LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_006218.4:c.3203dup
PIK3CA
· NP_006209.2:p.(Asn1068LysfsTer5)
· NM_006218.4
GRCh37: chr3:178952146 G>GA
·
GRCh38: chr3:179234358 G>GA
Gene:
PIK3CA
Transcript:
NM_006218.4
Final call
PM1_Supporting
PM2_Supporting
Variant details
Gene
PIK3CA
Transcript
NM_006218.4
Protein
NP_006209.2:p.(Asn1068LysfsTer5)
gnomAD AF
ClinVar
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The PIK3CA c.3203dup (p.Asn1068LysfsTer5; p.N1068Kfs*5) variant has been observed in somatic cancers in COSMIC (COSV55878665, 29 occurrences) and has also been reported in ClinVar as Likely pathogenic with criteria provided by a single submitter.
2
The variant was absent from both gnomAD v2.1 and gnomAD v4.1, supporting PM2 at the Brain Malformations VCEP supporting level and arguing against BA1, BS1, and BS2 population-based benign evidence.
3
The affected residue lies at Asn1068, and the Brain Malformations specification Table 4 lists a PIK3CA critical domain spanning amino acids 797-1068, supporting PM1_Supporting; however, although OncoKB and the literature triage point to likely gain-of-function biology, the workspace does not provide variant-specific validated assay details sufficient to adjudicate PS3.
4
SpliceAI predicts no significant splice impact for this variant (max delta score 0.03), but PP3 is not applicable in this gain-of-function VCEP and BP4/BP7 are restricted to synonymous, intronic, or UTR contexts rather than coding frameshift variants.
Final determination:
No final classification assigned because the explicit Brain Malformations Specification final-classification framework was retrieved only as an incomplete unstructured ruleset, so PM1_Supporting plus PM2_Supporting could not be mapped to a validated VCEP combination rule.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
| Criterion | Status | Rationale | Evidence used |
|---|---|---|---|
| PVS1 | N/A | The Brain Malformations VCEP specifies PVS1 as not applicable for PIK3CA because the disease mechanism is gain-of-function rather than loss-of-function, so this frameshift is not evaluated with PVS1 in this framework. |
vcep_db/PIK3CA/criteria.json:PVS1
output/final_classification_framework.json
|
| PS1 | N/A | PS1 is intended for the same amino acid change caused by a different nucleotide change. This variant is a frameshift event, not a single amino acid substitution, so PS1 was not applied. |
vcep_db/PIK3CA/criteria.json:PS1
output/prefetch.json:protein consequence
|
| PS2 | Not assessed | The VCEP requires parental absence and/or tissue mosaic distribution data for PS2. The workspace contains no parental testing results and no affected-vs-unaffected tissue allele-fraction data for this case. |
vcep_db/PIK3CA/criteria.json:PS2
output/case_summary.json
|
| PS3 | Not assessed | The workspace includes OncoKB annotation and flags PMID:29533785 as a functional paper, but it does not provide variant-specific assay results or enough assay-validation detail to confirm that PS3 requirements under the Brain Malformations VCEP/PMID:31892348 framework are met. |
output/evidence.json:oncokb
output/literature_pass.json:PMID 29533785
vcep_db/PIK3CA/criteria.json:PS3
|
| PS4 | Not assessed | The VCEP uses a phenotype-point system for PS4 and requires PM2 first. PM2 is supportable here, but the workspace does not provide pointable case-level phenotype data from the cited germline reports, so a PS4 strength cannot be assigned from the assembled materials alone. |
vcep_db/PIK3CA/criteria.json:PS4
output/evidence.json:clinvar
output/literature_pass.json:PMIDs 23946963 and 27631024
output/evidence.json:gnomad
|
| PM1 | Met | The Brain Malformations VCEP specifies PM1 at Supporting strength for residues affecting critical functional domains listed in Table 4. The normalized protein consequence is p.(Asn1068LysfsTer5), and Table 4 for PIK3CA includes a domain spanning amino acids 797-1068, placing residue 1068 within the listed critical region. |
output/prefetch.json:protein consequence
vcep_db/PIK3CA/files/clingen_brainmalform_acmg_specifications_v1_1.pdf:Table 4
vcep_db/PIK3CA/criteria.json:PM1
|
| PM2 | Met | The variant was absent from both gnomAD v2.1 and gnomAD v4.1 in the assembled workspace, satisfying the Brain Malformations VCEP PM2 requirement for absence/rarity in controls at Supporting strength. |
output/evidence.json:gnomad.GNOMAD_V2_1
output/evidence.json:gnomad.GNOMAD_V4_1
vcep_db/PIK3CA/criteria.json:PM2
|
| PM3 | N/A | The Brain Malformations VCEP marks PM3 as not applicable because these disorders are evaluated as heterozygous, not recessive. |
vcep_db/PIK3CA/criteria.json:PM3
|
