About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.1255_1264delinsA, p.(His419_Leu422delinsMet)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen PIK3CA VCEP v1.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Supporting
PM1 · supporting
This protein-altering variant affects residues 419 to 422, which fall within the PIK3CA kinase domain spanning amino acids 322 to 483. The Brain Malformations VCEP lists this interval as an approved critical functional domain, which supports PM1 at Supporting strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting that it is absent or extremely rare in population controls. Under the Brain Malformations VCEP, this meets PM2 at Supporting strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Brain Malformations Specification Tavtigian point framework: PM1_Supporting (+1) and PM2_Supporting (+1) yield 2 total points, which falls within the 0-5 Uncertain Significance range.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 5 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The PIK3CA c.1255_1264delinsA (p.His419_Leu422delinsMet; p.H419_L422delinsM) variant has not been reported in ClinVar, while OncoKB classifies it as Likely Oncogenic.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting that it is absent or extremely rare in population controls.
The altered residues fall within the PIK3CA kinase domain spanning amino acids 322 to 483, which is an approved Brain Malformations VCEP critical functional domain and supports PM1 at Supporting strength.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01.
No criteria match.
Met · 2
PM1 SupportingThis protein-altering variant affects residues 419 to 422, which fall within the PIK3CA kinase domain spanning amino acids 322 to 483. The Brain Malformations VCEP lists this interval as an approved critical functional domain, which supports PM1 at Supporting strength. Details ▾Hide ▴
Rule
Brain Malformations VCEP PM1_Supporting for variants in Table 4 approved domains.
Evidence considered
- Protein consequence is p.(His419_Leu422delinsMet).
- The VCEP Table 4-approved PIK3CA domain includes amino acids 322-483.
Sources
cspec ↗vcep_c_l_i_n_g_e_n___b_r_a_i_n_m_a_l_f_o_r_m___a_c_m_g___s_p_e_c_i_f_i_c_a_t_i_o_n_s___v_1___1
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting that it is absent or extremely rare in population controls. Under the Brain Malformations VCEP, this meets PM2 at Supporting strength. Details ▾Hide ▴
Rule
Brain Malformations VCEP PM2_Supporting for absence/rarity in population controls.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
Not met · 5 · evaluated, threshold not reached
PS1 No previously established pathogenic variant producing the same protein change was identified. This variant is absent from ClinVar, and no published case reports were identified to support PS1. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS1 (same amino acid change as a previously established pathogenic variant).
Evidence considered
- ClinVar search returned no result for NM_006218.4:c.1255_1264delinsA.
- No PMIDs were identified in the literature review.
Sources
PS4 This variant is absent from population databases and therefore satisfies the PM2 prerequisite for PS4 consideration, but no qualifying affected case reports or phenotype points were identified. Available evidence does not support any PS4 point total above the Supporting threshold of 0.5 points. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS4 point system: Supporting 0.5-1.25, Moderate 1.5-3.25, Strong 3.5-15.75, Very Strong >=16; requires PM2.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- No PMIDs were identified in the literature review.
- ClinVar search returned no result.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BA1 threshold of greater than 0.0926%. BA1 is therefore not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP BA1 Stand Alone: allele frequency >0.0926%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- BA1 threshold in this VCEP is >0.0926%.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 threshold of greater than 0.0185%. BS1 is therefore not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP BS1 Strong: allele frequency >0.0185%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- BS1 threshold in this VCEP is >0.0185%.
Sources
BS2 This variant has not been observed in gnomAD, so it does not meet the BS2 requirement of at least 3 homozygotes in population data. No evidence of at least 3 well-phenotyped unaffected heterozygous family members was identified. Details ▾Hide ▴
Rule
Brain Malformations VCEP BS2 Strong: >=3 homozygotes in gnomAD or >=3 well-phenotyped unaffected heterozygous family members.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- VCEP BS2 threshold is at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected heterozygotes in families.
Sources
Not assessed · 5 · no assessment recorded
PS2 No parental testing results or multi-tissue allele-fraction data were identified. Available evidence therefore does not establish the de novo or tissue-restricted mosaic findings required for PS2 under the Brain Malformations VCEP. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS2 Strong/Moderate for confirmed de novo or qualifying mosaic findings.
