Classification rationale

PM2 VUS

PIK3CA c.2171A>G

The PIK3CA c.2171A>G (p.Lys724Arg; p.K724R) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at Supporting strength under the Brain Malformations VCEP rarity rule.² Under the Brain Malformations VCEP specification, Lys724 is outside the approved PIK3CA PM1 domains at amino acids 322-483 and 797-1068, so PM1 is not met.³ Computational results were reviewed, but PP3 is not applicable for PIK3CA gain-of-function missense variants in this VCEP; SpliceAI predicts no significant splice effect with a max delta score of 0.02, REVEL is 0.399, and BayesDel is -0.142828.⁴

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1

4 cspec ↗spliceai ↗revelbayesdel

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 Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which satisfies the Brain Malformations VCEP PM2 rarity requirement and supports PM2 at Supporting strength.

gnomAD v2.1: absent.gnomAD v4.1: absent.The Brain Malformations VCEP specifies PM2 at Supporting strength for absent/rare variants in controls.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

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

Pathogenic

PS1 No evidence was identified that this nucleotide change results in the same amino acid substitution as a previously established pathogenic PIK3CA variant, so PS1 cannot be applied from the available data.

PS2 No case-level data were identified showing this variant in an affected tissue sample with absence from parental samples and tissue-comparison evidence required by the Brain Malformations VCEP, so PS2 cannot be applied from the available evidence.

PS3 No validated functional assay evidence was identified for this exact variant showing an abnormal gain-of-function effect under the Brain Malformations VCEP framework, so PS3 cannot be applied from the available evidence.

PS4 This variant meets the rarity prerequisite for PS4 because it is absent from gnomAD, but no affected-case evidence or phenotype-point total was identified to support PS4 under the Brain Malformations VCEP point system.

PM1 Under the Brain Malformations VCEP, PM1 for PIK3CA is limited to Supporting strength for variants in approved Table 4 domains.

PM5 No evidence was identified that a different missense change at Lys724 has already been established as pathogenic, so PM5 cannot be applied from the available data.

PP2 PP2 may be used by this VCEP for PIK3CA when the missense constraint z-score exceeds 3.09, but no qualifying missense-constraint evidence was provided in the available materials, so PP2 was not applied.

Benign

BA1 This variant is absent from gnomAD and therefore far below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%, so BA1 is not met.

BS1 This variant is absent from gnomAD and therefore below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%, so BS1 is not met.

BS2 This variant is absent from gnomAD, so the VCEP threshold for BS2 of at least 3 homozygotes in population data is not met, and no well-phenotyped unaffected family observations were identified.

BS3 No well-established functional studies were identified showing no damaging effect for this variant, so BS3 cannot be applied from the available evidence.

BP2 No phase data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 cannot be applied from the available evidence.

BP5 No evidence was identified that this variant was found in a case with an alternate molecular basis for disease, so BP5 cannot be applied from the available data.

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 = 0.02). REVEL score = 0.399. BayesDel score = -0.142828.

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 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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