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PIK3CAc.3G>AUncertain significance
Print report
Variant interpretation report

PIK3CA c.3G>A, p.(Met1?)

NM_006218.4:c.3G>A NP_006209.2:p.(Met1?) Initiation loss · exon 2 View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About PIK3CA

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

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

How it was classified

The recorded framework is ClinGen PIK3CA VCEP v1.1. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

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

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

Met at supporting: the variant has 0/1,513,740 alleles and 0 homozygotes in gnomAD v4.1, within the VCEP one-person maximum.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: PM2 (supporting) is the only met criterion and does not satisfy a generic ACMG/AMP pathogenic, benign, or likely benign combination rule.

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
0.014 maximum delta

Recorded SpliceAI maximum delta score: 0.014. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.

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 lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 5 not met · 6 not assessed · 16 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

VUS: PM2 supporting is met because the variant has 0 of 1,513,740 alleles and 0 homozygotes in gnomAD v4.1.

Met · 1

PM2 SupportingMet at supporting: the variant has 0/1,513,740 alleles and 0 homozygotes in gnomAD v4.1, within the VCEP one-person maximum. Details ▾Hide ▴
Reasoning

The governing ClinGen Brain Malformations VCEP defines PM2 as supporting evidence for a variant absent or rare in an ethnically matched population sample, with a one-person maximum to account for population-database errors. NM_006218.4:c.3G>A is absent from gnomAD v2.1 and has gnomAD v4.1 AC 0 of 1,513,740, AF 0, and zero homozygotes, satisfying PM2_Supporting.

Rule
Absent/rare from controls in an ethnically-matched cohort population sample (≤1).
Evidence considered
  • The ClinGen Brain Malformations VCEP specifies PM2 at supporting strength for an allele absent or rare in an ethnically matched population sample, with a one-person maximum.
  • gnomAD v2.1 reports the variant absent.
  • gnomAD v4.1 reports exome AC 0 of 1,361,480, total AC 0 of 1,513,740, AF 0, and zero homozygotes, including zero in the highest-observed African/African American population.
Still missing
  • No variant-specific entry for c.3G>A, p.Met1?, or p.M1? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; the VCEP's general PM2 rule therefore governs.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not met · 5 · evaluated, threshold not reached

PP5 Not met: ClinVar has no exact-variant expert-panel pathogenic or likely pathogenic classification for NM_006218.4:c.3G>A. Details ▾Hide ▴
Reasoning

No exact-variant ClinVar record or expert-panel classification was found for NM_006218.4:c.3G>A / p.(Met1?); therefore the required exact-variant ClinVar expert-panel pathogenic or likely pathogenic trigger for PP5 is absent. The governing VCEP also marks PP5 as not applicable and states it is not for use.

Rule
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
Evidence considered
  • ClinVar exact-variant searches returned no variation ID, no matching record, and no classification or review status for NM_006218.4:c.3G>A.
  • The governing specification states for PP5: "Not Applicable" and "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee."
Sources
clinvar ↗cspec ↗
BA1 Not met: gnomAD v4.1 allele frequency is 0/1,513,740 (0%), below the VCEP BA1 threshold of >0.0926%. Details ▾Hide ▴
Reasoning

The governing ClinGen Brain Malformations VCEP specifies BA1 when allele frequency is greater than 0.0926%. NM_006218.4:c.3G>A is absent from gnomAD v2.1 and has gnomAD v4.1 total AC 0, AN 1,513,740, AF 0, with zero observed alleles in every reported population, so the BA1 threshold is not met.

Rule
Allele frequency (>0.0926%).
Evidence considered
  • The ClinGen Brain Malformations VCEP specifies BA1 for allele frequency >0.0926% and notes this is a disease-specific adjustment.
  • gnomAD v2.1 reports the variant absent.
  • gnomAD v4.1 reports exome AC 0 of 1,361,480, total AC 0 of 1,513,740, AF 0, and zero homozygotes; the highest reported population frequency is also 0.
Still missing
  • No variant-specific entry for c.3G>A, p.Met1?, or p.M1? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; the VCEP's general BA1 rule therefore governs.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: gnomAD v4.1 allele frequency is 0/1,513,740 (0%), below the VCEP BS1 threshold of >0.0185%. Details ▾Hide ▴
Reasoning

The governing ClinGen Brain Malformations VCEP specifies BS1 when allele frequency is greater than 0.0185%. NM_006218.4:c.3G>A is absent from gnomAD v2.1 and has gnomAD v4.1 total AC 0, AN 1,513,740, AF 0, so it does not exceed the VCEP BS1 threshold.

