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PIK3CAc.3133G>AUncertain significance
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Variant interpretation report

PIK3CA c.3133G>A, p.(Asp1045Asn)

NM_006218.3:c.3133G>A NP_006209.2:p.(Asp1045Asn) View identifiers
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.

About PIK3CA

No gene-level summary was recorded for this case.

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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Supporting
PM1 · supporting

Residue p.Asp1045 lies within the PIK3CA C-terminal kinase domain (AA 797-1068), which is listed as a critical functional domain in Table 4 of the Brain Malformations VCEP specification. Per VCEP rules, PM1_Supporting is domain-based and does not require hotspot recurrence when the residue falls inside an approved Table 4 domain.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Per VCEP specification, PM2 is applied at Supporting strength for variants absent or rare (≤1) in an ethnically-matched cohort population sample.

PP2Supporting
PP2 · supporting

PIK3CA is a gene with a low rate of benign missense variation. Per the VCEP specification, PP2 is awarded for PIK3CA because the missense constraint Z-score in gnomAD/ExAC exceeds 3.09, and PIK3CA is explicitly listed as an applicable gene for this criterion.

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: PM1 supporting (+1) + PM2 supporting (+1) + PP2 supporting (+1) = 3 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.

SpliceAI score
0.050 maximum delta

Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

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
13 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55874677, n = 13 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
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: 3 met · 12 not met · 0 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The p.Asp1045Asn substitution lies within the PIK3CA C-terminal kinase domain (AA 797-1068), a critical functional domain defined in Table 4 of the Brain Malformations VCEP specification (PM1_Supporting).

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases (PM2_Supporting).

PIK3CA exhibits strong missense constraint with a gnomAD missense Z-score exceeding 3.09, meeting the VCEP threshold for PP2_Supporting.

Under the Brain Malformations VCEP Tavtigian point framework, total points = +3 (PM1_Supporting +1, PM2_Supporting +1, PP2_Supporting +1), which falls within the VUS range (0-5 points). The final classification is Uncertain Significance.

Met · 3

PM1 SupportingResidue p.Asp1045 lies within the PIK3CA C-terminal kinase domain (AA 797-1068), which is listed as a critical functional domain in Table 4 of the Brain Malformations VCEP specification. Per VCEP rules, PM1_Supporting is domain-based and does not require hotspot recurrence when the residue falls inside an approved Table 4 domain. Details ▾Hide ▴
Evidence considered
  • Residue D1045 is within the PIK3CA kinase domain (AA 797-1068) per VCEP Table 4 approved critical functional domains.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Per VCEP specification, PM2 is applied at Supporting strength for variants absent or rare (≤1) in an ethnically-matched cohort population sample. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • gnomAD v4.1
  • and gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP2 SupportingPIK3CA is a gene with a low rate of benign missense variation. Per the VCEP specification, PP2 is awarded for PIK3CA because the missense constraint Z-score in gnomAD/ExAC exceeds 3.09, and PIK3CA is explicitly listed as an applicable gene for this criterion. Details ▾Hide ▴
Evidence considered
  • PIK3CA missense Z-score in gnomAD exceeds the 3.09 threshold. VCEP explicitly lists PIK3CA as applicable for PP2.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1

