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PIK3CAc.3189dupUncertain significance
Print report
Variant interpretation report

PIK3CA c.3189dup, p.(Gln1064ThrfsTer9)

NM_006218.4:c.3189dup NP_006209.2:p.(Gln1064ThrfsTer9) Frameshift · exon 21 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

PIK3CA encodes the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), an enzyme that converts the membrane lipid PIP2 into PIP3, thereby activating signaling cascades such as the AKT-mTOR pathway that promote cell survival, proliferation, growth, and motility. It is among the most commonly mutated genes in cancer, and aberrant activation of PI3K signaling is a driving event in tumor development, with the gene implicated in cancers including cervical cancer. Because this pathway is central to tumor growth, it is a major target of cancer therapies, although drug-induced pathway activation can also contribute to treatment resistance.

NCBI Gene ↗ OncoKB ↗
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. 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

Met (Supporting): the exact variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Flagged for human review: indel population calls may be unreliable and coverage/quality metrics were not available.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

The PIK3CA Brain Malformations VCEP defines no combination framework, so generic ACMG/AMP 2015 rules applied; the sole met criterion (PM2, Supporting) satisfies no Pathogenic or Likely Pathogenic combination, yielding 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
0.011 maximum delta

Recorded SpliceAI maximum delta score: 0.011. 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 curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55934843, n = 1 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, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 3 not met · 6 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 contributes no pathogenic evidence because the governing PIK3CA Brain Malformations VCEP framework makes this criterion not applicable.

PM3 is not applicable under the governing PIK3CA Brain Malformations VCEP specification.

BP2 remains unassessed because cis/trans phase and a same-gene known pathogenic comparator are not documented in the case-evidence bundle.

Met · 1

PM2 SupportingMet (Supporting): the exact variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Flagged for human review: indel population calls may be unreliable and coverage/quality metrics were not available. Details ▾Hide ▴
Reasoning

PM2_Supporting is met under the PIK3CA Brain Malformations VCEP specification. The exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, satisfying the VCEP requirement for an absent/rare variant in at least one ethnically matched control population sample. Confidence is moderated and human review is recommended because the VCEP notes that population data for indels may be poorly called by next-generation sequencing and the bundle provides absence results without coverage or quality metrics.

Rule
Absent/rare from controls in an ethnically-matched cohort population sample (>=1).
Evidence considered
  • The applicable ClinGen Brain Malformations VCEP specification assigns PM2 at Supporting strength for an absent/rare variant in an ethnically matched cohort population sample, with at least one qualifying sample sufficient.
  • The exact variant NM_006218.4:c.3189dup was reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
  • The specification's generic PM2 caveat states that population data for indels may be poorly called by next-generation sequencing; no dataset-specific coverage or quality metrics were supplied in the case evidence bundle.
Still missing
  • Population-specific coverage and variant-calling quality metrics for this indel were not provided.
  • The available records do not provide a numerical allele count or allele-number denominator because the variant was reported absent.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 3 · evaluated, threshold not reached

BA1 Not met: the variant is absent (frequency 0) from all gnomAD sources, far below the VCEP BA1 threshold of >0.0926%. Details ▾Hide ▴
Reasoning

BA1 is not met. The PIK3CA Brain Malformations VCEP threshold is allele frequency >0.0926%; the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so no allele frequency approaches the BA1 threshold.

Rule
Allele frequency (>0.0926%). An allele frequency (>0.0926%) was approved. Note: this was adjusted from ACMG Guidelines due to maintaining the 5x threshold for benign.
Evidence considered
  • The applicable ClinGen Brain Malformations VCEP specification for PIK3CA defines BA1 as allele frequency >0.0926%.
  • The exact variant NM_006218.4:c.3189dup (NC_000003.11:g.178952134dup; GRCh38 3-179234343-T-TA) was reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Not met: the variant is absent from gnomAD, far below the VCEP BS1 threshold of >0.0185%. Details ▾Hide ▴
Reasoning

BS1 is not met. The PIK3CA Brain Malformations VCEP threshold is allele frequency >0.0185%; the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so no allele frequency exceeds the BS1 threshold.

