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PIK3CAc.1407_1409delUncertain significance
Print report
Variant interpretation report

PIK3CA c.1407_1409del, p.(Glu469_Thr470delinsAsp)

NM_006218.4:c.1407_1409del NP_006209.2:p.(Glu469_Thr470delinsAsp) In frame indel unknown · exon 9 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Supporting
PM1 · supporting

Met, Supporting: PIK3CA residues 469-470 fall within the VCEP-approved kinase domain spanning amino acids 322-483.

PM2Supporting
PM2 · supporting

Met at Supporting: the variant was absent from gnomAD v2.1 and v4.1, satisfying the VCEP one-person-maximum rarity rule, pending ancestry-match confirmation.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: PM1 (supporting) plus PM2 (supporting) provide two supporting criteria, insufficient for a pathogenic or benign ACMG/AMP 2015 combination.

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
0.008 maximum delta

Recorded SpliceAI maximum delta score: 0.008. 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
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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: 2 met · 3 not met · 6 not assessed · 17 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

All three requested computational criteria are not applicable under the governing ClinGen Brain Malformations VCEP specification because this is an exonic in-frame deletion and the VCEP restricts these criteria to other variant classes or explicitly excludes PP3.

The VCEP full-text file was searched for c.1407_1409del, p.Glu469_Thr470delinsAsp, and p.E469_T470delinsD; no variant-specific entry was found.

Population evidence is limited to the four requested criteria. The VCEP thresholds for BA1 and BS1 are not reached, BS2 is not met, and PM2 is met at Supporting strength based on absence from the queried gnomAD datasets, with ancestry matching requiring human confirmation.

Met · 2

PM1 SupportingVCEPMet, Supporting: PIK3CA residues 469-470 fall within the VCEP-approved kinase domain spanning amino acids 322-483. Details ▾Hide ▴
Reasoning

PM1_Supporting is met. The normalized protein consequence is NP_006209.2:p.(Glu469_Thr470delinsAsp), affecting residues 469-470 of PIK3CA. The authoritative vcep_materials.json domain_tables entry lists PIK3CA kinase domains at AA 322-483 and AA 797-1068; residues 469-470 fall within the approved AA 322-483 domain, and the variant is in exon 9. The governing specification allows a supporting point for a variant in an exon within an approved Table 4 functional domain and states that recurrent gain-of-function residues are handled by PS4 instead; no recurrent-hotspot finding is needed for this domain path.

VCEP rule
Brain Malformation Recommendation: A supporting point may be awarded if the variant of interest is located in an exon within one of the below approved functional domains Table 4. Please note that specific residues subject to recurrent gain-of-function mutations are not covered by this criterion; these are instead accounted for by PS4.
Evidence considered
  • vcep_materials.json domain_tables, PIK3CA row: kinase domains, AA 322-483 and AA 797-1068; the variant consequence is p.(Glu469_Thr470delinsAsp), affecting residues 469-470.
  • ClinGen Brain Malformations VCEP specification, Table 4: PIK3CA transcript NM_006218.3, kinase domains AA 322-483 and AA 797-1068.
  • Case normalization: NM_006218.4:c.1407_1409del -> NP_006209.2:p.(Glu469_Thr470delinsAsp); Variant Validator places the deletion in exon 9.
  • The governing specification states that a supporting point may be awarded when the variant is located in an exon within an approved functional domain in Table 4, and that specific recurrent gain-of-function residues are accounted for by PS4.
Still missing
  • The governing file /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PIK3CA/fulltext/clingen_brainmalform_acmg_specifications_v1_1.pdf.txt was searched for c.1407_1409del, p.Glu469_Thr470delinsAsp, and p.E469_T470delinsD; no exact variant entry was found. The PM1 decision is instead based on the governing Table 4 domain rule and the authoritative domain_tables entry.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗cspec ↗
PM2 SupportingVCEPMet at Supporting: the variant was absent from gnomAD v2.1 and v4.1, satisfying the VCEP one-person-maximum rarity rule, pending ancestry-match confirmation. Details ▾Hide ▴
Reasoning

The ClinGen Brain Malformations VCEP permits PM2 at Supporting strength for a variant absent or rare in a control population sample, with one person maximum. The variant was absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 datasets, and also absent from the available gnomAD v2.1 and v3.1 non-cancer searches. This supports PM2_Supporting; however, the case evidence does not document a patient-specific ancestry or an ancestry-matched subset, so that matching detail should be confirmed by a human reviewer. The governing VCEP file contained no notation of c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD.