| PM4 | N/A | Although this is an indel-derived protein-length change, the Brain Malformations VCEP explicitly states PM4 is not used for these genes because in-frame indels are exceptionally rare and PM4 remains unsuitable in this gain-of-function framework. |
vcep_db/PIK3CA/criteria.json:PM4
output/prefetch.json:protein consequence
|
| PM5 | N/A | PM5 is a novel missense-at-same-residue rule. This variant is a frameshift, so PM5 was not applied. |
vcep_db/PIK3CA/criteria.json:PM5
output/prefetch.json:protein consequence
|
| PM6 | N/A | The Brain Malformations VCEP states that PM6 is addressed under PS2 and will not be used separately. |
vcep_db/PIK3CA/criteria.json:PM6
|
| PP1 | N/A | The Brain Malformations VCEP marks PP1 as not applicable because disease-causing variants in this setting are generally de novo, mosaic, or post-zygotic rather than segregating through multiplex families. |
vcep_db/PIK3CA/criteria.json:PP1
|
| PP2 | N/A | Although the PIK3CA gene-level missense constraint rule exists in this VCEP, PP2 is a missense criterion and this variant is a frameshift, so PP2 was not applied. |
vcep_db/PIK3CA/criteria.json:PP2
output/prefetch.json:protein consequence
|
| PP3 | N/A | The Brain Malformations VCEP explicitly marks PP3 as not applicable for these gain-of-function genes. The available SpliceAI result therefore was not used to activate PP3. |
vcep_db/PIK3CA/criteria.json:PP3
output/evidence.json:spliceai
|
| PP4 | N/A | The Brain Malformations VCEP states PP4 is not applicable because phenotype specificity is accounted for under PS4. |
vcep_db/PIK3CA/criteria.json:PP4
|
| PP5 | N/A | The VCEP does not permit use of PP5. |
vcep_db/PIK3CA/criteria.json:PP5
|
| BA1 | Not met | The VCEP BA1 threshold is >0.0926%, but the variant was absent from both gnomAD v2.1 and v4.1, so BA1 is not met. |
output/evidence.json:gnomad.GNOMAD_V2_1
output/evidence.json:gnomad.GNOMAD_V4_1
vcep_db/PIK3CA/criteria.json:BA1
|
| BS1 | Not met | The VCEP BS1 threshold is >0.0185%, but the variant was absent from both gnomAD v2.1 and v4.1, so BS1 is not met. |
output/evidence.json:gnomad.GNOMAD_V2_1
output/evidence.json:gnomad.GNOMAD_V4_1
vcep_db/PIK3CA/criteria.json:BS1
|
| BS2 | Not met | BS2 requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped heterozygous family members. The workspace shows absence from gnomAD and provides no qualifying healthy-family observations. |
output/evidence.json:gnomad
vcep_db/PIK3CA/criteria.json:BS2
|
| BS3 | Not assessed | No well-established benign functional study for this exact variant is documented in the workspace. Available functional annotations instead point toward likely oncogenic/gain-of-function behavior, but the materials are not detailed enough for a formal benign BS3 assessment. |
output/evidence.json:oncokb
output/literature_pass.json:PMID 29533785
vcep_db/PIK3CA/criteria.json:BS3
|
| BS4 | N/A | The Brain Malformations VCEP marks BS4 as not applicable in this context because relevant variants are typically de novo, mosaic, or post-zygotic rather than evaluated through non-segregation. |
vcep_db/PIK3CA/criteria.json:BS4
|
| BP1 | N/A | The Brain Malformations VCEP marks BP1 as not applicable because loss-of-function is not the disease mechanism. |
vcep_db/PIK3CA/criteria.json:BP1
|
| BP2 | Not assessed | BP2 could apply if the variant were observed in cis or trans with a known pathogenic variant in PIK3CA, but no phase data or second-variant evidence was present in the reviewed workspace. |
vcep_db/PIK3CA/criteria.json:BP2
output/case_summary.json
|
| BP3 | N/A | The Brain Malformations VCEP marks BP3 as not applicable because these genes do not have relevant repetitive regions without known function for this rule. |
vcep_db/PIK3CA/criteria.json:BP3
|
| BP4 | N/A | Under this VCEP, BP4 is limited to synonymous, intronic non-canonical, or UTR variants when splicing tools predict no impact. This variant is a coding frameshift, so BP4 was not applied despite low SpliceAI scores. |
vcep_db/PIK3CA/criteria.json:BP4
output/evidence.json:spliceai
output/prefetch.json:protein consequence
|
| BP5 | Not assessed | No alternate molecular explanation for the phenotype was documented in the assembled workspace, so BP5 was not assessed. |
vcep_db/PIK3CA/criteria.json:BP5
output/case_summary.json
|
| BP6 | N/A | The VCEP does not permit use of BP6. |
vcep_db/PIK3CA/criteria.json:BP6
|
| BP7 | N/A | BP7 is limited to synonymous, intronic non-canonical, or UTR variants with low conservation/no splice impact. This variant is a coding frameshift, so BP7 was not applied. |
vcep_db/PIK3CA/criteria.json:BP7
output/prefetch.json:protein consequence
|
Disclaimer:
The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.