Rule
Allele frequency (>0.0185%). An allele frequency (>0.0185%) was approved.
Evidence considered
  • The applicable ClinGen Brain Malformations VCEP specification for PIK3CA defines BS1 as allele frequency >0.0185%.
  • The exact variant NM_006218.4:c.3189dup was reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; therefore an allele frequency above 0.0185% was not observed.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 Not met: BS2 requires at least 3 gnomAD homozygotes or 3 heterozygous well-phenotyped relatives; the variant is absent from gnomAD with no such family observations. Details ▾Hide ▴
Reasoning

BS2 is not met. The VCEP requires at least 3 homozygotes in gnomAD or at least 3 heterozygous occurrences in well-phenotyped family members. The case evidence reports the variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, and provides no well-phenotyped family observations.

Rule
Award BS2 if >=3 homozygotes present in gnomAD or >=3 heterozygous in well phenotyped family members.
Evidence considered
  • The applicable ClinGen Brain Malformations VCEP specification requires >=3 homozygotes in gnomAD or >=3 heterozygotes in well-phenotyped family members for BS2.
  • The exact variant was reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so the required homozygote observation threshold is not met.
  • No well-phenotyped family-member observations for this variant are present in the case evidence bundle.
Still missing
  • No independent well-phenotyped family dataset was provided; the available evidence does not establish the required three heterozygous family occurrences.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not assessed · 6 · no assessment recorded

PS2 Not assessed: no proband phenotype, parental genotypes, or de novo testing results were available, so de novo occurrence cannot be evaluated. Details ▾Hide ▴
Reasoning

The PIK3CA Brain Malformations VCEP permits PS2. PS2_Strong requires the variant to be detected in affected tissue, absent from parental samples with confirmed maternity and paternity, and absent or present at a lower allele fraction in another tissue; PS2_Moderate can be used when parental absence is demonstrated or when parents are unavailable but the tissue-distribution requirement is met. The case-evidence bundle contains no proband phenotype, parental genotypes, maternity or paternity confirmation, allele fractions, tissue comparison, or de novo testing results, so PS2 cannot be adjudicated.

Rule
VCEP PS2: PS2_Strong requires Criteria 1 AND Criteria 2. Criterion 1 is a detectable variant absent from parental samples with confirmed maternity and paternity; Criterion 2 is a detectable variant in affected tissue absent from or at a lower allele fraction in another tissue. PS2_Moderate applies when Criterion 1 is fulfilled, or when parents are unavailable but Criterion 2 is fulfilled.
Evidence considered
  • The governing ClinGen Brain Malformations VCEP specification for PIK3CA lists PS2 as applicable and defines PS2_Strong using both parental absence with confirmed maternity/paternity and tissue allele-fraction criteria; PS2_Moderate requires the parental-absence criterion or the tissue criterion when parents are unavailable.
  • The case-evidence bundle reports no family, parental-testing, de novo, allele-fraction, or tissue-distribution evidence for NM_006218.4:c.3189dup.
Still missing
  • Proband phenotype and affected-tissue context are not provided.
  • Maternal and paternal testing results are not provided.
  • Confirmed maternity and paternity are not documented.
  • Variant allele fractions in the proband and comparator tissues are not provided.
  • No evidence establishes constitutional de novo status or post-zygotic mosaic tissue distribution.
Sources
cspec ↗
PS3 Not assessed: no validated variant-specific functional assay or animal-model evidence was available. Details ▾Hide ▴
Reasoning

No variant-specific functional assay or animal-model evidence was identified in the case bundle. The applicable ClinGen Brain Malformations VCEP specification requires validated functional evidence, with positive and negative controls and additional assay-quality requirements for strength above supporting; those requirements cannot be evaluated here.