Rule
Allele frequency (>0.0185%).
Evidence considered
  • The ClinGen Brain Malformations VCEP specifies BS1 for allele frequency >0.0185%.
  • gnomAD v2.1 reports the variant absent.
  • gnomAD v4.1 reports exome AC 0 of 1,361,480, total AC 0 of 1,513,740, AF 0, and zero homozygotes; the highest reported population frequency is also 0.
Still missing
  • No variant-specific entry for c.3G>A, p.Met1?, or p.M1? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; the VCEP's general BS1 rule therefore governs.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS2 Not met: gnomAD v4.1 reports 0 homozygotes, below the VCEP requirement of at least 3 homozygotes or 3 qualifying family observations. Details ▾Hide ▴
Reasoning

The governing ClinGen Brain Malformations VCEP requires at least three homozygotes in gnomAD or at least three heterozygous occurrences in well-phenotyped family members for BS2. gnomAD v4.1 reports zero homozygotes and no qualifying family observations are documented in the case evidence.

Rule
Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members.
Evidence considered
  • The ClinGen Brain Malformations VCEP specifies BS2 when at least 3 homozygotes are present in gnomAD or at least 3 heterozygous occurrences are present in well-phenotyped family members.
  • gnomAD v4.1 reports total homozygote count 0, exome homozygote count 0, genome homozygote count 0, and zero homozygotes in the reported populations.
Still missing
  • No variant-specific entry for c.3G>A, p.Met1?, or p.M1? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; the VCEP's general BS2 rule therefore governs.
  • No well-phenotyped family observations qualifying for BS2 are documented in the supplied case evidence.
Sources
cspec ↗gnomad_v4 ↗
BP6 Not met: ClinVar has no exact-variant expert-panel benign or likely benign classification for NM_006218.4:c.3G>A. Details ▾Hide ▴
Reasoning

No exact-variant ClinVar record or expert-panel classification was found for NM_006218.4:c.3G>A / p.(Met1?); therefore the required exact-variant ClinVar expert-panel benign or likely benign trigger for BP6 is absent. The governing VCEP also marks BP6 as not applicable and states it is not for use.

Rule
Apply BP6 only for an exact-variant ClinVar expert-panel Benign/Likely benign classification; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
Evidence considered
  • ClinVar exact-variant searches returned no variation ID, no matching record, and no classification or review status for NM_006218.4:c.3G>A.
  • The governing specification states for BP6: "Not Applicable" and "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee."
Sources
clinvar ↗cspec ↗

Not assessed · 6 · no assessment recorded

PS2 Not assessed: no proband, parental testing, maternity/paternity confirmation, or tissue allele-fraction data are available to meet the VCEP PS2 criteria. Details ▾Hide ▴
Reasoning

The governing Brain Malformations VCEP specification defines PS2_Strong when the variant is detectable in affected tissue, absent from parental samples with confirmed maternity and paternity, and absent from or at lower allele fraction in another tissue; PS2_Moderate requires confirmed parental absence or, when parents are unavailable, fulfillment of the affected-tissue mosaic criterion. The case evidence contains no proband-level result, parental testing, maternity or paternity confirmation, affected-tissue allele fraction, comparison-tissue allele fraction, or family-history documentation for NM_006218.4:c.3G>A. Therefore PS2 cannot be assigned. The governing VCEP full-text file was searched for c.3G>A, p.Met1?, and p.M1?; no variant-specific entry was found.

