About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.370C>T, p.(Pro124Ser)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v4.1 (0/1,608,782 alleles, 0 homozygotes) and absent from gnomAD v2.1, meeting the VCEP PM2_Supporting criterion of absence or rarity in an ethnically-matched cohort population sample (≥1 individual threshold).
PP2Supporting
PP2 · supporting
PIK3CA has a high missense constraint z-score in gnomAD (z > 3.09), meeting the VCEP PP2_Supporting criterion for genes where missense variants are a common mechanism of disease and benign missense variation is depleted. The VCEP explicitly lists PIK3CA as applicable for PP2.
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) + PP2 supporting (+1) = 2 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
0 / 1,608,782 alleles
gnomAD v4.1: 0 / 1,608,782 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.060 maximum delta
Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55888156, n = 2 times).
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.
26 criteria with recorded statuses: 2 met · 12 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006218.3:c.370C>T (p.Pro124Ser) is a missense variant in PIK3CA, a gene in which gain-of-function missense variants cause brain malformations including megalencephaly and focal cortical dysplasia.
This variant is absent from gnomAD v4.1 (0/1,608,782 alleles) and gnomAD v2.1, supporting PM2_Supporting under the Brain Malformations VCEP population criterion.
PIK3CA has high missense constraint (gnomAD missense z-score >3.09), meeting PP2_Supporting under the VCEP specification.
Residue Pro124 lies within the adaptor-binding domain region, outside the VCEP Table 4 approved critical functional domains (AA 322-483 and AA 797-1068 kinase domains); PM1_Supporting is therefore not met.
No functional study has directly tested P124S. PMID:22430209 tested P124L (a different missense at the same residue) in a somatic cancer context and demonstrated gain-of-function activity, but this evidence is not transferable to P124S and does not satisfy VCEP PS3 requirements.
Total Tavtigian points: PM2_Supporting (+1) + PP2_Supporting (+1) = 2 points. Under the VCEP point framework (>10 Pathogenic, 6-9 Likely Pathogenic, 0-5 VUS), a score of 2 falls within the VUS range.
This variant is classified as a Variant of Uncertain Significance (VUS) under the ClinGen Brain Malformations Expert Panel specifications version 1.1.0.
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v4.1 (0/1,608,782 alleles, 0 homozygotes) and absent from gnomAD v2.1, meeting the VCEP PM2_Supporting criterion of absence or rarity in an ethnically-matched cohort population sample (≥1 individual threshold). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 exomes
- absent from gnomAD v4.1 (0/1
- 608
- 782 alleles across all populations).
Sources
PP2 SupportingPIK3CA has a high missense constraint z-score in gnomAD (z > 3.09), meeting the VCEP PP2_Supporting criterion for genes where missense variants are a common mechanism of disease and benign missense variation is depleted. The VCEP explicitly lists PIK3CA as applicable for PP2. Details ▾Hide ▴
Evidence considered
- VCEP specification awards PP2 if missense z-score > 3.09
- PIK3CA missense z-score in gnomAD is approximately 4.11
- well above the threshold. PIK3CA is explicitly listed as eligible for PP2 in the VCEP rule.
Still missing
- Exact current gnomAD missense z-score for PIK3CA should be confirmed at time of final report.
Sources
Not met · 12 · evaluated, threshold not reached
PS1 No previously established pathogenic variant with the same amino acid change (P124S) has been identified. The variant is absent from ClinVar, and no published report describes P124S as a pathogenic variant in any context. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no pathogenic or likely pathogenic classification exists for P124S.
Sources
PS2 No de novo observation has been reported for this variant. The VCEP PS2 criteria require confirmed maternity and paternity with absent parental variant (Strong) or at minimum evidence of tissue-specific mosaicism (Moderate). Neither is available. Details ▾Hide ▴
Evidence considered
- No de novo case reports or parental testing data available for this variant.
Still missing
- De novo confirmation with parental testing would be required to apply PS2.
PS3 No functional study has directly tested P124S (NM_006218.3:c.370C>T). The only functional study of the same residue tested P124L (a different amino acid substitution) in a somatic cancer context using NIH3T3 and NHUC cell lines; that study demonstrated gain-of-function activity for P124L but did not examine P124S. Under VCEP PS3 criteria, the exact variant must be tested unless a systematic range characterization including the variant position is available, which is not the case here. Details ▾Hide ▴
Evidence considered
- PMID:22430209 tested P124L
- not P124S
- results are not transferable to a different amino acid substitution.
Still missing
- Direct functional testing of P124S in a validated assay is needed to apply PS3.
PS4 No probands with brain malformation phenotypes have been reported for this variant. The VCEP PS4 is point-based and requires PM2 as a prerequisite. COSMIC reports two somatic occurrences, which under Table 2A would contribute at most 0.25 points each (0.50 total), falling below the PS4_Supporting threshold of 0.5–1.25 points. No germline case reports with relevant phenotypes exist. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD (PM2 met)
- COSMIC reports 2 somatic occurrences insufficient for even PS4_Supporting
- no germline brain malformation probands reported.