Rule
Follow the ClinGen Brain Malformations VCEP PS3 specification and SVI functional-assay recommendations; apply only when variant-specific functional evidence meets the required assay-quality and validation-control criteria.
Evidence considered
  • The applicable ClinGen Brain Malformations VCEP specification (version 1.1) governs PS3 for PIK3CA and directs curators to the SVI recommendations with BMVCEP assay-quality and minimum-validation-control requirements; it allows supporting evidence from an acceptable assay, while moderate or strong evidence requires appropriate positive and negative controls and specified assay validation metrics.
  • The consolidated case bundle reports no literature PMIDs, and paper_extracts.json and fulltext_map.json are empty; therefore no paper-based variant-specific functional evidence was available for review.
  • The available case evidence contains only variant normalization and non-functional database/context results; it does not document a functional assay for NM_006218.4:c.3189dup / NP_006209.2:p.(Gln1064ThrfsTer9).
Still missing
  • No variant-specific in vitro or in vivo functional study was available.
  • No assay methodology, biological replicates, technical replicates, positive controls, negative controls, or validation metrics were available for this variant.
Sources
cspec ↗
PS4 Not assessed: no affected cerebral-malformation cases, case-control data, or phenotype-point evidence for this exact variant were available. Details ▾Hide ▴
Reasoning

The applicable Brain Malformations VCEP specification requires PM2 eligibility plus phenotype-point evidence for this exact variant. The available bundle documents absence from gnomAD but contains no affected cerebral-malformation cases, case-control analysis, or reportable phenotype-point total for NM_006218.4:c.3189dup; PS4 cannot be assigned.

Rule
Brain Malformations VCEP PS4: assign Table 2A phenotype points only after PM2 eligibility, then apply Table 2B strength thresholds.
Evidence considered
  • The Brain Malformations VCEP specifies PS4 phenotype-point thresholds: Supporting 0.5–1.25, Moderate 1.5–3.25, Strong 3.5–15.75, and Very Strong at least 16 points; use requires PM2-level absence/rarity.
  • The variant is reported absent from gnomAD v2.1 and gnomAD v4.1, satisfying the population-data prerequisite but not supplying affected-case phenotype points.
  • The evidence bundle contains no literature PMIDs, full-text records, or extracted paper findings for this exact variant.
Still missing
  • Variant-specific affected-case data with phenotypes sufficient for Table 2A scoring are unavailable.
  • No case-control enrichment estimate or phenotype-point total is available.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 Not assessed: no functional assay or animal-model evidence demonstrating absence of a damaging effect was available. Details ▾Hide ▴
Reasoning

No variant-specific functional assay or animal-model evidence showing absence of a damaging effect was identified in the case bundle. The applicable ClinGen Brain Malformations VCEP specification requires validated functional evidence and appropriate assay controls for BS3 strength calibration, so BS3 cannot be assessed.

Rule
Follow the ClinGen Brain Malformations VCEP BS3 specification and SVI functional-assay recommendations; apply only when variant-specific functional evidence showing no damaging effect meets the required assay-quality and validation-control criteria.
Evidence considered
  • The applicable ClinGen Brain Malformations VCEP specification (version 1.1) lists BS3 as applicable with VCEP specification and requires the SVI recommendations together with Brain Malformation Group quality metrics and minimum validation controls; no such study-level data are present in the case bundle.
  • The consolidated case bundle reports no literature PMIDs, and paper_extracts.json and fulltext_map.json are empty; therefore no paper-based variant-specific benign functional evidence was available for review.
  • The available case evidence contains no functional result demonstrating that NM_006218.4:c.3189dup / NP_006209.2:p.(Gln1064ThrfsTer9) has no damaging effect on PIK3CA function or splicing.
Still missing
  • No variant-specific in vitro or in vivo functional study demonstrating a benign or non-damaging effect was available.
  • No assay methodology, biological replicates, technical replicates, positive controls, negative controls, or validation metrics were available for this variant.
Sources
cspec ↗
BP2 Not assessed: no genotype data, second PIK3CA variant, or phase information was available to assess cis/trans status with a pathogenic allele. Details ▾Hide ▴
Reasoning

The governing PIK3CA VCEP permits BP2 at Supporting strength when the variant is observed in cis or trans with a known pathogenic variant in the same gene. The case bundle contains no affected-proband genotype data, second PIK3CA variant, pathogenic comparator, or phase information; therefore BP2 cannot be assessed.

