Final classification

Uncertain Significance

PM1PM2

PIK3CA

c.1255_1264delinsA

p.His419_Leu422delinsMet

This variant

The PIK3CA c.1255_1264delinsA (p.His419_Leu422delinsMet; p.H419_L422delinsM) variant has not been reported in ClinVar, while OncoKB classifies it as Likely Oncogenic.

Transcript

NM_006218.4

HGVS · transcript:coding

NM_006218.4:c.1255_1264delinsA

GRCh38

chr3:179210189 CACTGTCCAT>A

GRCh37

chr3:178927977 CACTGTCCAT>A

Brain Malformations Specification Tavtigian point framework: PM1_Supporting (+1) and PM2_Supporting (+1) yield 2 total points, which falls within the 0-5 Uncertain Significance range.

Classification rationale

PM1PM2 Uncertain Significance

PIK3CA c.1255_1264delinsA

The PIK3CA c.1255_1264delinsA (p.His419_Leu422delinsMet; p.H419_L422delinsM) variant has not been reported in ClinVar, while OncoKB classifies it as Likely Oncogenic.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting that it is absent or extremely rare in population controls.² The altered residues fall within the PIK3CA kinase domain spanning amino acids 322 to 483, which is an approved Brain Malformations VCEP critical functional domain and supports PM1 at Supporting strength.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01.⁴

PM1 + PM2 → Uncertain Significance

1 clinvar ↗oncokb ↗

2 gnomad_v2 ↗gnomad_v4 ↗

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 ↗

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 · 10 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

This protein-altering variant affects residues 419 to 422, which fall within the PIK3CA kinase domain spanning amino acids 322 to 483. The Brain Malformations VCEP lists this interval as an approved critical functional domain, which supports PM1 at Supporting strength.

Protein consequence is p.(His419_Leu422delinsMet).The VCEP Table 4-approved PIK3CA domain includes amino acids 322-483.

cspec ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting that it is absent or extremely rare in population controls. Under the Brain Malformations VCEP, this meets PM2 at Supporting strength.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

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

Pathogenic

PS1 No previously established pathogenic variant producing the same protein change was identified.

PS2 No parental testing results or multi-tissue allele-fraction data were identified.

PS3 No validated functional assay data specific to this variant were identified.

PS4 This variant is absent from population databases and therefore satisfies the PM2 prerequisite for PS4 consideration, but no qualifying affected case reports or phenotype points were identified.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BA1 threshold of greater than 0.0926%.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 threshold of greater than 0.0185%.

BS2 This variant has not been observed in gnomAD, so it does not meet the BS2 requirement of at least 3 homozygotes in population data.

BS3 No well-established functional studies showing no damaging effect were identified.

BP2 No data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant.

BP5 No alternate molecular diagnosis or other established molecular basis for the reported phenotype was identified.

N/A · 16 PVS1 · 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 = 0.01).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

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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