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PIK3CAc.1631C>AUncertain significance
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Variant interpretation report

PIK3CA c.1631C>A, p.(Thr544Asn)

NM_006218.2:c.1631C>A NP_006209.2:p.(Thr544Asn) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About PIK3CA

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen PIK3CA VCEP v1.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at Supporting strength under the Brain Malformations VCEP specification for a rare control frequency.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PM2 supporting (+1) = 1 points, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

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 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
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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1.0, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 4 not met · 9 not assessed · 14 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

The PIK3CA c.1631C>A (p.Thr544Asn, T544N) variant has been reported in ClinVar and is currently classified as uncertain significance by the ClinGen Brain Malformations Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at Supporting strength under the Brain Malformations VCEP specification.

This variant lies outside the VCEP-approved PIK3CA PM1 domains at amino acids 322-483 and 797-1068, so PM1 is not met.

SpliceAI predicts no significant splice impact (max delta score 0.00), REVEL is 0.164, and BayesDel is -0.174013; however, the Brain Malformations VCEP does not apply PP3 or BP4 missense computational criteria to gain-of-function PIK3CA variants.

Met · 1

PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at Supporting strength under the Brain Malformations VCEP specification for a rare control frequency. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • The VCEP specifies PM2 at Supporting strength for variants absent/rare in controls.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1

Not met · 4 · evaluated, threshold not reached

PM1 For PIK3CA, the VCEP allows PM1 only at Supporting strength for variants within the approved Table 4 domains at amino acids 322-483 and 797-1068. Thr544 lies outside these intervals, so PM1 is not met. Details ▾Hide ▴
Evidence considered
  • VCEP-approved PIK3CA PM1 domains are aa 322-483 and aa 797-1068.
  • The variant changes residue Thr544.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1 This variant is absent from gnomAD v2.1 and v4.1 and therefore does not exceed the VCEP BA1 threshold of greater than 0.0926%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • BA1 threshold is >0.0926% under the VCEP.
Sources
gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BS1 This variant is absent from gnomAD v2.1 and v4.1 and therefore does not exceed the VCEP BS1 threshold of greater than 0.0185%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • BS1 threshold is >0.0185% under the VCEP.
Sources
gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BS2 This variant is absent from gnomAD, and no evidence of at least 3 homozygotes in population data or at least 3 well-phenotyped unaffected family members was identified, so BS2 is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • VCEP requires at least 3 homozygotes in gnomAD or 3 well-phenotyped unaffected family members for BS2.
Still missing
  • Family-based phenotyping data were not available.
Sources
gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1