Rule
Observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
  • The PIK3CA Brain Malformations VCEP rule states: observed in cis or trans with a known pathogenic variant in the same gene; the specified strength is Supporting.
  • The case bundle reports no case literature PMIDs, no ClinVar record for the queried variant, and no proband or family phase observations documenting a second pathogenic PIK3CA variant.
Still missing
  • Obtain proband-level or family-level evidence showing a second known pathogenic PIK3CA variant in cis or trans with NM_006218.4:c.3189dup.
  • Obtain reliable phase testing or parent/offspring data establishing cis or trans configuration.
  • Confirm that the comparator PIK3CA variant is known pathogenic under an appropriate expert-reviewed or otherwise well-supported assessment.
Sources
cspec ↗
BP5 Not assessed: no individual carrying this variant with an alternate molecular diagnosis was reported. Details ▾Hide ▴
Reasoning

BP5 remains applicable as originally described by the VCEP, but the bundle provides no individual with this variant and no evidence of an alternate molecular diagnosis explaining a relevant phenotype.

Rule
Brain Malformations VCEP BP5: applicable as originally described; require a case with an alternate molecular basis for disease.
Evidence considered
  • The VCEP retains BP5 without modification: it requires the variant to be found in a case with an alternate molecular basis for disease.
  • No variant-specific clinical cases or alternative molecular diagnoses are present in the evidence bundle.
Still missing
  • Variant-specific clinical case data assessing an alternate molecular basis for disease are unavailable.
Sources
cspec ↗
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable: the ClinGen Brain Malformations VCEP excludes PVS1 because PIK3CA brain malformations arise from gain-of-function, not loss of function. Details ▾Hide ▴
Reasoning

NM_006218.4:c.3189dup is a frameshift in exon 21, predicted to produce p.(Gln1064ThrfsTer9) near the C terminus. However, the governing ClinGen Brain Malformations VCEP specification explicitly designates PVS1 as not applicable for PIK3CA brain malformations because loss of function/haploinsufficiency has not been clearly identified as the disease mechanism and the relevant mechanism is gain of function. Therefore NMD prediction, distal exon position, protein-length loss, and repeat-region considerations cannot support PVS1 in this case.

VCEP rule
ClinGen Brain Malformations VCEP PVS1: not applicable for PIK3CA brain malformations because the relevant disease mechanism is gain of function, not established loss of function/haploinsufficiency.
Evidence considered
  • The normalized MANE Select transcript NM_006218.4 identifies a coding single-nucleotide duplication in exon 21 with predicted consequence NP_006209.2:p.(Gln1064ThrfsTer9).
  • The applicable ClinGen Brain Malformations VCEP specification states for PVS1: "LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF)."
Sources
cspec ↗
PS1 N/ANot applicable: PS1 requires the same amino acid change as a previously established pathogenic variant, but a frameshift produces no amino acid change to compare. Details ▾Hide ▴
Reasoning

PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_006218.4:c.3189dup in PIK3CA is a frameshift variant predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: frameshift (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM1 N/ANot applicable: PM1 requires a missense change in a mutational hotspot; this frameshift produces no altered residue to evaluate. Details ▾Hide ▴
Reasoning

PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_006218.4:c.3189dup in PIK3CA is a frameshift variant predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: frameshift (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM3 VCEPNot applicable: PM3 is reserved for recessive disorders, whereas PIK3CA brain-malformation variants are heterozygous. Details ▾Hide ▴
Reasoning

PM3 is not applicable under the ClinGen Brain Malformations VCEP specification for PIK3CA because the disease-causing variants are heterozygous; PM3 is reserved for recessive disorders with a pathogenic variant demonstrated in trans.

