About PIK3CB
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CB c.3200A>T, p.(Asp1067Val)
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 Not recorded. 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
PM1Moderate
PM1 · moderate
Asp1067 is located in the C-terminal kinase domain of PIK3Cβ, a critical functional domain. The residue lies in a statistically significant hotspot (cancerhotspots.org). PMID:25982275 demonstrates that D1067V is the most recurrent missense mutation in the PIK3Cβ kinase domain, accounting for ~15% of missense mutations in this domain. Multiple sequence alignment confirms D1067 is highly conserved across species.
PM2Moderate
PM2 · moderate
NM_006219.2:c.3200A>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes). The variant has an allele frequency of 0.0 in all population databases, which is well below the PM2 threshold of <0.1% for non-VCEP generic ACMG assessment.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate; combination = 2 moderate, 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. 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 identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
16 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV56683107, n = 16 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006219.2:c.3200A>T (p.Asp1067Val) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0).
The variant is absent from ClinVar and has no germline classification from any submitter.
Asp1067 resides in the C-terminal kinase domain of PIK3Cβ and lies within a statistically significant mutational hotspot (cancerhotspots.org). PMID:25982275 reports that D1067V is the most recurrent missense mutation in the PIK3Cβ kinase domain, accounting for ~15% of kinase domain missense mutations, and that D1067 is highly conserved across species.
Functional studies in PMID:25982275 demonstrate that PIK3Cβ/D1067V is a gain-of-function activating mutation in somatic cancer models (enhanced AKT/S6 phosphorylation, increased cell growth in vitro, tumor formation in vivo, erlotinib resistance). This evidence was not applied toward PS3 because the demonstrated gain-of-function mechanism does not align with the reported germline loss-of-function disease mechanism.
REVEL score of 0.65 suggests possible pathogenicity, but BayesDel (0.313) is borderline and SpliceAI predicts no splicing impact (max delta = 0.00). In silico evidence does not provide multiple converging lines for PP3 or BP4.
The variant has been observed 16 times in somatic cancers (COSMIC COSV56683107) and is classified as Oncogenic by OncoKB, but these pertain to somatic context and are not directly applicable to germline classification.
Two moderate pathogenicity criteria are met: PM1 (kinase domain hotspot) and PM2 (absent from population databases). No benign criteria are met. Per generic ACMG/AMP 2015 combination rules, two moderate criteria in the absence of benign criteria yields a classification of Likely Pathogenic.
No criteria match.
Met · 2
PM1 ModerateAsp1067 is located in the C-terminal kinase domain of PIK3Cβ, a critical functional domain. The residue lies in a statistically significant hotspot (cancerhotspots.org). PMID:25982275 demonstrates that D1067V is the most recurrent missense mutation in the PIK3Cβ kinase domain, accounting for ~15% of missense mutations in this domain. Multiple sequence alignment confirms D1067 is highly conserved across species. Details ▾Hide ▴
Evidence considered
- Statistically significant hotspot at residue D1067 (cancerhotspots.org)
- D1067V is the most recurrent kinase domain missense mutation (~15% of all kinase domain missense mutations per PMID:25982275)
- D1067 is highly conserved across species
- located in functionally critical kinase domain.
Sources
PM2 ModerateNM_006219.2:c.3200A>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes). The variant has an allele frequency of 0.0 in all population databases, which is well below the PM2 threshold of <0.1% for non-VCEP generic ACMG assessment. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada v1.0
- AF = 0.0 in all populations.
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No same-amino-acid pathogenic comparator variant was identified. ClinVar is absent for this variant entirely, and the PM5 candidate search found zero same-residue comparator variants. Without a different nucleotide change at Asp1067 classified as pathogenic, PS1 cannot be applied. Details ▾Hide ▴
Evidence considered
- No ClinVar entries at this residue
- no PM5 comparator candidates.
Still missing
- No pathogenic missense variants reported at Asp1067.
Sources
clinvar ↗pm5_candidates
PS2 No de novo observation with confirmed maternity and paternity was identified for this variant in any data source. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No parental genotyping data.
PS3 PMID:25982275 provides well-established functional evidence that PIK3Cβ/D1067V is a gain-of-function activating mutation (enhanced PI3K pathway signaling, increased cell growth in vitro, tumor formation in vivo, erlotinib resistance). However, this evidence is exclusively in a somatic cancer context demonstrating oncogenic activation. The germline disease mechanism reported for PIK3CB is loss of function, with which gain-of-function functional data do not align. Functional evidence from a somatic oncogenic context does not support a damaging effect consistent with the germline loss-of-function disease mechanism. Details ▾Hide ▴
Evidence considered
- Functional studies in PMID:25982275 demonstrate gain-of-function PI3K pathway activation in somatic cancer models (NIH-3T3
- H3255
- A498 cells).