Not assessed · 9 · no assessment recorded

PS1 No pathogenic variant with the same p.Thr544Asn amino-acid change from a different nucleotide substitution was identified, so PS1 is not applied at this time. Details ▾Hide ▴
Evidence considered
  • ClinVar currently lists this exact variant as uncertain significance by the Brain Malformations expert panel.
  • The VCEP uses PS1 as originally described.
Still missing
  • A curated record or publication showing the same amino-acid substitution caused by a different nucleotide change and established as pathogenic would be needed.
Sources
clinvar ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PS2 No confirmed de novo result with parental testing and no demonstrated higher allele fraction in affected tissue relative to another tissue were identified for this variant, so PS2 is not applied. Details ▾Hide ▴
Evidence considered
  • The VCEP requires confirmed parental absence and/or tissue distribution evidence for PS2.
Still missing
  • Case-level parental testing data were not available.
  • Case-level mosaic tissue distribution data were not available.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3 No accepted variant-specific functional assay meeting Brain Malformations VCEP requirements was identified for p.Thr544Asn, so PS3 is not applied. Details ▾Hide ▴
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence.
  • The VCEP requires validated functional evidence for PS3.
Still missing
  • Variant-specific functional assay data meeting VCEP validation requirements were not available.
Sources
oncokb ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PS4 This variant satisfies PM2 because it is absent from gnomAD v2.1 and v4.1, but no scored series of affected individuals reaching the VCEP PS4_Supporting threshold of 0.5 points was identified, so PS4 is not applied. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • The VCEP requires PM2 plus phenotype-based point totals for PS4.
Still missing
  • Case-level brain malformation phenotype reports and VCEP point assignments were not available.
  • No publication-based point total for this exact variant was identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM5 No different missense variant at residue Thr544 established as pathogenic was identified, so PM5 is not applied at this time. Details ▾Hide ▴
Evidence considered
  • ClinVar currently lists this exact variant as uncertain significance by the Brain Malformations expert panel.
  • The VCEP uses PM5 as originally described.
Still missing
  • A curated pathogenic missense variant affecting the same codon would be needed.
Sources
clinvar ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2 The Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the gene-level missense constraint z-score is greater than 3.09, but that z-score was not provided here, so PP2 is left unassessed. Details ▾Hide ▴
Evidence considered
  • The VCEP allows PP2 if the missense constraint z-score is >3.09 for PIK3CA.
Still missing
  • Gene-level missense constraint z-score supporting or refuting the >3.09 threshold was not available in the supplied materials.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
BS3 No well-established functional study showing normal or non-damaging effect for p.Thr544Asn was identified, so BS3 is not applied. Details ▾Hide ▴
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence.
  • The VCEP requires well-established functional evidence showing no damaging effect for BS3.
Still missing
  • Variant-specific benign functional assay data were not available.
Sources
oncokb ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2 No observation of this variant in cis or trans with a known pathogenic PIK3CA variant was identified, so BP2 is not applied. Details ▾Hide ▴
Evidence considered
  • The VCEP uses BP2 for cis or trans observations with a known pathogenic variant.
Still missing
  • Phase data with another pathogenic PIK3CA variant were not available.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP5 No alternate molecular diagnosis explaining the phenotype was identified together with this variant, so BP5 is not applied. Details ▾Hide ▴
Evidence considered
  • The VCEP uses BP5 as originally described.
Still missing
  • Comprehensive phenotype-level molecular workup data were not available.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable under the Brain Malformations VCEP because the relevant disease mechanism for PIK3CA is gain of function, and this is a missense variant rather than a null variant. Details ▾Hide ▴
Evidence considered
  • The VCEP marks PVS1 as not applicable for PIK3CA.
  • The variant is p.Thr544Asn
  • a missense change.
  • The generic PVS1 scaffold does not place this variant in a null-variant bucket.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1pvs1_gene_contextpvs1_variant_assessment
PM3 N/APM3 is not applicable because the relevant PIK3CA disorders in this framework are not interpreted as recessive conditions requiring trans observations. Details ▾Hide ▴
Evidence considered
  • The VCEP marks PM3 as not applicable.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
PM4 N/APM4 is not applicable under the Brain Malformations VCEP for this PIK3CA missense variant. Details ▾Hide ▴
Evidence considered
  • The VCEP marks PM4 as not applicable.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
PM6 N/APM6 is not used in this framework because de novo evidence is handled through PS2. Details ▾Hide ▴
Evidence considered
  • The VCEP marks PM6 as not applicable.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1 N/APP1 is not applicable under the Brain Malformations VCEP because disease-causing variants are typically de novo or mosaic rather than supported by informative familial segregation. Details ▾Hide ▴
Evidence considered
  • The VCEP marks PP1 as not applicable.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3 N/ASpliceAI predicts no significant splice effect for this variant (max delta score 0.00), REVEL is 0.164, and BayesDel is -0.174013; however, the Brain Malformations VCEP does not apply PP3 to gain-of-function PIK3CA missense variants. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
  • REVEL score 0.164.
  • BayesDel score -0.174013.
  • The VCEP marks PP3 as not applicable for these gain-of-function variants.
Sources
spliceai ↗revelbayesdelvcep_clingen_brainmalform_acmg_specifications_v1_1
PP4 N/AUnder the Brain Malformations VCEP specification, PP4 is not used because phenotype specificity is incorporated into PS4. Details ▾Hide ▴
Evidence considered
  • The VCEP marks PP4 as not applicable.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5 N/APP5 is not used under current ClinGen SVI and Brain Malformations VCEP guidance. Details ▾Hide ▴
Evidence considered
  • The VCEP marks PP5 as not applicable.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
BS4 N/AUnder the Brain Malformations VCEP specification, BS4 is not applicable because these disorders are typically caused by de novo, germline mosaic, or post-zygotic variants rather than informative multigenerational segregation patterns. Details ▾Hide ▴
Evidence considered
  • The VCEP marks BS4 as not applicable.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1 N/ABP1 is not applicable because loss of function is not the relevant disease mechanism in this PIK3CA VCEP framework. Details ▾Hide ▴
Evidence considered
  • The VCEP marks BP1 as not applicable.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3 N/ABP3 is not applicable under the Brain Malformations VCEP for these genes because the relevant exon regions do not contain repetitive regions without known function. Details ▾Hide ▴
Evidence considered
  • The VCEP marks BP3 as not applicable.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP4 N/ASpliceAI predicts no significant splice effect for this variant (max delta score 0.00), but the Brain Malformations VCEP applies BP4 only to synonymous, intronic, or UTR variants evaluated with splicing predictors. Because this is a missense variant, BP4 is not applicable. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
  • The VCEP restricts BP4 to synonymous
  • intronic
  • or UTR variants.
Sources
spliceai ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP6 N/ABP6 is not used under current ClinGen SVI and Brain Malformations VCEP guidance. Details ▾Hide ▴
Evidence considered
  • The VCEP marks BP6 as not applicable.
Sources
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7 N/ABP7 is limited to synonymous, intronic, or UTR variants with no predicted splice effect and low conservation; this variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • The variant is p.Thr544Asn
  • a missense change.
  • SpliceAI max delta score 0.00.
  • The VCEP restricts BP7 to synonymous
  • intronic
  • or UTR variants.
Sources
spliceai ↗vcep_clingen_brainmalform_acmg_specifications_v1_1

