Classification rationale

BP6 VUS

PIK3CA c.2040T>C

The PIK3CA c.2040T>C (p.Val680=) variant has been reported in ClinVar and is classified as likely benign by the ClinGen Brain Malformations Variant Curation Expert Panel.¹ This variant is present in gnomAD at 0.00080% in v2.1 (2/248908 alleles) and 0.00248% in v4.1 (40/1612688 alleles), which is below the VCEP BS1 threshold of 0.0185% and BA1 threshold of 0.0926% but exceeds the VCEP PM2 one-person maximum.² SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, although additional VCEP-specified splicing predictors and a conservation score were not identified for BP4 and BP7 assessment.³

BP6 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 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_006218.2 · variants mapped to exon structure

PIK3CA NM_006218.2

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 14 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

BP6 supporting Benign

Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Likely benign.

VCEP lists BP6 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 7 not met · 7 not assessed

Pathogenic

PS1 This is a synonymous variant, p.(Val680=), and no evidence was identified that it results in the same established pathogenic amino acid change as a previously classified pathogenic variant.

PS2 No confirmed de novo evidence was identified for this variant, and no tissue-distribution data were identified showing a higher allele fraction in affected tissue than in another tissue as required by the VCEP framework.

PS3 No published functional or RNA study was identified showing a damaging effect of this exact synonymous variant under the VCEP/SVI assay standards.

PS4 The VCEP requires PM2 before PS4 can be used.

PM1 The VCEP allows PM1_Supporting for PIK3CA variants in approved Table 4 domains at amino acids 322-483 or 797-1068.

PM2 The VCEP applies PM2 only at Supporting strength and limits it to a maximum of one person in controls.

Benign

BA1 The VCEP BA1 threshold is >0.0926%.

BS1 The VCEP BS1 threshold is >0.0185%.

BS2 The VCEP applies BS2 when there are at least 3 homozygotes in population data or at least 3 well-phenotyped unaffected heterozygous family members.

BS3 No published functional or RNA study was identified showing that this exact variant has no damaging effect under the VCEP/SVI assay standards.

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

BP4 This synonymous non-canonical variant has a low SpliceAI score, with a maximum delta score of 0.01, which is consistent with no significant splice effect.

BP5 No evidence was identified that this variant was found in an individual with an alternate molecular explanation for the phenotype.

BP7 This is a synonymous variant outside the canonical splice consensus, but BP7 requires a non-conserved nucleotide with PhyloP <0.1.

N/A · 13 PVS1 · PM3 · PM4 · PM5 · PM6 · PP1 · PP2 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 2.48033e-05; MAF= 0.00248%, 40/1612688 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.22259e-05; MAF= 0.00322%, 38/1179176 alleles, homozygotes = 0); grpmax FAF= 2.395e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 8.0351e-06; MAF= 0.00080%, 2/248908 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.77001e-05; MAF= 0.00177%, 2/112994 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0025% · 40 / 1,612,688
0 hom · FAF 0.0024%

European (non-Finnish) 38 / 1,179,176	0.0032%
Remaining individuals 1 / 62,406	0.0016%
African/African American 1 / 74,878	0.0013%

+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0008% · 2 / 248,908
0 hom · FAF 0.00029%

European (non-Finnish)

2 / 112,994

0.0018%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Likely benign by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel). (ClinVarID = 456534)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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

Check your email

Reset your password

Enter an access code

Your allowance