Still missing
- Probands with brain malformation phenotypes and this variant would be needed to apply PS4.
Sources
PM1 Residue Pro124 falls within the p85-binding/adaptor-binding domain (ABD) region of PIK3CA, outside the VCEP Table 4 approved critical functional domains for PM1_Supporting (AA 322–483 kinase domain and AA 797–1068 kinase domain). Although the literature supports functional relevance of position 124 for p85α interaction, it does not meet the VCEP domain criteria for PM1 application. Details ▾Hide ▴
Evidence considered
- VCEP Table 4 domains for PIK3CA are AA 322-483 and AA 797-1068
- residue 124 is outside both intervals. PMID:22430209 shows P124L affects p85α interaction but this does not satisfy VCEP domain criteria.
Sources
PM5 No different missense variant at residue Pro124 has been classified as pathogenic in ClinVar. P124L was reported in PMID:22430209 as a rare somatic variant in urothelial carcinoma with gain-of-function activity, but has never been classified as pathogenic in a germline context and lacks a ClinVar pathogenic assertion. The VCEP PM5 (Moderate, 'No change' from original ACMG) requires a previously established pathogenic missense at the same residue, which is not available. Details ▾Hide ▴
Evidence considered
- ClinVar contains no pathogenic missense variant at residue 124. P124L reported in somatic cancer context (PMID:22430209) without germline pathogenic classification.
Still missing
- A germline pathogenic classification for a different missense at residue 124 would be needed to apply PM5.
Sources
BA1 The variant is absent from gnomAD v4.1 (allele frequency 0.00%). The VCEP BA1 Stand Alone threshold is >0.0926%, which is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 0.00% (0/1
- 608
- 782 alleles)
- well below the VCEP BA1 threshold of >0.0926%.
Sources
BS1 The variant is absent from gnomAD v4.1 (allele frequency 0.00%). The VCEP BS1 Strong threshold is >0.0185%, which is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 0.00% (0/1
- 608
- 782 alleles)
- well below the VCEP BS1 threshold of >0.0185%.
Sources
BS2 No homozygotes are present in gnomAD (0 homozygotes in v4.1), and no well-phenotyped heterozygous family members have been reported. The VCEP BS2 Strong requires ≥3 homozygotes in gnomAD or ≥3 heterozygous well-phenotyped family members. Details ▾Hide ▴
Evidence considered
- Zero homozygotes in gnomAD v4.1
- no published reports of unaffected heterozygous carriers.
Sources
BS3 No functional study has demonstrated that P124S has no damaging effect on protein function. The only functional study at this residue (PMID:22430209) tested P124L and demonstrated gain-of-function activity, which would be in the opposite direction of BS3. No well-established in vitro or in vivo studies show a benign functional effect for P124S. Details ▾Hide ▴
Evidence considered
- PMID:22430209 tested P124L (not P124S) and showed GOF activity
- which does not support BS3. No benign functional data exist for P124S.
Still missing
- Functional studies directly testing P124S and demonstrating no damaging effect would be needed.
BP2 No evidence that this variant has been observed in cis or trans with a known pathogenic variant in PIK3CA. No phase information is available. Details ▾Hide ▴
Evidence considered
- No reports of this variant co-occurring in cis or trans with a pathogenic PIK3CA variant.
Still missing
- Observation in cis or trans with a known pathogenic PIK3CA variant would be needed.
BP5 No case has been reported in which this variant was found in an individual with an alternate molecular basis for disease. The VCEP BP5 (Supporting, 'No change') requires evidence of an alternate molecular diagnosis in a case harboring this variant. Details ▾Hide ▴
Evidence considered
- No reports of this variant co-occurring with an alternate molecular diagnosis.
Still missing
- A case with this variant and a confirmed alternate molecular etiology would be needed.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is not applicable under the ClinGen Brain Malformations VCEP because the disease mechanism for PIK3CA is gain of function, not loss of function or haploinsufficiency. Details ▾Hide ▴
Evidence considered
- VCEP criteria specify PVS1 as Not Applicable for this VCEP: 'LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes.'
Sources
PM6 VCEPPM6 is not applicable under the ClinGen Brain Malformations VCEP: 'This point is addressed according to PS2 and will not be used.' Details ▾Hide ▴
Evidence considered
- VCEP specification states PM6 is addressed according to PS2 and will not be used.
Sources
PP1 VCEPPP1 is not applicable under the ClinGen Brain Malformations VCEP: 'Not applicable since disease-causing variants are germline mosaic, de novo or mosaic.' Details ▾Hide ▴
PP3 VCEPPP3 is not applicable under the ClinGen Brain Malformations VCEP: 'This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.' Details ▾Hide ▴
Evidence considered
- VCEP specification states PP3 is not applicable for GOF genes
- in silico predictors focus on LOF mechanisms.
Sources
PP4 VCEPPP4 is not applicable under the ClinGen Brain Malformations VCEP: 'Not applicable since this criterion is accounted for under PS4.' Details ▾Hide ▴
PP5 VCEPPP5 is not applicable: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
Evidence considered
- VCEP specification states PP5 is not for use per ClinGen SVI VCEP Review Committee.