Identifiers

Gene
PIK3CA
Transcript
NM_006218.2
Coding (HGVS c.)
NM_006218.2:c.1631C>A
Protein (HGVS p.)
NP_006209.2:p.(Thr544Asn)
GRCh38
chr3:179218301 C>A
GRCh37
chr3:178936089 C>A

Gene diagram

Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.2. Select a row to find it on the plot.

PIK3CANM_006218.2
Fetching transcript structure from UCSC…
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/ASpliceAI predicts no significant splice effect for this variant (max delta score 0.00), REVEL is 0.164, and BayesDel is -0.174013; however, the Brain Malformations VCEP does not apply PP3 to gain-of-function PIK3CA missense variants. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
  • REVEL score 0.164.
  • BayesDel score -0.174013.
  • The VCEP marks PP3 as not applicable for these gain-of-function variants.
Sources
spliceai ↗revelbayesdelvcep_clingen_brainmalform_acmg_specifications_v1_1
BP4 N/ASpliceAI predicts no significant splice effect for this variant (max delta score 0.00), but the Brain Malformations VCEP applies BP4 only to synonymous, intronic, or UTR variants evaluated with splicing predictors. Because this is a missense variant, BP4 is not applicable. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
  • The VCEP restricts BP4 to synonymous
  • intronic
  • or UTR variants.
Sources
spliceai ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7 N/ABP7 is limited to synonymous, intronic, or UTR variants with no predicted splice effect and low conservation; this variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
  • The variant is p.Thr544Asn
  • a missense change.
  • SpliceAI max delta score 0.00.
  • The VCEP restricts BP7 to synonymous
  • intronic
  • or UTR variants.
Sources
spliceai ↗vcep_clingen_brainmalform_acmg_specifications_v1_1

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.164. BayesDel score = -0.174013.

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

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 has been reported in ClinVar as Uncertain Significance by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.164. BayesDel score = -0.174013.

Functional

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

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55880047, n = 7 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.