VCEP rule
Absent/rare from controls in an ethnically-matched cohort population sample ( ≤1).
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, page 9 PM2_Supporting rule: absent/rare from controls in an ethnically-matched cohort population sample, with one person maximum; the specification notes this accounts for sequencing and calling artifacts in ExAC/gnomAD.
  • gnomAD v2.1 (exome), query 3-178928220-AAAC-A: search status absent.
  • gnomAD v4.1, query 3-179210432-AAAC-A: search status absent.
  • The available non-cancer searches also reported absence: gnomAD v2.1 non-cancer (exomes) and gnomAD v3.1 non-cancer (genomes). These were not separately cited because no corresponding non-cancer keys exist in source_registry.json.
  • The declared VCEP file clingen_brainmalform_acmg_specifications_v1_1.pdf was searched for c.1407_1409del, p.Glu469_Thr470delinsAsp, and p.E469_T470delinsD; no entry was found.
Still missing
  • Patient-specific ancestry and an explicitly ancestry-matched population subset were not documented in the available evidence.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not met · 3 · evaluated, threshold not reached

BA1 VCEPNot met: the variant was absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BA1 allele-frequency threshold of 0.0926%. Details ▾Hide ▴
Reasoning

The ClinGen Brain Malformations VCEP sets BA1 at an allele frequency greater than 0.0926%. The variant was absent from gnomAD v2.1 and gnomAD v4.1, so no allele frequency exceeding the BA1 threshold was observed. The governing VCEP file contained no notation of c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD.

VCEP rule
An allele frequency (>0.0926%) was approved. ... Note: this was adjusted from ACMG Guidelines due to maintaining the 5x threshold for benign (consistent with previously established guidelines)
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, Table 1/page 10 BA1 rule: allele frequency >0.0926%.
  • gnomAD v2.1 (exome), query 3-178928220-AAAC-A: search status absent; no record or allele frequency returned.
  • gnomAD v4.1, query 3-179210432-AAAC-A: search status absent; no record or allele frequency returned.
  • The declared VCEP file clingen_brainmalform_acmg_specifications_v1_1.pdf was searched for c.1407_1409del, p.Glu469_Thr470delinsAsp, and p.E469_T470delinsD; no entry was found.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 VCEPNot met: the variant was absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BS1 allele-frequency threshold of 0.0185%. Details ▾Hide ▴
Reasoning

The ClinGen Brain Malformations VCEP sets BS1 at an allele frequency greater than 0.0185%. The variant was absent from gnomAD v2.1 and gnomAD v4.1, so no allele frequency exceeding the BS1 threshold was observed. The governing VCEP file contained no notation of c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD.

VCEP rule
An allele frequency (>0.0185%) was approved. (Supplemental Table 3).
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, Table 1/page 10 BS1 rule: allele frequency >0.0185%, with Supplemental Table 3 cited by the rule.
  • gnomAD v2.1 (exome), query 3-178928220-AAAC-A: search status absent; no record or allele frequency returned.
  • gnomAD v4.1, query 3-179210432-AAAC-A: search status absent; no record or allele frequency returned.
  • The declared VCEP file clingen_brainmalform_acmg_specifications_v1_1.pdf was searched for c.1407_1409del, p.Glu469_Thr470delinsAsp, and p.E469_T470delinsD; no entry was found.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS2 VCEPNot met: gnomAD contained no variant record and no evidence showed the VCEP-required minimum of 3 homozygotes or 3 well-phenotyped heterozygous relatives. Details ▾Hide ▴
Reasoning

The VCEP requires at least 3 homozygotes in gnomAD or at least 3 heterozygous observations in well-phenotyped family members. The variant was absent from gnomAD v2.1 and v4.1, providing no qualifying homozygote observations, and no well-phenotyped family-member observations were available. Therefore the BS2 Strong requirement is not met. The governing VCEP file contained no notation of c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD.