Rule
Award PS2_Strong if Criteria 1 and Criteria 2 are fulfilled: the variant is present at a detectable allele fraction but absent from parental samples with confirmed maternity and paternity, and is present at a detectable allele fraction in affected tissue but absent from or detected at a lower allelic fraction in another tissue. Award PS2_Moderate if Criteria 1 is fulfilled, or if parents are unavailable but Criteria 2 is fulfilled.
Evidence considered
  • The Brain Malformations VCEP PS2 rule requires detectable variant presence in affected tissue, parental absence with confirmed maternity and paternity, and for PS2_Strong a lower or absent allele fraction in another tissue; PS2_Moderate permits the parental-absence criterion alone or the affected-tissue criterion when parents are unavailable.
  • The case materials provide no proband, parent, maternity, paternity, family-history, affected-tissue allele-fraction, or comparison-tissue allele-fraction evidence for NM_006218.4:c.3G>A.
  • The governing VCEP full-text file was searched for c.3G>A, p.Met1?, and p.M1?; no variant-specific entry was found.
Still missing
  • No proband-level de novo or mosaic result is documented for NM_006218.4:c.3G>A.
  • No parental testing with confirmed maternity and paternity is documented.
  • No affected-tissue and comparison-tissue allele fractions are documented.
  • No variant-specific c.3G>A, p.Met1?, or p.M1? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt after searching all three notations.
Sources
cspec ↗
PS3 Not assessed: available functional papers do not test c.3G>A (p.M1?), so no variant-specific damaging assay result meets the VCEP PS3 requirements. Details ▾Hide ▴
Reasoning

The governing ClinGen Brain Malformations VCEP specification requires functional evidence to meet SVI/BMVCEP assay acceptability criteria; supporting evidence may establish PS3 at supporting strength, while moderate or strong evidence additionally requires positive and negative validation controls, with 8–34 tested variants for moderate and at least 35 for strong. The available functional papers (PMID:29533785 and PMID:31996845) do not mention NM_006218.4:c.3G>A, p.(Met1?), or p.(M1?), and therefore provide no variant-specific damaging assay result. No variant-specific phosphorylation, DEPTOR-binding, cell-survivability, cell-proliferation, or qualifying in vivo assay evidence was available to assess PS3.

Rule
Follow SVI recommendations with BMVCEP quality metrics and minimum validation controls; supporting evidence may be used for PS3 supporting, while evidence above supporting requires positive and negative validation controls, 8–34 variants for moderate, and 35 or more variants for strong.
Evidence considered
  • The governing VCEP specification states that PS3 follows SVI/BMVCEP functional-assay acceptability requirements; any publication may support PS3 at supporting strength, but evidence above supporting requires positive and negative validation controls.
  • The VCEP supplemental functional-assay requirements identify phosphorylation, DEPTOR binding, cell survivability, and cell proliferation as historically accepted assay classes; moderate evidence requires 8–34 variants and strong evidence requires at least 35 variants.
  • PMID:29533785 reports functional screening of other PIK3CA mutations in Ba/F3 and MCF10A models, but its extracted finding states that c.3G>A and p.(M1?) were searched for and not mentioned.
  • PMID:31996845 reports in vivo and cellular studies of other PIK3CA variants in glioma models, but its extracted finding states that c.3G>A and p.(M1?) were searched for and not mentioned.
Still missing
  • No entry for c.3G>A, p.Met1?, or p.M1? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; the file was searched for all three notations.
  • No variant-specific functional assay result with documented assay controls and replicate information was available.
  • The two fetched functional papers, PMID:29533785 and PMID:31996845, explicitly do not mention this variant.
Sources
cspec ↗PMID:29533785 ↗PMID:31996845 ↗
PS4 Not assessed: the variant is absent from gnomAD, but no verified affected-individual phenotype observation was available to assign Table 2A PS4 points. Details ▾Hide ▴
Reasoning

The governing Brain Malformations VCEP specification requires PS4 points from Table 2A phenotype observations and permits PS4 only when PM2 is met. The variant is absent from gnomAD v2.1, gnomAD v4.1 (0/1,513,740 alleles), and gnomAD-Canada, satisfying the population prerequisite, but the case bundle contains no verified affected-individual phenotype observation for NM_006218.4:c.3G>A (NP_006209.2:p.(Met1?)/p.(M1?)) from the searched literature. The two fetched papers (PMIDs 29533785 and 31996845) explicitly do not mention this variant, so no Table 2A points or PS4 strength can be assigned.