Evidence considered
- No parental or tissue-specific mosaic data were present in the retrieved evidence.
Still missing
- Parental testing with confirmed maternity and paternity.
- Affected and unaffected tissue allele-fraction data if mosaicism is suspected.
Sources
PS3 No validated functional assay data specific to this variant were identified. PS3 therefore cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS3 for validated damaging functional evidence.
Evidence considered
- No qualifying functional assay evidence was identified.
Still missing
- Variant-specific functional studies meeting Brain Malformations VCEP assay requirements.
Sources
BS3 No well-established functional studies showing no damaging effect were identified. BS3 therefore cannot be assessed. Details ▾Hide ▴
Rule
Brain Malformations VCEP BS3 for validated non-damaging functional evidence.
Evidence considered
- No benign functional assay evidence was identified.
Still missing
- Validated functional studies showing no damaging effect on protein function or splicing.
Sources
BP2 No data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant. BP2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
ACMG/AMP BP2 for cis or trans occurrence with a known pathogenic variant.
Evidence considered
- No cis/trans observations were identified in the retrieved evidence.
Still missing
- Phase data demonstrating cis or trans occurrence with a known pathogenic PIK3CA variant.
BP5 No alternate molecular diagnosis or other established molecular basis for the reported phenotype was identified. BP5 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
ACMG/AMP BP5 for an alternate molecular basis for disease.
Evidence considered
- No alternate molecular diagnosis was documented in the retrieved evidence.
Still missing
- Case-level testing results showing an alternate molecular explanation for the phenotype.
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable for PIK3CA in the Brain Malformations VCEP because the disease mechanism is gain of function rather than loss of function. The variant-specific PVS1 scaffold also does not place this delins variant into a generic null-variant category. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks PVS1 not applicable for PIK3CA.
Evidence considered
- The VCEP states that PVS1 is not applicable because the disease mechanism is gain of function.
- The generic PVS1 scaffold states this variant is not in the default nonsense
- frameshift
- or canonical splice buckets.
Sources
PM3 N/APM3 is not applicable because the relevant PIK3CA brain malformation disorders are not interpreted as recessive conditions in this VCEP. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks PM3 not applicable.
Evidence considered
- The VCEP marks PM3 as not applicable because disease-causing variants are heterozygous.
Sources
PM4 N/AAlthough this is an in-frame deletion-insertion, the Brain Malformations VCEP specifically does not use PM4 for these gain-of-function genes. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks PM4 not applicable.
Evidence considered
- The VCEP marks PM4 as not applicable even though in-frame indels can rarely be gain of function in these genes.
Sources
PM5 N/APM5 is a novel missense criterion for a different missense change at the same residue. This variant is an in-frame deletion-insertion rather than a missense substitution, so PM5 does not apply. Details ▾Hide ▴
Rule
ACMG/AMP PM5 for novel missense changes at a residue with another pathogenic missense variant.
Evidence considered
- Protein consequence is p.(His419_Leu422delinsMet)
- not a missense substitution.
- The VCEP PM5 rule is written for missense changes at an amino acid residue.
Sources
PM6 N/APM6 is not applied in this VCEP because de novo evidence is addressed through PS2. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks PM6 not applicable.
Evidence considered
- The VCEP marks PM6 as not applicable because it is addressed according to PS2.
Sources
PP1 N/APP1 is not applicable under this VCEP because disease-causing variants are typically de novo or mosaic rather than segregating through families. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks PP1 not applicable.
Evidence considered
- The VCEP marks PP1 as not applicable.
Sources
PP2 N/APP2 in this VCEP is a missense-constraint criterion for missense variants. This variant is an in-frame deletion-insertion rather than a missense change, so PP2 does not apply. Details ▾Hide ▴
Rule
Brain Malformations VCEP PP2 applies to missense variants when gene missense constraint criteria are satisfied.
Evidence considered
- Protein consequence is p.(His419_Leu422delinsMet)
- an in-frame delins rather than a missense substitution.
- The VCEP PP2 rule is written for missense variants.
Sources
PP3 N/APP3 is not applicable under this VCEP because these disorders are driven by gain-of-function mechanisms, and conventional pathogenicity prediction tools are not considered reliable for this purpose. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks PP3 not applicable.
Evidence considered
- The VCEP marks PP3 as not applicable for these gain-of-function disorders.