VCEP rule
Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, Table 1/page 4 BS2 rule: award BS2 if at least 3 homozygotes are present in gnomAD or at least 3 heterozygous observations occur in well-phenotyped family members; gnomAD homozygous occurrences can be counted.
  • gnomAD v2.1 (exome), query 3-178928220-AAAC-A: search status absent; no homozygote or other variant record returned.
  • gnomAD v4.1, query 3-179210432-AAAC-A: search status absent; no homozygote or other variant record returned.
  • No well-phenotyped family-member observations were present in the available case evidence.
  • The declared VCEP file clingen_brainmalform_acmg_specifications_v1_1.pdf was searched for c.1407_1409del, p.Glu469_Thr470delinsAsp, and p.E469_T470delinsD; no entry was found.
Still missing
  • No well-phenotyped family-member data were available for the alternative BS2 pathway.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 6 · no assessment recorded

PS2 VCEPNot assessed: no proband, parental-testing, maternity/paternity, or tissue allele-fraction evidence is available to evaluate the VCEP PS2 criteria. Details ▾Hide ▴
Reasoning

The governing VCEP requires detectable variant evidence in the proband, absence from parental samples with confirmed maternity and paternity, and, for PS2_Strong, tissue-level allele-fraction comparison. The case materials provide no proband, parental-testing, maternity/paternity, affected-tissue, or alternate-tissue results, so PS2 cannot be evaluated. The VCEP full-text file contained no entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD.

VCEP rule
Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled. ... Criteria 1. The variant is present at a detectable allele fraction but is absent from parental samples with confirmed maternity and paternity. ... Criteria 2. The variant is present at a detectable allele fraction in an affected tissue sample but is absent from or detected at a lower allelic fraction in another tissue
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, PS2: the strong point requires Criteria 1 and Criteria 2; Criteria 1 requires a detectable allele fraction in the proband, absence from parental samples with confirmed maternity and paternity, and Criteria 2 requires affected-tissue versus another-tissue allele-fraction evidence.
  • The case evidence bundle contains no segregation, parental-testing, maternity/paternity, proband allele-fraction, or tissue allele-fraction results.
Still missing
  • No proband-level de novo result or detectable allele fraction is available.
  • No parental samples or confirmed maternity and paternity results are available.
  • No affected-tissue versus alternate-tissue allele-fraction comparison is available.
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PIK3CA/fulltext/clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗
PS3 VCEPNot assessed: no variant-specific functional assay publication, experimental result, or assay-control data are available to evaluate the VCEP PS3 requirements. Details ▾Hide ▴
Reasoning

No variant-specific functional assay publication, experimental result, assay-control description, or animal-model result is available in the case evidence. The VCEP requires PS3 evaluation from functional assays meeting the BMVCEP acceptability criteria, with quality metrics and minimum validation controls specified in Supplementary Document 1; the available evidence contains no such assay data. The VCEP file was searched for c.1407_1409del, p.Glu469_Thr470delinsAsp, and p.E469_T470delinsD, with no matching entry. Therefore PS3 cannot be assessed rather than being considered absent or not met.

VCEP rule
Award PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP. Quality metrics and minimum validation controls required can be found in Supplementary Document 1.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, PS3 rule: functional assay evidence must meet the BMVCEP acceptability criteria, with quality metrics and minimum validation controls in Supplementary Document 1.
  • The case evidence records zero literature PMIDs, an empty paper_extracts.json, and no variant-specific functional assay or animal-model result.
  • The governing VCEP full-text file was searched for c.1407_1409del, p.Glu469_Thr470delinsAsp, and p.E469_T470delinsD; no matching variant entry was found.
Still missing
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
  • Variant-specific functional assay results and the required assay quality metrics and validation controls are unavailable.
  • No relevant publication PMID was identified; paper_extracts.json is empty and the literature pass reports zero PMIDs.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PS4 VCEPNot assessed: gnomAD absence supports the PM2 prerequisite, but no affected-person phenotype data are available to assign PS4 Table 2A points. Details ▾Hide ▴
Reasoning

The ClinGen Brain Malformations VCEP requires PS4 phenotype points under Table 2A, with PS4 strength determined by Table 2B, and requires PM2. The case evidence shows the variant is absent from gnomAD v2.1 and v4.1, but provides no affected-person phenotype observations or reportable variant-specific cases from which Table 2A points can be assigned; the governing VCEP file contains no entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD. Therefore PS4 cannot be assessed from the available evidence.