Rule
Points are assigned for phenotype according to Table 2A; phenotype criteria can only be used if the variant meets PM2; PS4_Supporting = 0.5–1.25 points, PS4_Moderate = 1.5–3.25 points, PS4_Strong = 3.5–15.75 points, and PS4_VeryStrong ≥16 points.
Evidence considered
  • The governing specification states: "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2)." It defines PS4_Supporting as 0.5–1.25 points, PS4_Moderate as 1.5–3.25 points, PS4_Strong as 3.5–15.75 points, and PS4_VeryStrong as ≥16 points.
  • Population evidence records 0 alternate alleles in gnomAD v4.1 (0/1,513,740), absence from gnomAD v2.1, and absence from gnomAD-Canada.
  • PMID:29533785 searched for c.3G>A, NP_006209.2:p.(M1?), and p.(M1?); its extraction states the specific variant is not mentioned.
  • PMID:31996845 searched for c.3G>A, NP_006209.2:p.(M1?), and p.M1?; its extraction states the specific variant is not mentioned.
Still missing
  • No verified affected-individual phenotype observation or case count was identified for NM_006218.4:c.3G>A in the consolidated evidence or searched papers.
  • No exact-variant entry was found when searching clingen_brainmalform_acmg_specifications_v1_1.pdf.txt for c.3G>A, p.Met1?, and p.M1?.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗PMID:29533785 ↗PMID:31996845 ↗
BS3 Not assessed: no fetched functional paper tests c.3G>A (p.M1?) and reports a validated normal-function result required for BS3. Details ▾Hide ▴
Reasoning

The governing ClinGen Brain Malformations VCEP specification requires BS3 functional evidence to follow SVI/BMVCEP quality metrics and minimum validation controls. The available functional papers (PMID:29533785 and PMID:31996845) do not mention NM_006218.4:c.3G>A, p.(Met1?), or p.(M1?), and provide no variant-specific normal-function or non-damaging result. Consequently, there is insufficient validated assay evidence to apply BS3 at supporting or strong strength.

Rule
Follow SVI recommendations with BMVCEP quality metrics and minimum validation controls for BS3 supporting or strong evidence.
Evidence considered
  • The governing VCEP specification defines BS3 as well-established in vitro or in vivo functional evidence showing no damaging effect and requires SVI/BMVCEP quality metrics and minimum validation controls.
  • PMID:29533785 includes wild-type and other PIK3CA functional comparisons, but its extracted finding states that c.3G>A and p.(M1?) were searched for and not mentioned; those results cannot establish BS3 for this variant.
  • PMID:31996845 includes in vivo and cellular functional studies of other PIK3CA variants, but its extracted finding states that c.3G>A and p.(M1?) were searched for and not mentioned; those results cannot establish BS3 for this variant.
Still missing
  • No entry for c.3G>A, p.Met1?, or p.M1? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; the file was searched for all three notations.
  • No variant-specific benign or normal-function assay result with the VCEP-required quality metrics and controls was available.
  • The two fetched functional papers, PMID:29533785 and PMID:31996845, explicitly do not mention this variant.
Sources
cspec ↗PMID:29533785 ↗PMID:31996845 ↗
BP2 Not assessed: no documented cis/trans PIK3CA pathogenic-variant pair or phase result is available for NM_006218.4:c.3G>A. Details ▾Hide ▴
Reasoning

The governing VCEP permits BP2 at Supporting strength when the variant is observed in cis or trans with a known pathogenic variant in the same gene. The available case evidence does not document a phased PIK3CA pathogenic-variant pair, affected-proband observation, parental testing, or another cis/trans result for NM_006218.4:c.3G>A (NP_006209.2:p.(Met1?)); therefore BP2 cannot be assessed.

Rule
Observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
  • The governing ClinGen Brain Malformations VCEP rule for BP2 is: observed in cis or trans with a known pathogenic variant in the same gene, at Supporting strength.
  • The consolidated allelic evidence contains no documented phase, cis/trans relationship, affected-proband genotype context, parental testing, or same-gene pathogenic partner for this variant.
  • The variant-specific notations c.3G>A, p.Met1?, and p.M1? were not found in the governing VCEP full text.
Still missing
  • No affected-proband, parental, segregation, haplotype, or laboratory phase data were found for this variant in the consolidated allelic evidence bundle.
  • The governing VCEP full text was searched for c.3G>A, p.Met1?, and p.M1?; no variant-specific entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
  • A known pathogenic PIK3CA variant and its cis/trans relationship to NM_006218.4:c.3G>A are not documented.
Sources
cspec ↗
BP5 Not assessed: no case was documented in which this exact variant co-occurred with a confirmed alternate molecular basis in another gene. Details ▾Hide ▴
Reasoning

The governing Brain Malformations VCEP defines BP5 as a variant found in a case with an alternate molecular basis for disease, specifically in a different gene. The available evidence documents no case containing this exact variant with a confirmed alternate molecular diagnosis, so BP5 cannot be assessed.