Still missing
- No germline-relevant functional data
- somatic GOF does not align with reported germline LOF mechanism.
Sources
PS4 No case-control data comparing affected individuals to controls is available for this variant. Details ▾Hide ▴
Evidence considered
- No case-control or prevalence data identified.
Still missing
- No affected-vs-control population studies.
PM6 No de novo observation (with or without confirmed parentage) was identified for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No trio or de novo sequencing data.
PP1 No co-segregation data in affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation or family studies identified.
Still missing
- No family-based segregation analysis.
PP2 No HCI prior probability score is available for PIK3CB (gene not supported in HCI database). Without an established low rate of benign missense variation and evidence that missense variants are a common disease mechanism, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- HCI prior not available for PIK3CB
- cannot establish low benign missense rate.
Still missing
- No HCI prior score for PIK3CB
- gene not covered by HCI database.
PP3 In silico evidence is mixed and does not provide multiple converging lines supporting a deleterious effect. REVEL score is 0.65 (above the 0.5 threshold), but BayesDel is 0.313 (borderline, just above ~0.27 threshold), and SpliceAI predicts no splicing impact (max delta = 0.00). Only one predictor (REVEL) clearly supports pathogenicity; this does not constitute multiple lines of computational evidence. Details ▾Hide ▴
Evidence considered
- REVEL: 0.65 (supports pathogenicity)
- BayesDel: 0.313 (borderline)
- SpliceAI max delta: 0.00 (no splicing impact).
Still missing
- No HCI prior
- only REVEL clearly supports pathogenicity.
Sources
PP4 No patient phenotype or family history information is available to assess specificity for a PIK3CB-related disease. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data provided.
Still missing
- No patient clinical information available.
PP5 No reputable source has reported this variant as pathogenic in a germline context. OncoKB classification of Oncogenic pertains to somatic cancer, not germline disease. Details ▾Hide ▴
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0.0, far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.0 in all population databases
- does not meet BA1 threshold.
Sources
BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0.0, far below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.0 in all population databases
- does not meet BS1 threshold.
Sources
BS2 No data are available regarding observation of this variant in healthy adults for a disorder with expected full penetrance at an early age. Details ▾Hide ▴
Evidence considered
- No healthy adult carrier data available.
Still missing
- No population data on healthy adult carriers.
BS3 Functional evidence from PMID:25982275 demonstrates a gain-of-function activating effect (enhanced PI3K signaling, increased cell growth, tumor formation), not a benign or neutral effect on protein function. This does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
- Functional studies show gain-of-function activation
- not a benign effect.
Sources
BS4 No segregation data in affected family members are available to assess lack of segregation. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family-based segregation analysis.
BP1 While the PVS1 gene context reports loss-of-function as a supported disease mechanism, the evidence that primarily truncating variants (rather than missense) cause PIK3CB-related disease is not firmly established. The supporting germline disease papers are tangentially related (FMRP/fragile X, PTEN/autism, testicular cancer, addiction) and do not specifically establish a PIK3CB truncating-variant disease spectrum. BP1 cannot be applied without clear evidence that truncating variants are the primary cause of disease. Details ▾Hide ▴
Evidence considered
- PVS1 gene context reports LOF mechanism supported
- but the germline disease association evidence is weak and does not clearly establish truncating variants as the primary disease cause.
Still missing
- No established PIK3CB germline disease spectrum
- supporting papers do not directly study PIK3CB truncating germline variants.
Sources
pvs1_gene_context
BP2 No data are available regarding observation of this variant in trans with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No trans-phase data available.
Still missing
- No data on co-occurrence with other pathogenic variants.
BP4 In silico evidence does not support a benign interpretation. REVEL score of 0.65 suggests pathogenicity. BayesDel of 0.313 is borderline but does not clearly indicate benign effect. Multiple lines do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.65 (supports pathogenicity
- not benign)
- BayesDel: 0.313 (borderline
- not clearly benign)
- SpliceAI: 0.00 (neutral for splicing).
Sources
BP5 No data are available identifying this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
Still missing
- No data on co-occurring pathogenic variants in other genes.
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no benign classification from any source.
Still missing
- No germline classification data of any kind.
Sources
PS5 No reputable source has reported this variant as pathogenic in a germline context. OncoKB classifies it as Oncogenic in a somatic cancer context, which does not constitute a germline pathogenic assertion. Details ▾Hide ▴
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_006219.2:c.3200A>T is a missense variant (p.Asp1067Val) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The PVS1 variant assessment confirmed variant_bucket='other' and apply_generic_pvs1_framework=false. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a predicted null variant.