Not met · 12 · evaluated, threshold not reached

PS1 No other nucleotide change resulting in the same amino acid substitution (p.Asp1045Asn) has been identified as pathogenic in ClinVar or the literature. The variant is reported only as Uncertain significance by a single clinical submitter (ClinVar 3774060). Details ▾Hide ▴
Evidence considered
  • ClinVar variation 3774060 shows only a single VUS submission with no pathogenic classifications for this codon.
Sources
clinvar ↗
PS2 No de novo evidence is available. Under the VCEP, PS2 requires confirmed maternity/paternity with variant absent from parental samples (Criteria 1) and differential tissue allelic fraction (Criteria 2) for Strong, or at least one of these criteria for Moderate. No de novo reports exist for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in ClinVar submissions or literature.
Still missing
  • No parental testing data available.
Sources
cspec ↗
PS3 No variant-specific functional studies were identified. OncoKB classifies this variant as Unknown Oncogenic Effect. No publications with functional data for NM_006218.3:c.3133G>A were found in the literature search. Details ▾Hide ▴
Evidence considered
  • OncoKB reports Unknown Oncogenic Effect for this variant. No functional studies identified in literature.
Still missing
  • No functional studies (phosphorylation
  • DEPTOR binding
  • cell proliferation
  • or animal models) available for this variant.
Sources
oncokb ↗
PS4 Under the VCEP PS4 point-based system, phenotyped cases from literature are required for point assignment. No phenotyped cases were identified in the literature. COSMIC somatic occurrence data (n=13) can contribute only 0.25 points per occurrence category under Table 2A and cannot independently yield PS4 evidence without phenotyped cases. PM2 is met, but no meaningful PS4 points can be assigned without case-level data. Details ▾Hide ▴
Evidence considered
  • COSMIC reports 13 somatic occurrences (COSV55874677) but no phenotyped clinical cases were identified in the literature.
Still missing
  • No phenotyped clinical cases reported in literature.
Sources
cspec ↗
PM5 No different pathogenic missense variant has been identified at the same amino acid residue (p.Asp1045). The PM5 candidate search found zero comparator variants at this residue in ClinVar. Although the variant is a missense change (p.Asp1045Asn), there is no pathogenic comparator to satisfy PM5. Details ▾Hide ▴
Evidence considered
  • Zero candidate variants identified at residue D1045 in ClinVar. Only this variant (3774060
  • VUS) is reported.
Still missing
  • No pathogenic comparators at the same residue.
Sources
pm5_candidatesclinvar ↗
BA1 The VCEP BA1 threshold is allele frequency >0.0926%. This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, falling well below the BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Variant absent from all available population databases. Allele frequency is 0%
  • below the BA1 threshold of >0.0926%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The VCEP BS1 threshold is allele frequency >0.0185%. This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, falling below the BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Variant absent from all available population databases. Allele frequency is 0%
  • below the BS1 threshold of >0.0185%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 Under the VCEP, BS2 requires ≥3 homozygotes in gnomAD or ≥3 heterozygous in well-phenotyped family members. This variant is absent from all gnomAD populations and no family member data are available. Details ▾Hide ▴
Evidence considered
  • Zero homozygotes in gnomAD (variant is entirely absent). No well-phenotyped family members reported.
Still missing
  • No family member phenotyping data available.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing were identified for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies identified. OncoKB reports Unknown Oncogenic Effect.
Still missing
  • No functional data available to assess absence of damaging effect.
Sources
oncokb ↗
BP2 No evidence that this variant has been observed in cis or trans with a known pathogenic variant in PIK3CA. Details ▾Hide ▴
Evidence considered
  • No reports of this variant in cis or trans with a known pathogenic PIK3CA variant.
Still missing
  • No data on phase with other PIK3CA variants.
BP5 No alternate molecular basis for disease has been identified in a case carrying this variant. Details ▾Hide ▴
Evidence considered
  • No reports of this variant co-occurring with an alternate molecular diagnosis.
Still missing
  • No case-level data available.
PS5 No different amino acid change at the same nucleotide position (c.3133G) has been established as pathogenic. The only variant reported at this nucleotide is c.3133G>A (p.Asp1045Asn), which is classified as VUS in ClinVar. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no pathogenic classifications for any nucleotide change at c.3133.
Sources
clinvar ↗
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable under the Brain Malformations VCEP because the disease mechanism for PIK3CA is gain of function; loss of function and haploinsufficiency have not been established as disease mechanisms for brain malformations associated with this gene. Details ▾Hide ▴
Evidence considered
  • VCEP specification version 1.1.0 declares PVS1 not applicable for PIK3CA brain malformations due to gain-of-function mechanism.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM6 VCEPNot applicable under the Brain Malformations VCEP. This criterion is addressed according to PS2 and will not be used separately. Details ▾Hide ▴
Evidence considered
  • VCEP specification version 1.1.0 states PM6 is addressed according to PS2 and will not be used.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1 VCEPNot applicable under the Brain Malformations VCEP because disease-causing variants in PIK3CA are germline mosaic, de novo, or mosaic rather than inherited in a pattern amenable to co-segregation analysis. Details ▾Hide ▴
Evidence considered
  • VCEP specification version 1.1.0 declares PP1 not applicable since disease-causing variants are germline mosaic
  • de novo
  • or mosaic.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3 VCEPNot applicable under the Brain Malformations VCEP because PIK3CA variants are gain of function, and traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms. The VCEP states this criterion can be revisited if GOF-specific predictive algorithms become available. Details ▾Hide ▴
Evidence considered
  • VCEP specification version 1.1.0 declares PP3 not applicable for GOF variants
  • traditional algorithms focus on LOF mechanisms.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4 VCEPNot applicable under the Brain Malformations VCEP because this criterion is accounted for under PS4. Details ▾Hide ▴
Evidence considered
  • VCEP specification version 1.1.0 declares PP4 not applicable since it is accounted for under PS4.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5 VCEPNot for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
  • VCEP specification version 1.1.0 declares PP5 not applicable
  • not for use per ClinGen SVI VCEP Review Committee.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BS4 VCEPNot applicable under the Brain Malformations VCEP because disease-causing variants are de novo, germline mosaic, or post-zygotic mutations; lack of segregation analysis does not apply. Details ▾Hide ▴
Evidence considered
  • VCEP specification version 1.1.0 declares BS4 not applicable as these are de novo
  • germline mosaic or post-zygotic mutations.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1 VCEPNot applicable under the Brain Malformations VCEP because loss of function is not the disease mechanism for PIK3CA brain malformations. Details ▾Hide ▴
Evidence considered
  • VCEP specification version 1.1.0 declares BP1 not applicable as LOF is not the disease mechanism.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP4 N/AUnder the VCEP, BP4 is only applicable for synonymous, intronic (except canonical splice sites), and non-coding UTR variants. This is a missense variant (c.3133G>A, p.Asp1045Asn) and is explicitly excluded from BP4 under the VCEP specification. 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 missense variant is excluded.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP6 VCEPNot for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
  • VCEP specification version 1.1.0 declares BP6 not applicable
  • not for use per ClinGen SVI VCEP Review Committee.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7 N/AUnder the VCEP, BP7 is only applicable for synonymous, intronic (except canonical splice sites), and non-coding UTR variants. This is a missense variant (c.3133G>A, p.Asp1045Asn) and does not meet the variant type requirement for BP7. Details ▾Hide ▴
Evidence considered
  • VCEP BP7 rule is limited to synonymous
  • intronic
  • and UTR variants. This missense variant is excluded.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1

