Final classification

Uncertain Significance

PM1PM2

PIK3CA

c.1265del

p.Leu422TrpfsTer6

This variant

The PIK3CA c.1265del (p.(Leu422TrpfsTer6)) variant has not been reported in ClinVar.

Transcript

NM_006218.4

HGVS · transcript:coding

NM_006218.4:c.1265del

GRCh38

chr3:179210197 AT>A

GRCh37

chr3:178927985 AT>A

Brain Malformations Specification Tavtigian point framework from the CSPEC/VCEP final-classification framework: PM1_Supporting (+1) and PM2_Supporting (+1) for a total of 2 points.

Classification rationale

PM1PM2 Uncertain Significance

PIK3CA c.1265del

The PIK3CA c.1265del (p.(Leu422TrpfsTer6)) variant has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at Supporting strength, and its observed population frequency of 0% is below the VCEP BS1 threshold of >0.0185% and BA1 threshold of >0.0926%.² The altered residue lies within the approved PIK3CA kinase-domain interval spanning amino acids 322-483, which is a Brain Malformations VCEP critical functional domain and supports PM1_Supporting.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.07, although computational pathogenicity criteria are not applied for PIK3CA gain-of-function interpretation in this VCEP framework.⁴

PM1 + PM2 → Uncertain Significance

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗vcep_c_l_i_n_g_e_n___b_r_a_i_n_m_a_l_f_o_r_m___a_c_m_g___s_p_e_c_i_f_i_c_a_t_i_o_n_s___v_1___1

4 spliceai ↗cspec ↗

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 · 2 applied · 9 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 · 2

Strength Supporting Moderate Strong Very strong

PM1 supporting Pathogenic

The altered residue Leu422 lies within the approved PIK3CA kinase-domain interval spanning amino acids 322-483 in the Brain Malformations VCEP specification. This location is a listed critical functional domain, which supports PM1 at Supporting strength.

Protein consequence is p.(Leu422TrpfsTer6).Leu422 falls within the VCEP-approved kinase domain AA 322-483.

cspec ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the Brain Malformations VCEP PM2 threshold requiring absence or rarity in controls with no more than one person observed. These data support PM2 at Supporting strength.

gnomAD v2.1: absent.gnomAD v4.1: absent.VCEP PM2 is Supporting for absent/rare control data.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 4 not met · 5 not assessed

Pathogenic

PS2 No confirmed de novo or tissue-mosaic data were identified.

PS3 No validated functional studies demonstrating an abnormal effect of this specific variant were identified, so PS3 is not assessed.

PS4 This variant meets the PM2 population prerequisite because it is absent from gnomAD v2.1 and v4.1, but the available case-level observation data do not reach the VCEP PS4 threshold.

Benign

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

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

BS2 BS2 requires at least 3 homozygotes in gnomAD or at least 3 heterozygous occurrences in well-phenotyped family members.

BS3 No well-validated functional studies demonstrating a normal effect for this specific variant were identified, so BS3 is not assessed.

BP2 No evidence was identified showing this variant in cis or trans with a known pathogenic variant in PIK3CA, so BP2 is not assessed.

BP5 No evidence was identified showing an alternate molecular explanation that would account for the phenotype independently of this variant, so BP5 is not assessed.

N/A · 17 PVS1 · PS1 · PM3 · PM4 · PM5 · PM6 · PP1 · PP2 · 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 = 0.07).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

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; COSV104381249, n = 1 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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