VCEP rule
Not applicable since disease-causing variants are heterozygous.
Evidence considered
  • The PIK3CA Brain Malformations VCEP specification explicitly designates PM3 as not applicable because disease-causing variants are heterozygous.
  • The case variant is NM_006218.4:c.3189dup, a heterozygous-context allelic criterion assessment for PIK3CA; no recessive inheritance model is established in the governing framework.
Sources
cspec ↗
PM4 VCEPNot applicable: PM4 is defined for in-frame insertions/deletions and stop-loss extensions; this frameshift does not meet that structural premise. Details ▾Hide ▴
Reasoning

PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_006218.4:c.3189dup in PIK3CA is a frameshift variant predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

VCEP rule
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
Evidence considered
  • Deterministic consequence classification: frameshift (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PM5 N/ANot applicable: PM5 requires a missense change at a residue where a different pathogenic missense is established; a frameshift produces no missense change. Details ▾Hide ▴
Reasoning

PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_006218.4:c.3189dup in PIK3CA is a frameshift variant predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: frameshift (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM6 VCEPNot applicable: per the VCEP, de novo evidence is addressed through PS2, not PM6. Details ▾Hide ▴
Reasoning

The PIK3CA Brain Malformations VCEP specifies that PM6 is not applicable and is addressed according to PS2. Therefore assumed de novo status without confirmation of paternity or maternity is not reported as PM6 under this framework.

VCEP rule
VCEP PM6: Not applicable for this VCEP; this point is addressed according to PS2 and will not be used.
Evidence considered
  • The governing PIK3CA VCEP specification marks PM6 as not applicable and states that this point is addressed according to PS2 and will not be used.
Sources
cspec ↗
PP1 VCEPNot applicable: per the VCEP, co-segregation does not apply to variants that arise de novo or as germline or post-zygotic mosaics. Details ▾Hide ▴
Reasoning

The PIK3CA Brain Malformations VCEP specifies that PP1 is not applicable because disease-causing variants in this context are germline mosaic, de novo, or mosaic rather than being evaluated through conventional familial co-segregation.

VCEP rule
VCEP PP1: Not applicable for this VCEP because disease-causing variants are germline mosaic, de novo, or mosaic.
Evidence considered
  • The governing PIK3CA VCEP specification marks PP1 as not applicable and states that it is not applicable because disease-causing variants are germline mosaic, de novo, or mosaic.
Sources
cspec ↗
PP2 N/ANot applicable: PP2 is defined for missense variants in genes with low benign missense variation; this frameshift has no missense change. Details ▾Hide ▴
Reasoning

PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_006218.4:c.3189dup in PIK3CA is a frameshift variant predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: frameshift (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PP3 VCEPNot applicable: the VCEP excludes PP3 because prediction tools target loss-of-function, while PIK3CA brain malformations are gain-of-function. Details ▾Hide ▴
Reasoning

Not applicable under the governing ClinGen Brain Malformations VCEP specification: PIK3CA-related brain malformations are attributed to gain-of-function mechanisms, and the VCEP states that PP3 is not applicable because traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms.

VCEP rule
VCEP PP3: Not applicable for this VCEP because disease variants are gain of function and traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms.
Evidence considered
  • The governing Brain Malformations VCEP specification explicitly marks PP3 as not applicable and states: 'This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.'
  • The variant is an exonic frameshift, NM_006218.4:c.3189dup, predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9); no calibrated missense predictor score is available or applicable for this non-SNV variant.
Sources
cspec ↗
PP4 VCEPNot applicable: the VCEP accounts for phenotype evidence under PS4. Details ▾Hide ▴
Reasoning

PP4 is explicitly not applicable in the PIK3CA Brain Malformations VCEP specification because phenotype evidence is accounted for under PS4.

