About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.2171A>G, p.(Lys724Arg)
Classification
Uncertain significance
Variant description:
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.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
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.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PM2 supporting (+1) = 1 points, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 4 not met · 9 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 1
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
PM2_Supporting for absent/rare variants in population controls.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- The Brain Malformations VCEP specifies PM2 at Supporting strength for absent/rare variants in controls.
Sources
Not met · 4 · evaluated, threshold not reached
PM1 Under the Brain Malformations VCEP, PM1 for PIK3CA is limited to Supporting strength for variants in approved Table 4 domains. Lys724 is outside the listed kinase-domain intervals of amino acids 322-483 and 797-1068, so PM1 is not met. Details ▾Hide ▴
Rule
PM1_Supporting for variants in approved Table 4 domains.
Evidence considered
- The VCEP-approved PIK3CA PM1 domains are amino acids 322-483 and 797-1068.
- The variant protein consequence is p.Lys724Arg.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
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. Details ▾Hide ▴
Rule
BA1 if allele frequency is greater than 0.0926%.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- BA1 threshold under the VCEP is greater than 0.0926%.
Sources
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. Details ▾Hide ▴
Rule
BS1 if allele frequency is greater than 0.0185%.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- BS1 threshold under the VCEP is greater than 0.0185%.
Sources
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. Details ▾Hide ▴
Rule
BS2 if at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected family members.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- The Brain Malformations VCEP requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected family observations.
Still missing
- No unaffected family-based evidence was identified.
Sources
Not assessed · 9 · no assessment recorded
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. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant.
Evidence considered
- ClinVar did not list this variant.
- The Brain Malformations VCEP allows PS1 only when the same amino acid change has already been established as pathogenic.
Still missing
- No qualifying previously established pathogenic alternate nucleotide change at p.Lys724Arg was identified.
Sources
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. Details ▾Hide ▴
Rule
PS2_Strong requires parental absence plus affected-tissue enrichment; PS2_Moderate requires one of these elements per VCEP.
Evidence considered
- ClinVar did not list this variant.
- The Brain Malformations VCEP requires defined de novo and/or tissue mosaicism evidence for PS2.
Still missing
- No confirmed parental testing data were identified.
- No tissue-comparison allele fraction data were identified.
Sources
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. Details ▾Hide ▴
Rule
Well-established functional studies supportive of a damaging effect under VCEP specifications.
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
- The Brain Malformations VCEP requires validated functional evidence for PS3.
Still missing
- No variant-specific validated functional study was identified.
Sources
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. Details ▾Hide ▴
Rule
PS4 strength is based on Table 2 phenotype points after PM2 is satisfied.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- ClinVar: no result.
- COSMIC: no result.
- The Brain Malformations VCEP requires PM2 first and then phenotype-point accumulation for PS4.
Still missing
- No confirmed affected-case reports or phenotype point assignments were identified.
- No literature or database observations were identified to total PS4 points.
Sources
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. Details ▾Hide ▴
Rule
Novel missense change at a residue where a different pathogenic missense change has been seen before.
Evidence considered
- ClinVar did not list this variant.
- No same-codon pathogenic comparator was identified in the available materials.
Still missing
- No established pathogenic alternate missense variant at codon 724 was identified.
Sources
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. Details ▾Hide ▴
Rule
PP2 if missense constraint z-score is greater than 3.09.
Evidence considered
- The Brain Malformations VCEP allows PP2 if the missense constraint z-score is greater than 3.09.
Still missing
- No PIK3CA missense constraint z-score evidence was identified in the reviewed materials.
Sources
BS3 No well-established functional studies were identified showing no damaging effect for this variant, so BS3 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
Well-established functional studies show no damaging effect.
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
- The Brain Malformations VCEP requires validated functional evidence for BS3.
Still missing
- No benign functional assay data were identified for p.Lys724Arg.
Sources
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. Details ▾Hide ▴
Rule
Observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
- No ClinVar record or case-level phasing information was identified.
- The Brain Malformations VCEP allows BP2 when a variant is observed in cis or trans with a known pathogenic variant.
Still missing
- No phasing data or second-variant data were identified.
Sources
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. Details ▾Hide ▴
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable under the Brain Malformations VCEP because the disease mechanism for PIK3CA in this framework is gain of function, and this variant is a missense substitution rather than a null variant. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- The Brain Malformations VCEP marks PVS1 as not applicable for PIK3CA gain-of-function disease.
- The variant-level PVS1 scaffold identifies this change as outside the generic null-variant buckets.
Sources
PM3 N/APM3 is not applicable under the Brain Malformations VCEP because PIK3CA-related disease in this framework is not interpreted as a recessive condition requiring trans observations. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- The Brain Malformations VCEP marks PM3 as not applicable.
Sources
PM4 N/APM4 is not applicable under the Brain Malformations VCEP and this variant is not an in-frame insertion, deletion, or stop-loss change. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- The Brain Malformations VCEP marks PM4 as not applicable.
Sources
PM6 N/APM6 is not applicable under the Brain Malformations VCEP because de novo and mosaic evidence is addressed through the PS2 framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- The Brain Malformations VCEP marks PM6 as not applicable.
