About PIK3CA
No gene-level summary was recorded for this case.
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.No gene-level summary was recorded for this case.
The recorded framework is ClinGen PIK3CA VCEP v1.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
The variant results in p.Ala442Pro, which lies within the PIK3CA kinase domain interval AA 322-483, an approved critical functional domain in Table 4 of the Brain Malformations VCEP specification. PM1_Supporting is awarded based on domain membership, independent of hotspot recurrence.
The variant is rare in population databases. gnomAD v2.1 reports 1 allele in 233,204 (AF 4.29e-06), meeting the VCEP threshold of ≤1 allele for PM2_Supporting. gnomAD v4.1 reports 8 alleles in 1,597,406 (AF 5.01e-06). The variant is absent from gnomAD-Canada.
PP2 is applicable to PIK3CA per the Brain Malformations VCEP when the missense constraint z-score exceeds 3.09. PIK3CA has a well-established high missense constraint in gnomAD (z-score well above 3.09), supporting that missense variants are a common mechanism of disease in this gene and that benign missense variation is low.
No benign criterion marked as applied in the recorded assessment.
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PM1 supporting (+1) + PM2 supporting (+1) + PP2 supporting (+1) = 3 points, which maps to VUS.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 8 / 1,597,406 alleles. Recorded AF 5.00812e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 4.28809e-06; MAF= 0.00043%, 1/233204 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.18139e-06; MAF= 0.00092%, 1/108916 alleles, homozygotes = 0).
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Uncertain significance.
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.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1.0, with the data and sources behind each one.
27 criteria with recorded statuses: 3 met · 11 not met · 0 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The variant NM_006218.4:c.1324G>C (p.Ala442Pro) lies within the PIK3CA kinase domain (AA 322-483), an approved critical functional domain per the Brain Malformations VCEP Table 4, supporting PM1 at Supporting strength (+1 point).
The variant is rare in population databases: gnomAD v2.1 reports 1 allele in 233,204 (AF 4.29e-06) and v4.1 reports 8 alleles in 1,597,406 (AF 5.01e-06). The variant meets the VCEP PM2_Supporting threshold of ≤1 allele based on v2.1 data (+1 point). gnomAD v4.1 showing 8 alleles is noted for reviewer consideration.
PIK3CA has a high missense constraint z-score in gnomAD (well above the 3.09 threshold specified by the VCEP), supporting PP2 at Supporting strength (+1 point). Missense variants are a recognized mechanism of disease in this gene, and the rate of benign missense variation is low.
No variant-specific functional studies were identified: OncoKB reports Unknown Oncogenic Effect, COSMIC has no entry, and none of the six reviewed publications contained variant-specific functional data. PS3 is not met.
No affected individuals with this variant have been reported in ClinVar (single submitter, Uncertain significance, no case-level detail) or the literature. PS4 cannot be assessed without phenotype data.
Under the Brain Malformations VCEP Tavtigian point framework (page 12), the total evidence score is +3 points (PM1_Supporting +1, PM2_Supporting +1, PP2_Supporting +1), which falls in the VUS range (0 to 5 points). The variant is classified as Uncertain Significance.
No criteria match.
No further detail was recorded.
No further detail was recorded.
Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)8 / 1,175,900 | 6.8e-06 |
| European (non-Finnish)1 / 108,916 | 9.2e-06 |
This variant is present in gnomAD v4.1 (AF= 5.00812e-06; MAF= 0.00050%, 8/1597406 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.8033e-06; MAF= 0.00068%, 8/1175900 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
This variant is present in gnomAD v2.1 (AF= 4.28809e-06; MAF= 0.00043%, 1/233204 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.18139e-06; MAF= 0.00092%, 1/108916 alleles, homozygotes = 0).
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.636. BayesDel score = 0.269546.
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 5.00812e-06; MAF= 0.00050%, 8/1597406 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.8033e-06; MAF= 0.00068%, 8/1175900 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
This variant is present in gnomAD v2.1 (AF= 4.28809e-06; MAF= 0.00043%, 1/233204 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.18139e-06; MAF= 0.00092%, 1/108916 alleles, homozygotes = 0).
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 570411)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.636. BayesDel score = 0.269546.
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.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.