VCEP rule
Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant meets criteria for (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_VeryStrong ≥ 16 points. ... Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Strong = 3.5-15.75 points. ... Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Moderate = 1.5-3.25 points. ... Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Supporting = 0.5 – 1.25 points.
Evidence considered
  • ClinGen Brain Malformations VCEP specification, Table 2A and Table 2B: no variant-specific case row is present for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD; no phenotype points can therefore be assigned.
  • The case evidence reports the variant as absent from gnomAD v2.1 and gnomAD v4.1, satisfying the available population-evidence prerequisite direction for PM2, but this does not provide PS4 phenotype points.
Still missing
  • No affected-person phenotype or variant-specific case data are available for Table 2A point assignment.
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 VCEPNot assessed: no variant-specific benign functional result or assay-control data are available to evaluate the VCEP BS3 requirements or strength. Details ▾Hide ▴
Reasoning

No variant-specific benign functional assay publication, experimental result, assay-control description, or splicing assay is available in the case evidence. The VCEP requires BS3 evaluation under the SVI recommendations together with Brain Malformation Group specifications for quality metrics and minimum validation controls; the available evidence contains no functional data to establish a non-damaging result or to calibrate supporting versus strong strength. The VCEP file was searched for c.1407_1409del, p.Glu469_Thr470delinsAsp, and p.E469_T470delinsD, with no matching entry. Therefore BS3 cannot be assessed rather than being considered absent or not met.

VCEP rule
Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, BS3 rule: follow SVI recommendations together with Brain Malformation Group specifications for quality metrics and minimum validation controls.
  • The case evidence records zero literature PMIDs, an empty paper_extracts.json, and no variant-specific benign functional assay or experimental result.
  • The governing VCEP full-text file was searched for c.1407_1409del, p.Glu469_Thr470delinsAsp, and p.E469_T470delinsD; no matching variant entry was found.
Still missing
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
  • Variant-specific benign functional results and the required assay quality metrics and validation controls are unavailable.
  • No relevant publication PMID was identified; paper_extracts.json is empty and the literature pass reports zero PMIDs.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BP2 VCEPNot assessed: no documented cis/trans phase with a known pathogenic PIK3CA variant is available. Details ▾Hide ▴
Reasoning

BP2 is applicable at Supporting strength when the variant is observed in cis or trans with a known pathogenic variant in the same gene. The available case evidence documents no affected-proband observation, pathogenic same-gene variant, parental testing, or cis/trans phase for c.1407_1409del; therefore BP2 cannot be assessed. The governing VCEP file contains no case-specific entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD.

VCEP rule
Observed in cis or trans with a known pathogenic variant in the same gene
Evidence considered
  • ClinGen Brain Malformations VCEP BP2 row: 'Observed in cis or trans with a known pathogenic variant in the same gene.'
  • The case bundle contains no literature records, paper extracts, affected-proband observations, parental phase data, or documented pathogenic variant in cis or trans with this PIK3CA variant.
Still missing
  • No documented cis/trans phase or known pathogenic same-gene variant is available for this case.
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BP5 ACMG_2015Not assessed: no affected case with an alternate molecular basis for disease is available to evaluate BP5. Details ▾Hide ▴
Reasoning

The VCEP applies BP5 as originally described: it requires the variant to be found in a case with an alternate molecular basis for disease. The available case evidence contains no such affected case or alternate molecular diagnosis, and no variant-specific entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt. BP5 is therefore not assessed rather than treated as absent evidence of the criterion.

