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 ↗

Gene diagram · NM_006218.2 · variants mapped to exon structure

PIK3CA NM_006218.2

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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