnomAD, but no affected-case phenotype point data were identified to reach the VCEP PS4 thresholds of at least 0.5 points for supporting evidence.

PM1 The p.Ile112Thr change affects residue 112, which is outside the PIK3CA Table 4 approved kinase-domain intervals of amino acids 322-483 and 797-1068, so PM1 is not met.

PM5 No validated same-residue pathogenic comparator variant was identified for codon 112, so PM5 could not be assessed from the available evidence.

PP2 PP2 may be applicable for PIK3CA missense variants when the missense constraint z-score is greater than 3.09, but the required gene-level constraint value was not identified in the available evidence, so PP2 could not be assessed.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0%, which is below the VCEP BA1 threshold of greater than 0.0926%.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0%, which is below the VCEP BS1 threshold of greater than 0.0185%.

BS2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so there are 0 observed homozygotes, which is below the VCEP BS2 threshold of at least 3 homozygotes or at least 3 well-phenotyped unaffected heterozygous family members.

BS3 No validated functional study was identified showing normal or non-damaging function for p.Ile112Thr, so BS3 could not be assessed.

BP2 No phase data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 could not be assessed.

BP5 No evidence was identified showing an alternate molecular explanation for the reported phenotype in a person carrying this variant, so BP5 could not be assessed.

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 is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.39. BayesDel score = 0.238394.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant lies 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

Check your email

Reset your password

Enter an access code

Your allowance