Rule
Variant found in a case with an alternate molecular basis for disease.
Evidence considered
  • The case evidence provides no affected individual with a documented alternate molecular basis for disease and no alternate-gene diagnosis linked to this variant.
Still missing
  • No affected case with an alternate molecular basis for disease is available.
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable: the VCEP excludes PVS1 for this gene. Details ▾Hide ▴
Reasoning

The ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 marks PVS1 as not applicable. The VCEP states: "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)." NM_006218.4:c.1407_1409del in PIK3CA is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_006209.2:p.(Glu469_Thr470delinsAsp). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.

VCEP rule
deterministic_prefilter: vcep_not_applicable
Evidence considered
  • Deterministic consequence classification: in_frame_indel_unknown (prefetch.json normalized protein consequence)
  • VCEP criterion policy: vcep_not_applicable
Sources
cspec ↗
PS1 N/ANot applicable: PS1 requires a missense variant, and this is an in-frame indel. 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.1407_1409del in PIK3CA is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_006209.2:p.(Glu469_Thr470delinsAsp). 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. The ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 applies PS1 as originally described in ACMG/AMP 2015, so the original definition governs. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: in_frame_indel_unknown (prefetch.json normalized protein consequence)
  • VCEP criterion policy: vcep_unchanged
Sources
generic_acmg_combination_rulescspec ↗
PM3 VCEPNot applicable: the VCEP states disease-causing variants are heterozygous. Details ▾Hide ▴
Reasoning

PM3 is not applicable under the ClinGen Brain Malformations VCEP specification because the disease-causing variants for this disorder are heterozygous, so recessive trans-phase evidence is not used. The governing VCEP file contains no case-specific entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD.

VCEP rule
Brain Malformation Recommendation: Not applicable since disease-causing variants are heterozygous
Evidence considered
  • ClinGen Brain Malformations VCEP PM3 row: 'Brain Malformation Recommendation: Not applicable since disease-causing variants are heterozygous.'
Still missing
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PM4 VCEPNot applicable: the VCEP explicitly does not use PM4 for these genes, including rare in-frame indels that might produce gain of function. Details ▾Hide ▴
Reasoning

PM4 is not applicable under the Brain Malformations VCEP specification. Although this variant is an in-frame three-nucleotide deletion producing NP_006209.2:p.(Glu469_Thr470delinsAsp), the VCEP states that PM4 will not be used for these genes because most indels are associated with loss of function, despite the possibility of a gain-of-function in-frame indel.

VCEP rule
Although there have been reported in-frame deletion/insertions in these genes which cause the overgrowth phenotype, they are exceptionally rare. Most insertion/deletions are associated with a LoF disease mechanism and so this point will still not be used even though we recognize that it is possible that a variant is an in-frame indel that results in a GoF mechanism.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, PM4 entry: the VCEP marks PM4 not applicable for this VCEP and specifically addresses in-frame deletion/insertion variants in these genes.
  • Variant consequence: NM_006218.4:c.1407_1409del is an in-frame three-nucleotide deletion with predicted protein consequence NP_006209.2:p.(Glu469_Thr470delinsAsp).
Sources
cspec ↗
PM5 N/ANot applicable: PM5 requires a missense variant, and this is an in-frame indel. 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.1407_1409del in PIK3CA is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_006209.2:p.(Glu469_Thr470delinsAsp). 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. The ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 applies PM5 as originally described in ACMG/AMP 2015, so the original definition governs. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.

Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: in_frame_indel_unknown (prefetch.json normalized protein consequence)
  • VCEP criterion policy: vcep_unchanged
Sources
generic_acmg_combination_rulescspec ↗
PM6 VCEPNot applicable: the VCEP states that PM6 is addressed according to PS2 and will not be used. Details ▾Hide ▴
Reasoning

The VCEP explicitly addresses PM6 through PS2 and states that PM6 will not be used; therefore this criterion is not applicable under the governing specification.

VCEP rule
Brain Malformation Recommendation: This point is addressed according to PS2 and will not be used.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, PM6 row: assumed de novo without confirmed paternity and maternity is addressed according to PS2 and will not be used.
Sources
cspec ↗
PP1 VCEPNot applicable: the VCEP excludes PP1 because disease-causing variants are germline mosaic, de novo, or mosaic. Details ▾Hide ▴
Reasoning

The VCEP marks PP1 not applicable because disease-causing variants in this framework are germline mosaic, de novo, or mosaic; no segregation strength is assigned.