Sources
pvs1_variant_assessmentpvs1_gene_context
PM5 N/ANo same-residue comparator missense variants were identified in ClinVar. The PM5 candidate search found zero candidates with a different amino acid change at Asp1067. Without a confirmed pathogenic comparator at the same residue, PM5 cannot be assessed. Details ▾Hide ▴
Evidence considered
- No ClinVar entries at Asp1067
- zero same-residue PM5 comparator candidates found.
Sources
pm5_candidatesclinvar ↗
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not an in-frame indel.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_006219.2:c.3200A>T is a missense variant (p.Asp1067Val), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous.
Identifiers
- Gene
- PIK3CB
- Transcript
- NM_006219.2
- Coding (HGVS c.)
- NM_006219.2:c.3200A>T
- Protein (HGVS p.)
- NP_006210.1:p.(Asp1067Val)
- GRCh38
- chr3:138655402 T>A
- GRCh37
- chr3:138374244 T>A
- COSMIC
- COSV56683107
Gene diagram
Every interpreted variant in PIK3CB, mapped onto the exon structure of NM_006219.2. Select a row to find it on the plot.
PIK3CBNM_006219.2
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 PIK3CB
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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
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.650
- BayesDel
- 0.313
How the predictions were used
PP3 In silico evidence is mixed and does not provide multiple converging lines supporting a deleterious effect. REVEL score is 0.65 (above the 0.5 threshold), but BayesDel is 0.313 (borderline, just above ~0.27 threshold), and SpliceAI predicts no splicing impact (max delta = 0.00). Only one predictor (REVEL) clearly supports pathogenicity; this does not constitute multiple lines of computational evidence. Details ▾Hide ▴
Evidence considered
- REVEL: 0.65 (supports pathogenicity)
- BayesDel: 0.313 (borderline)
- SpliceAI max delta: 0.00 (no splicing impact).
Still missing
- No HCI prior
- only REVEL clearly supports pathogenicity.
Sources
BP4 In silico evidence does not support a benign interpretation. REVEL score of 0.65 suggests pathogenicity. BayesDel of 0.313 is borderline but does not clearly indicate benign effect. Multiple lines do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.65 (supports pathogenicity
- not benign)
- BayesDel: 0.313 (borderline
- not clearly benign)
- SpliceAI: 0.00 (neutral for splicing).
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_006219.2:c.3200A>T is a missense variant (p.Asp1067Val), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.65. BayesDel score = 0.312683.
1 paper record listed. 1 cited in the classification.
Cited in the classification
-
PMID 25982275 ↗Oncogenic activation of the PI3-kinase p110β isoform via the tumor-derived PIK3Cβ(D1067V) kinase domain mutation.PIK3Cβ/D1067V demonstrated gain-of-function activation of PI3K pathway signaling (increased phosphorylated AKT and S6 kinase compared to wild-type), enhanced cell growth in vitro in NIH-3T3 cells, and was sufficient for tumor formation in vivo in immunocompromised mice. In patient-derived A498 renal-cell carcinoma cells with endogenous PIK3Cβ/D1067V, genetic and pharmacologic inhibition of p110β suppressed growth and PI3K signaling. Expression of PIK3Cβ/D1067V in EGFR-mutant H3255 NSCLC cells sustained AKT/S6 phosphorylation during erlotinib treatment and promoted drug resistance. D1067V was identified as the most recurrent missense mutation in the PIK3Cβ kinase domain (~15% of mutations) and was observed across multiple tumor types (NSCLC, RCC, GBM, HNSCC, melanoma, thyroid, endometrial).→ PM1 Names this variant
Source detail
PIK3CβD1067V activated PI3K pathway downstream signaling, as measured by the levels of phosphorylated AKT and S6 kinase, to a greater degree than PIK3CβWT
Location Abstract; Results and Discussion, pages 1-7; Figures 1-4
Context NIH-3T3 fibroblasts (stable retroviral transduction), H3255 EGFR-mutant NSCLC cells, A498 renal-cell carcinoma cells (endogenous heterozygous D1067V); immunoblot, CellTiterGLO viability assays, tumor allograft assays in immunocompromised mice, pharmacologic inhibition with TGX-221 (p110β-selective) and BKM-120 (pan-PI3K)
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
Recorded maximum delta 0.000
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 ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_006219.2%3Ac.3200A%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-138374244-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-138655402-T-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-138655402-T-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006219.2%3Ac.3200…
- OncoKB ↗www.oncokb.org/gene/PIK3CB/D1067V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=124355665
- 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.
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 = 0.00). REVEL score = 0.65. BayesDel score = 0.312683.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56683107, n = 16 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.