VCEP rule
Brain Malformations VCEP: PP4 not applicable; phenotype specificity is evaluated within PS4.
Evidence considered
  • The VCEP states that PP4 is not applicable because this criterion is accounted for under PS4.
Sources
cspec ↗
PP5 VCEPNot applicable: the VCEP does not use PP5, and no ClinVar record for this exact variant exists. Details ▾Hide ▴
Reasoning

PP5 is not applicable under the governing Brain Malformations VCEP specification. Independently, the exact variant has no ClinVar record, so there is no exact-variant pathogenic/likely pathogenic expert-panel assertion that could support PP5.

VCEP rule
PP5 requires an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion; the governing VCEP otherwise designates PP5 not applicable.
Evidence considered
  • The VCEP states that PP5 is not for use.
  • ClinVar returned no result for NM_006218.4:c.3189dup; therefore no exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification is present.
Sources
cspec ↗clinvar ↗
BS4 VCEPNot applicable: per the VCEP, lack of segregation (BS4) does not apply because these variants are de novo, germline mosaic, or post-zygotic. Details ▾Hide ▴
Reasoning

The PIK3CA Brain Malformations VCEP specifies that BS4 is not applicable because these variants are de novo, germline mosaic, or post-zygotic mutations. Lack of segregation in affected family members therefore is not used for this VCEP criterion.

VCEP rule
VCEP BS4: Not applicable as these are de novo, germline mosaic, or post-zygotic mutations.
Evidence considered
  • The governing PIK3CA VCEP specification marks BS4 as not applicable and states that it is not applicable because these are de novo, germline mosaic, or post-zygotic mutations.
Sources
cspec ↗
BP1 VCEPNot applicable: BP1 is defined for missense variants in genes where truncating variants cause disease; this frameshift has no missense change. Details ▾Hide ▴
Reasoning

BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_006218.4:c.3189dup in PIK3CA is a frameshift variant predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

VCEP rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: frameshift (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP3 VCEPNot applicable: BP3 is defined for in-frame indels in repetitive regions; this frameshift is outside its scope. Details ▾Hide ▴
Reasoning

BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_006218.4:c.3189dup in PIK3CA is a frameshift variant predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

VCEP rule
deterministic_prefilter: requires_repeat_region_indel
Evidence considered
  • Deterministic consequence classification: frameshift (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
BP4 N/ANot applicable: BP4 is restricted to synonymous, intronic, or non-coding variants; this exonic frameshift is ineligible. Details ▾Hide ▴
Reasoning

Not applicable under the governing ClinGen Brain Malformations VCEP specification. BP4 is restricted to synonymous variants, intronic variants outside canonical splice sites, and non-coding UTR variants when at least two of varSEAK, SpliceAI, and MaxEntScan predict no splice effect. NM_006218.4:c.3189dup is an exonic frameshift, so it is outside the eligible variant classes.

Rule
VCEP BP4: applicable only to synonymous, eligible intronic, or UTR variants when two of varSEAK, SpliceAI, and MaxEntScan predict no splice impact.
Evidence considered
  • The governing Brain Malformations VCEP specification restricts BP4 to synonymous, eligible intronic, and UTR variants, requiring two of three no-impact predictions from varSEAK, SpliceAI, and MaxEntScan.
  • NM_006218.4:c.3189dup is an exonic frameshift predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9), not a synonymous, intronic, or UTR variant. SpliceAI reports a low maximum delta score of 0.011, but a single prediction cannot overcome the VCEP's variant-type restriction or its two-of-three predictor requirement.
Sources
cspec ↗
BP6 VCEPNot applicable: the VCEP does not use BP6, and no ClinVar record for this exact variant exists. Details ▾Hide ▴
Reasoning

BP6 is not applicable under the governing Brain Malformations VCEP specification. Independently, the exact variant has no ClinVar record, so there is no exact-variant ClinVar expert-panel Benign/Likely benign assertion that could support BP6.