Sources
BS4 VCEPBS4 is not applicable under the ClinGen Brain Malformations VCEP: 'Not applicable as these are de novo, germline mosaic or post-zygotic mutations.' Details ▾Hide ▴
Evidence considered
- VCEP specification states BS4 is not applicable for these variant types.
Sources
BP1 VCEPBP1 is not applicable under the ClinGen Brain Malformations VCEP: 'Not applicable as LOF is not the disease mechanism.' Details ▾Hide ▴
Evidence considered
- VCEP specification states BP1 is not applicable because the disease mechanism is GOF
- not LOF.
Sources
BP4 N/ABP4 under this VCEP is restricted to synonymous variants, intronic positions (except canonical splice sites), and non-coding variants in UTRs. NM_006218.3:c.370C>T is a missense variant and does not qualify for BP4 application. Details ▾Hide ▴
Evidence considered
- VCEP BP4 rule states: 'Not applicable for any variant type except for synonymous
- intronic positions (except canonical splice sites) and non-coding variants in the UTRs.' This variant is a missense substitution.
Sources
BP6 VCEPBP6 is not applicable: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
Evidence considered
- VCEP specification states BP6 is not for use per ClinGen SVI VCEP Review Committee.
Sources
BP7 N/ABP7 under this VCEP is restricted to synonymous variants, intronic positions (except canonical splice sites), and non-coding variants in UTRs. NM_006218.3:c.370C>T is a missense variant and does not qualify for BP7 application. Details ▾Hide ▴
Evidence considered
- VCEP BP7 rule applies only to synonymous
- intronic
- and UTR variants. This variant is a missense substitution.
Sources
PS5 N/APS5 is not a recognized criterion in the ClinGen Brain Malformations VCEP specification and is not included in the CSPEC criteria list for PIK3CA. Details ▾Hide ▴
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.3
- Coding (HGVS c.)
- NM_006218.3:c.370C>T
- Protein (HGVS p.)
- NP_006209.2:p.(Pro124Ser)
- GRCh38
- chr3:179199707 C>T
- GRCh37
- chr3:178917495 C>T
- COSMIC
- COSV55888156
Gene diagram
Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.3. Select a row to find it on the plot.
PIK3CANM_006218.3
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
0 / 1,608,782 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,608,782 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1608782 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74876 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.189
- BayesDel
- -0.024
How the predictions were used
PP3 VCEPPP3 is not applicable under the ClinGen Brain Malformations VCEP: 'This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.' Details ▾Hide ▴
Evidence considered
- VCEP specification states PP3 is not applicable for GOF genes
- in silico predictors focus on LOF mechanisms.
Sources
BP4 N/ABP4 under this VCEP is restricted to synonymous variants, intronic positions (except canonical splice sites), and non-coding variants in UTRs. NM_006218.3:c.370C>T is a missense variant and does not qualify for BP4 application. Details ▾Hide ▴
Evidence considered
- VCEP BP4 rule states: 'Not applicable for any variant type except for synonymous
- intronic positions (except canonical splice sites) and non-coding variants in the UTRs.' This variant is a missense substitution.
Sources
BP7 N/ABP7 under this VCEP is restricted to synonymous variants, intronic positions (except canonical splice sites), and non-coding variants in UTRs. NM_006218.3:c.370C>T is a missense variant and does not qualify for BP7 application. Details ▾Hide ▴
Evidence considered
- VCEP BP7 rule applies only to synonymous
- intronic
- and UTR variants. This variant is a missense substitution.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.189. BayesDel score = -0.0235373.
1 paper record 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.
Recorded publications
-
PMID 22430209 ↗PIK3CA mutation spectrum in urothelial carcinoma reflects cell context-dependent signaling and phenotypic outputs.Ross et al. investigated phenotypic and signaling consequences of hotspot and rare PIK3CA mutations in immortalized normal human urothelial cells (NHUC) and mouse fibroblasts (NIH3T3). P124L was tested among 7 rare UC-associated PIK3CA variants and demonstrated gain-of-function activity including AKT pathway activation, colony formation in agar, and increased cell motility. In silico analysis suggested P124L may alter the regulatory interaction of p85α with p110α at the adaptor-binding domain. NM_006218.3:c.370C>T (P124S) was not tested or mentioned in this paper.Does not name this variant
Quoted passage
Mutations identified in UC include rare mutations found in other cancers (E545G, E545Q, G1007R, D1017H, M1043I and H1047L) and novel mutations (P124L, V136I Q643R and A1066V)
Abstract; Results, paragraphs on rare mutant analysis; Discussion, paragraph on P124L structural analysis; Materials and Methods, list of mutants generated (line 593-594)
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,608,782 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.060
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_006218.3%3Ac.370C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178917495-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179199707-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-179199707-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.3%3Ac.370C…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/P124S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=119974273
- 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
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1608782 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74876 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.189. BayesDel score = -0.0235373.
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 previously been reported in somatic cancers (COSMIC; COSV55888156, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.