Sources
PP1 N/APP1 is not applicable under the Brain Malformations VCEP because disease-causing variants in this setting are typically de novo, germline mosaic, or post-zygotic rather than assessed through segregation. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- The Brain Malformations VCEP marks PP1 as not applicable.
Sources
PP3 N/APP3 is not applicable under the Brain Malformations VCEP for PIK3CA gain-of-function variants. Computational results were reviewed, including SpliceAI max delta 0.02, REVEL 0.399, and BayesDel -0.142828, but they do not override the VCEP rule excluding PP3 for this variant class. Details ▾Hide ▴
Rule
Not applicable for this VCEP because traditional prediction algorithms are not used for these gain-of-function variants.
Evidence considered
- The Brain Malformations VCEP states PP3 is not applicable for these gain-of-function genes.
- SpliceAI max delta score: 0.02.
- REVEL score: 0.399.
- BayesDel score: -0.142828.
Sources
PP4 N/APP4 is not applicable under the Brain Malformations VCEP because phenotype specificity is accounted for within the VCEP PS4 framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- The Brain Malformations VCEP marks PP4 as not applicable.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5 N/APP5 is not used under current ClinGen VCEP recommendations, so it is not applicable for this review. Details ▾Hide ▴
Rule
Not for use.
Evidence considered
- The Brain Malformations VCEP marks PP5 as not applicable.
Sources
BS4 N/ABS4 is not applicable under the Brain Malformations VCEP because disease-associated variants in this setting are typically de novo, germline mosaic, or post-zygotic rather than evaluated through lack of segregation. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- The Brain Malformations VCEP marks BS4 as not applicable.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1 N/ABP1 is not applicable under the Brain Malformations VCEP because loss of function is not the disease mechanism for PIK3CA in this setting. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- The Brain Malformations VCEP marks BP1 as not applicable.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3 N/ABP3 is not applicable under the Brain Malformations VCEP for these genes. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- The Brain Malformations VCEP marks BP3 as not applicable.
Sources
BP4 N/ABP4 under the Brain Malformations VCEP applies only to synonymous, intronic, or non-coding variants evaluated for splicing. This missense variant is therefore not eligible for BP4, although SpliceAI predicts no significant splice impact with a max delta score of 0.02. Details ▾Hide ▴
Rule
BP4 for qualifying non-missense variants when splicing tools predict no impact.
Evidence considered
- The Brain Malformations VCEP limits BP4 to synonymous
- intronic
- and non-coding variants.
- SpliceAI max delta score: 0.02.
Sources
BP6 N/ABP6 is not used under current ClinGen VCEP recommendations, so it is not applicable for this review. Details ▾Hide ▴
Rule
Not for use.
Evidence considered
- The Brain Malformations VCEP marks BP6 as not applicable.
Sources
BP7 N/ABP7 is restricted to synonymous, intronic, or certain non-coding variants. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 for qualifying synonymous, intronic, or non-coding variants with low conservation.
Evidence considered
- The variant consequence is p.Lys724Arg missense.
- The Brain Malformations VCEP limits BP7 to synonymous
- intronic
- or non-coding variants.
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.2171A>G
- Protein (HGVS p.)
- NP_006209.2:p.(Lys724Arg)
- GRCh38
- chr3:179221141 A>G
- GRCh37
- chr3:178938929 A>G
Gene diagram
Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.4. Select a row to find it on the plot.
PIK3CANM_006218.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PIK3CA
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is not applicable under the Brain Malformations VCEP for PIK3CA gain-of-function variants. Computational results were reviewed, including SpliceAI max delta 0.02, REVEL 0.399, and BayesDel -0.142828, but they do not override the VCEP rule excluding PP3 for this variant class. Details ▾Hide ▴
Rule
Not applicable for this VCEP because traditional prediction algorithms are not used for these gain-of-function variants.
Evidence considered
- The Brain Malformations VCEP states PP3 is not applicable for these gain-of-function genes.
- SpliceAI max delta score: 0.02.
- REVEL score: 0.399.
- BayesDel score: -0.142828.
Sources
BP4 N/ABP4 under the Brain Malformations VCEP applies only to synonymous, intronic, or non-coding variants evaluated for splicing. This missense variant is therefore not eligible for BP4, although SpliceAI predicts no significant splice impact with a max delta score of 0.02. Details ▾Hide ▴
Rule
BP4 for qualifying non-missense variants when splicing tools predict no impact.
Evidence considered
- The Brain Malformations VCEP limits BP4 to synonymous
- intronic
- and non-coding variants.
- SpliceAI max delta score: 0.02.
Sources
BP7 N/ABP7 is restricted to synonymous, intronic, or certain non-coding variants. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 for qualifying synonymous, intronic, or non-coding variants with low conservation.
Evidence considered
- The variant consequence is p.Lys724Arg missense.
- The Brain Malformations VCEP limits BP7 to synonymous
- intronic
- or non-coding variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.399. BayesDel score = -0.142828.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/467907148
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_006218.4%3Ac.2171A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178938929-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179221141-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.2171…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/K724R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.2171A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from 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.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.