VCEP rule
BP6 requires an exact-variant ClinVar expert-panel Benign or Likely benign assertion; the governing VCEP otherwise designates BP6 not applicable.
Evidence considered
  • The VCEP states that BP6 is not for use.
  • ClinVar returned no result for NM_006218.4:c.3189dup; therefore no exact-variant ClinVar expert-panel Benign/Likely benign classification is present.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: BP7 is defined for synonymous variants with no predicted splice impact; this frameshift changes the protein sequence. Details ▾Hide ▴
Reasoning

BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006218.4:c.3189dup in PIK3CA is a frameshift variant predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: frameshift (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules

Identifiers

Gene
PIK3CA
Transcript
NM_006218.4
Coding (HGVS c.)
NM_006218.4:c.3189dup
Protein (HGVS p.)
NP_006209.2:p.(Gln1064ThrfsTer9)
GRCh38
chr3:179234343 T>TA
GRCh37
chr3:178952131 T>TA
Location and type
Exon 21 · frameshift
COSMIC
COSV55934843

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…
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 -242 bp
0.001
SpliceAI acceptor gainat -249 bp
0.011
SpliceAI donor lossat +443 bp
0.000
SpliceAI donor gainat +445 bp
0.001
Pangolin splice lossmagnitude shown
-0.005
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 VCEPNot applicable: the VCEP excludes PP3 because prediction tools target loss-of-function, while PIK3CA brain malformations are gain-of-function. Details ▾Hide ▴
Reasoning

Not applicable under the governing ClinGen Brain Malformations VCEP specification: PIK3CA-related brain malformations are attributed to gain-of-function mechanisms, and the VCEP states that PP3 is not applicable because traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms.

VCEP rule
VCEP PP3: Not applicable for this VCEP because disease variants are gain of function and traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms.
Evidence considered
  • The governing Brain Malformations VCEP specification explicitly marks PP3 as not applicable and states: 'This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.'
  • The variant is an exonic frameshift, NM_006218.4:c.3189dup, predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9); no calibrated missense predictor score is available or applicable for this non-SNV variant.
Sources
cspec ↗
BP4 N/ANot applicable: BP4 is restricted to synonymous, intronic, or non-coding variants; this exonic frameshift is ineligible. Details ▾Hide ▴
Reasoning

Not applicable under the governing ClinGen Brain Malformations VCEP specification. BP4 is restricted to synonymous variants, intronic variants outside canonical splice sites, and non-coding UTR variants when at least two of varSEAK, SpliceAI, and MaxEntScan predict no splice effect. NM_006218.4:c.3189dup is an exonic frameshift, so it is outside the eligible variant classes.

Rule
VCEP BP4: applicable only to synonymous, eligible intronic, or UTR variants when two of varSEAK, SpliceAI, and MaxEntScan predict no splice impact.
Evidence considered
  • The governing Brain Malformations VCEP specification restricts BP4 to synonymous, eligible intronic, and UTR variants, requiring two of three no-impact predictions from varSEAK, SpliceAI, and MaxEntScan.
  • NM_006218.4:c.3189dup is an exonic frameshift predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9), not a synonymous, intronic, or UTR variant. SpliceAI reports a low maximum delta score of 0.011, but a single prediction cannot overcome the VCEP's variant-type restriction or its two-of-three predictor requirement.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is defined for synonymous variants with no predicted splice impact; this frameshift changes the protein sequence. Details ▾Hide ▴
Reasoning

BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006218.4:c.3189dup in PIK3CA is a frameshift variant predicted to produce NP_006209.2:p.(Gln1064ThrfsTer9). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: frameshift (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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 0.011 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

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 = 0.01).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55934843, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.