VCEP rule
Brain Malformation Recommendation: Not applicable since disease-causing variants are germline mosaic, de novo or mosaic.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, PP1 row: co-segregation is not applicable because disease-causing variants are germline mosaic, de novo, or mosaic.
Sources
cspec ↗
PP2 N/ANot applicable: PP2 is restricted to missense variants, whereas this variant is an in-frame deletion/indel consequence. Details ▾Hide ▴
Reasoning

PP2 is not applicable because the governing VCEP rule is explicitly for missense constraint and the case variant is an in-frame deletion/duplication consequence, p.(Glu469_Thr470delinsAsp), not a missense variant. No PP2 z-score is required or applicable to this variant type.

VCEP rule
Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09. (applicable to MTOR, PIK3CA and AKT3 but not PIK3R2).
Evidence considered
  • ClinGen Brain Malformations VCEP PP2 rule: missense constraint computed in ExAC/gnomAD, with PP2 awarded only when the z-score is >3.09 and applicability listed for MTOR, PIK3CA, and AKT3.
  • Case normalization: NM_006218.4:c.1407_1409del -> NP_006209.2:p.(Glu469_Thr470delinsAsp); the consequence is an in-frame deletion/indel rather than a missense substitution.
Still missing
  • The governing file /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PIK3CA/fulltext/clingen_brainmalform_acmg_specifications_v1_1.pdf.txt was searched for c.1407_1409del, p.Glu469_Thr470delinsAsp, and p.E469_T470delinsD; no exact variant entry was found. This does not affect PP2 because the VCEP rule is limited to missense variants and the case consequence is an in-frame indel.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗cspec ↗
PP3 VCEPNot applicable: the VCEP excludes PP3 for these gain-of-function PIK3CA variants, regardless of available computational predictor scores. Details ▾Hide ▴
Reasoning

The VCEP explicitly marks PP3 not applicable for these PIK3CA variants because the disease mechanism is gain of function and traditional pathogenicity predictors focus on loss-of-function mechanisms. The variant is an exonic in-frame deletion resulting in p.(Glu469_Thr470delinsAsp), so no computational predictor score can activate PP3 under this VCEP rule.

VCEP rule
This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms. Use of this criterion can be revisited if there emerges additional published experience with predictive algorithms specifically designed to detect gain of function mutations.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1 marks PP3 as not applicable for these gain-of-function variants because traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms.
  • Case normalization identifies NM_006218.4:c.1407_1409del as an exonic in-frame deletion with protein consequence NP_006209.2:p.(Glu469_Thr470delinsAsp).
Still missing
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; the VCEP's explicit PP3 applicability rule is determinative.
Sources
cspec ↗
PP4 VCEPNot applicable: the VCEP explicitly accounts for phenotype specificity under PS4 rather than PP4. Details ▾Hide ▴
Reasoning

The VCEP explicitly makes PP4 not applicable because phenotype specificity is accounted for under PS4.

VCEP rule
Not applicable since this criterion is accounted for under PS4.
Evidence considered
  • ClinGen Brain Malformations VCEP specification, PP4 entry: the criterion is marked not applicable because it is accounted for under PS4.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PP5 VCEPNot applicable: the VCEP prohibits PP5 use under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Reasoning

The VCEP explicitly prohibits use of PP5 under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ClinGen Brain Malformations VCEP specification, PP5 entry: PP5 is marked not applicable and not for use.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BS4 VCEPNot applicable: the VCEP excludes BS4 for de novo, germline mosaic, or post-zygotic mutations. Details ▾Hide ▴
Reasoning

The VCEP explicitly marks BS4 not applicable because these are de novo, germline mosaic, or post-zygotic mutations; lack of segregation is therefore not evaluated under this specification.