Sources
PP4 N/APP4 is not applicable under the Brain Malformations VCEP because phenotype specificity is incorporated into the PS4 point-based framework. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks PP4 not applicable.
Evidence considered
- The VCEP marks PP4 as not applicable because phenotype evidence is addressed under PS4.
Sources
PP5 N/APP5 is not used under current ClinGen SVI recommendations and is explicitly marked not applicable in this VCEP. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks PP5 not applicable.
Evidence considered
- The VCEP marks PP5 as not applicable.
Sources
BS4 N/ABS4 is not applicable under the Brain Malformations VCEP because these disorders are typically caused by de novo, germline mosaic, or post-zygotic variants, so lack of segregation is not used. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks BS4 not applicable.
Evidence considered
- The VCEP marks BS4 as not applicable.
Sources
BP1 N/ABP1 is not applicable because the Brain Malformations VCEP does not use loss-of-function-based benign reasoning for PIK3CA gain-of-function disease. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks BP1 not applicable.
Evidence considered
- The VCEP marks BP1 as not applicable because loss of function is not the disease mechanism.
Sources
BP3 N/ABP3 is not applicable under this VCEP because these genes are not interpreted using a repetitive-region benign framework for in-frame indels. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks BP3 not applicable.
Evidence considered
- The VCEP marks BP3 as not applicable for these genes.
Sources
BP4 N/ABP4 is restricted by this VCEP to synonymous, intronic, or UTR variants evaluated with splice-prediction tools. Although SpliceAI predicts a low splice effect for this variant (max delta score 0.01), BP4 is not applicable to this protein-altering delins variant. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP4 applies only to synonymous, intronic, or UTR variants with predicted no splice impact.
Evidence considered
- SpliceAI max delta score is 0.01.
- The VCEP limits BP4 to synonymous
- intronic
- or UTR variants.
Sources
BP6 N/ABP6 is not used under current ClinGen SVI recommendations and is explicitly marked not applicable in this VCEP. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks BP6 not applicable.
Evidence considered
- The VCEP marks BP6 as not applicable.
Sources
BP7 N/ABP7 is restricted to synonymous, intronic, or UTR variants. This is a protein-altering in-frame delins variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP7 applies only to synonymous, intronic, or UTR variants.
Evidence considered
- The VCEP limits BP7 to synonymous
- intronic
- and UTR variants.
- Protein consequence is p.(His419_Leu422delinsMet).
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.1255_1264delinsA
- Protein (HGVS p.)
- NP_006209.2:p.(His419_Leu422delinsMet)
- GRCh38
- chr3:179210189 CACTGTCCAT>A
- GRCh37
- chr3:178927977 CACTGTCCAT>A
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PIK3CA
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is not applicable under this VCEP because these disorders are driven by gain-of-function mechanisms, and conventional pathogenicity prediction tools are not considered reliable for this purpose. Details ▾Hide ▴
Rule
Brain Malformations VCEP marks PP3 not applicable.
Evidence considered
- The VCEP marks PP3 as not applicable for these gain-of-function disorders.
Sources
BP4 N/ABP4 is restricted by this VCEP to synonymous, intronic, or UTR variants evaluated with splice-prediction tools. Although SpliceAI predicts a low splice effect for this variant (max delta score 0.01), BP4 is not applicable to this protein-altering delins variant. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP4 applies only to synonymous, intronic, or UTR variants with predicted no splice impact.
Evidence considered
- SpliceAI max delta score is 0.01.
- The VCEP limits BP4 to synonymous
- intronic
- or UTR variants.
Sources
BP7 N/ABP7 is restricted to synonymous, intronic, or UTR variants. This is a protein-altering in-frame delins variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP7 applies only to synonymous, intronic, or UTR variants.
Evidence considered
- The VCEP limits BP7 to synonymous
- intronic
- and UTR variants.
- Protein consequence is p.(His419_Leu422delinsMet).
Sources
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
Captured SpliceAI source record
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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/467907148
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_006218.4%3Ac.1255_1264delinsA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178927977-CACTGTCCAT-A?data…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179210189-CACTGTCCAT-A?d…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.1255…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/H419_L422delinsM
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.1255_1264delinsA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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 classifies this variant as Likely Oncogenic.
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.