Identifiers

Gene
PIK3CA
Transcript
NM_006218.3
Coding (HGVS c.)
NM_006218.3:c.3133G>A
Protein (HGVS p.)
NP_006209.2:p.(Asp1045Asn)
GRCh38
chr3:179234290 G>A
GRCh37
chr3:178952078 G>A
ClinVar
3774060
COSMIC
COSV55874677

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…
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

SpliceAI acceptor lossat -196 bp
0.050
SpliceAI acceptor gainat +481 bp
0.000
SpliceAI donor lossat -338 bp
0.000
SpliceAI donor gainat +498 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.377
BayesDel
-0.281

How the predictions were used

PP3 VCEPNot applicable under the Brain Malformations VCEP because PIK3CA variants are gain of function, and traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms. The VCEP states this criterion can be revisited if GOF-specific predictive algorithms become available. Details ▾Hide ▴
Evidence considered
  • VCEP specification version 1.1.0 declares PP3 not applicable for GOF variants
  • traditional algorithms focus on LOF mechanisms.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP4 N/AUnder the VCEP, BP4 is only applicable for synonymous, intronic (except canonical splice sites), and non-coding UTR variants. This is a missense variant (c.3133G>A, p.Asp1045Asn) and is explicitly excluded from BP4 under the VCEP specification. 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 missense variant is excluded.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7 N/AUnder the VCEP, BP7 is only applicable for synonymous, intronic (except canonical splice sites), and non-coding UTR variants. This is a missense variant (c.3133G>A, p.Asp1045Asn) and does not meet the variant type requirement for BP7. Details ▾Hide ▴
Evidence considered
  • VCEP BP7 rule is limited to synonymous
  • intronic
  • and UTR variants. This missense variant is excluded.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.377. BayesDel score = -0.280982.

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 Recorded maximum delta 0.050 Open source ↗
ClinVar 1 Uncertain significance 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

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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3774060)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.377. BayesDel score = -0.280982.

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; COSV55874677, n = 13 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.