VCEP rule
Brain Malformation Recommendation: Not applicable as these are de novo, germline mosaic or post-zygotic mutations.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, BS4 row: lack of segregation in affected family members is not applicable for de novo, germline mosaic, or post-zygotic mutations.
Sources
cspec ↗
BP1 VCEPNot applicable: the VCEP excludes BP1 for this gene. Details ▾Hide ▴
Reasoning

The ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 marks BP1 as not applicable. The VCEP states: "Not applicable as LOF is not the disease mechanism." NM_006218.4:c.1407_1409del in PIK3CA is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_006209.2:p.(Glu469_Thr470delinsAsp). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.

VCEP rule
deterministic_prefilter: vcep_not_applicable
Evidence considered
  • Deterministic consequence classification: in_frame_indel_unknown (prefetch.json normalized protein consequence)
  • VCEP criterion policy: vcep_not_applicable
Sources
cspec ↗
BP3 VCEPNot applicable: the VCEP states these genes lack exon regions that are repetitive and without a known function. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the Brain Malformations VCEP specification. The VCEP states that the specified genes do not have exon regions consisting of repetitive regions without a known function; therefore the in-frame protein change cannot receive BP3.

VCEP rule
This is not applicable for the genes specified since the exon regions do not have repetitive regions without a known function.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, BP3 entry: the VCEP marks BP3 not applicable because the specified genes do not have exon regions that are repetitive and without a known function.
  • Variant consequence: NM_006218.4:c.1407_1409del is an in-frame deletion affecting exon 9 and producing NP_006209.2:p.(Glu469_Thr470delinsAsp).
Sources
cspec ↗
BP4 N/ANot applicable: BP4 covers only synonymous, noncanonical intronic, or UTR variants, whereas this is an exonic in-frame deletion. Details ▾Hide ▴
Reasoning

The VCEP limits BP4 to synonymous variants, intronic positions except canonical splice sites, and non-coding UTR variants, requiring two of varSEAK, SpliceAI, and MaxEntScan to predict no splice impact. This variant is an exonic in-frame deletion, outside the specified scope. SpliceAI max delta 0.008 is therefore not evidence for BP4.

VCEP rule
Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function. ... Not applicable for any variant type except for synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs,. This criterion can be applied when two of three splicing prediction tools predict no splicing change. The splicing prediction tools used are: varSEAK, spliceAI and MaxEntScan.
Evidence considered
  • ClinGen Brain Malformations VCEP BP4 rule restricts the criterion to synonymous, noncanonical intronic, or UTR variants and names varSEAK, spliceAI, and MaxEntScan as the three splicing tools.
  • Case normalization places NM_006218.4:c.1407_1409del in exon 9 and classifies it as an in-frame deletion producing p.(Glu469_Thr470delinsAsp).
  • SpliceAI reported DS_AG 0.006, DS_AL 0.005, DS_DG 0.001, and DS_DL 0.008, with max delta score 0.008; this score was not used because the variant is outside BP4 scope.
Still missing
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; the variant is outside BP4 scope before predictor evidence is considered.
Sources
cspec ↗spliceai ↗
BP6 VCEPNot applicable: the VCEP explicitly prohibits BP6 use under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Reasoning

The VCEP explicitly marks BP6 not applicable and states that it is not for use under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ClinGen Brain Malformations VCEP specification, BP6 entry: BP6 is marked not applicable and not for use.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous, noncanonical intronic, or UTR variants, while this variant is an exonic in-frame deletion. Details ▾Hide ▴
Reasoning

The VCEP limits BP7 to synonymous variants, intronic positions except canonical splice sites, and non-coding UTR variants with a non-conserved nucleotide. This variant is an exonic in-frame deletion, not a synonymous, intronic, or UTR variant, so BP7 is not applicable and PhyloP or splice predictions are not required.

VCEP rule
For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1).
Evidence considered
  • ClinGen Brain Malformations VCEP BP7 rule restricts the criterion to synonymous, noncanonical intronic, and non-coding UTR variants when the nucleotide is non-conserved.
  • Case normalization identifies NM_006218.4:c.1407_1409del as an exonic in-frame deletion with protein consequence NP_006209.2:p.(Glu469_Thr470delinsAsp).
Still missing
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; the variant is outside BP7 scope before conservation evidence is considered.
Sources
cspec ↗

Identifiers

Gene
PIK3CA
Transcript
NM_006218.4
Coding (HGVS c.)
NM_006218.4:c.1407_1409del
Protein (HGVS p.)
NP_006209.2:p.(Glu469_Thr470delinsAsp)
GRCh38
chr3:179210432 AAAC>A
GRCh37
chr3:178928220 AAAC>A
Location and type
Exon 9 · in frame indel unknown

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 -197 bp
0.005
SpliceAI acceptor gainat +15 bp
0.006
SpliceAI donor lossat -89 bp
0.008
SpliceAI donor gainat +87 bp
0.001

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 VCEPNot applicable: the VCEP excludes PP3 for these gain-of-function PIK3CA variants, regardless of available computational predictor scores. Details ▾Hide ▴
Reasoning

The VCEP explicitly marks PP3 not applicable for these PIK3CA variants because the disease mechanism is gain of function and traditional pathogenicity predictors focus on loss-of-function mechanisms. The variant is an exonic in-frame deletion resulting in p.(Glu469_Thr470delinsAsp), so no computational predictor score can activate PP3 under this VCEP rule.

VCEP rule
This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms. Use of this criterion can be revisited if there emerges additional published experience with predictive algorithms specifically designed to detect gain of function mutations.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1 marks PP3 as not applicable for these gain-of-function variants because traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms.
  • Case normalization identifies NM_006218.4:c.1407_1409del as an exonic in-frame deletion with protein consequence NP_006209.2:p.(Glu469_Thr470delinsAsp).
Still missing
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; the VCEP's explicit PP3 applicability rule is determinative.
Sources
cspec ↗
BP4 N/ANot applicable: BP4 covers only synonymous, noncanonical intronic, or UTR variants, whereas this is an exonic in-frame deletion. Details ▾Hide ▴
Reasoning

The VCEP limits BP4 to synonymous variants, intronic positions except canonical splice sites, and non-coding UTR variants, requiring two of varSEAK, SpliceAI, and MaxEntScan to predict no splice impact. This variant is an exonic in-frame deletion, outside the specified scope. SpliceAI max delta 0.008 is therefore not evidence for BP4.

VCEP rule
Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function. ... Not applicable for any variant type except for synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs,. This criterion can be applied when two of three splicing prediction tools predict no splicing change. The splicing prediction tools used are: varSEAK, spliceAI and MaxEntScan.
Evidence considered
  • ClinGen Brain Malformations VCEP BP4 rule restricts the criterion to synonymous, noncanonical intronic, or UTR variants and names varSEAK, spliceAI, and MaxEntScan as the three splicing tools.
  • Case normalization places NM_006218.4:c.1407_1409del in exon 9 and classifies it as an in-frame deletion producing p.(Glu469_Thr470delinsAsp).
  • SpliceAI reported DS_AG 0.006, DS_AL 0.005, DS_DG 0.001, and DS_DL 0.008, with max delta score 0.008; this score was not used because the variant is outside BP4 scope.
Still missing
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; the variant is outside BP4 scope before predictor evidence is considered.
Sources
cspec ↗spliceai ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous, noncanonical intronic, or UTR variants, while this variant is an exonic in-frame deletion. Details ▾Hide ▴
Reasoning

The VCEP limits BP7 to synonymous variants, intronic positions except canonical splice sites, and non-coding UTR variants with a non-conserved nucleotide. This variant is an exonic in-frame deletion, not a synonymous, intronic, or UTR variant, so BP7 is not applicable and PhyloP or splice predictions are not required.

VCEP rule
For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1).
Evidence considered
  • ClinGen Brain Malformations VCEP BP7 rule restricts the criterion to synonymous, noncanonical intronic, and non-coding UTR variants when the nucleotide is non-conserved.
  • Case normalization identifies NM_006218.4:c.1407_1409del as an exonic in-frame deletion with protein consequence NP_006209.2:p.(Glu469_Thr470delinsAsp).
Still missing
  • No entry for c.1407_1409del, p.Glu469_Thr470delinsAsp, or p.E469_T470delinsD was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; the variant is outside BP7 scope before conservation evidence is considered.
Sources
cspec ↗

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 0.008 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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.