Rule
BP5 Supporting requires the variant to be observed in a case with an alternate molecular basis for disease in a different gene.
Evidence considered
  • The governing specification defines BP5 as "Variant found in a case with an alternate molecular basis for disease" and specifies observation in a case with an alternate molecular basis in a different gene.
  • The consolidated case evidence contains no verified exact-variant case with a documented alternate molecular diagnosis.
Still missing
  • No exact-variant case report with a confirmed alternate molecular basis in a different gene was identified.
Sources
cspec ↗
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable: the governing VCEP identifies PIK3CA brain-malformation disease as gain of function, so PVS1 is not used for this initiation-codon variant. Details ▾Hide ▴
Reasoning

PVS1 is not applicable under the governing ClinGen Brain Malformations VCEP specification. The specification states that loss of function and/or haploinsufficiency have not been clearly identified as disease mechanisms for PIK3CA-related brain malformations and that the disease mechanism is gain of function; therefore, an initiation-codon variant, NM_006218.4:c.3G>A (NP_006209.2:p.(Met1?)/p.(M1?)), cannot receive PVS1 in this framework despite its predicted initiation-loss consequence. The variant is on the governing PIK3CA transcript framework (NM_006218.3/4), lies in exon 2, and has uncertain protein consequence, but these features do not override the VCEP-level non-applicability rule. The governing VCEP file was searched for c.3G>A, p.Met1?, and p.M1?; no variant-specific pre-assigned PVS1 entry was found.

VCEP rule
ClinGen Brain Malformations VCEP PVS1: not applicable because LOF/haploinsufficiency is not the established disease mechanism for these PIK3CA-related brain malformations; disease mechanism is gain of function.
Evidence considered
  • The ClinGen Brain Malformations VCEP specification defines PVS1 as a null-variant criterion but states that LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms for these brain malformations and that the mechanism is gain of function.
  • The case normalization identifies NM_006218.4:c.3G>A as NP_006209.2:p.(Met1?)/p.(M1?) with consequence class initiation_loss and exon 2; the protein consequence remains uncertain.
  • The governing VCEP text was searched for c.3G>A, p.Met1?, and p.M1? without finding a variant-specific PVS1 assignment.
Still missing
  • No variant-specific entry for c.3G>A, p.Met1?, or p.M1? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this is a search result, not evidence that the variant is absent from all sources.
Sources
cspec ↗
PS1 N/APS1 (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.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: initiation_loss (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM1 N/APM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_006218.4:c.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: initiation_loss (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM3 VCEPNot applicable: the VCEP specifies PM3 is not applicable because disease-causing PIK3CA variants are heterozygous. Details ▾Hide ▴
Reasoning

The ClinGen Brain Malformations VCEP specification explicitly designates PM3 as not applicable because the disease-causing PIK3CA variants in this disorder are heterozygous; therefore recessive trans-phase evidence cannot be used for this variant.

VCEP rule
Not applicable since disease-causing variants are heterozygous.
Evidence considered
  • The governing ClinGen Brain Malformations VCEP specification states for PM3: not applicable since disease-causing variants are heterozygous.
  • The case evidence contains no phase, compound-heterozygous, or recessive inheritance observation that could override the VCEP applicability rule.
Still missing
  • The governing VCEP full text was searched for c.3G>A, p.Met1?, and p.M1?; no variant-specific entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗
PM4 VCEPPM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_006218.4:c.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
VCEP rule
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
Evidence considered
  • Deterministic consequence classification: initiation_loss (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PM5 N/APM5 (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.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: initiation_loss (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM6 VCEPNot applicable: the VCEP explicitly routes assumed de novo evidence without parental confirmation to PS2 rather than allowing PM6. Details ▾Hide ▴
Reasoning

The governing Brain Malformations VCEP explicitly marks PM6 as not applicable, states that assumed de novo without confirmation of paternity and maternity is addressed according to PS2, and provides no separate PM6 strength rule. The VCEP full-text file was searched for c.3G>A, p.Met1?, and p.M1?; no variant-specific entry was found.

VCEP rule
PM6 is not applicable for this VCEP; this point is addressed according to PS2 and will not be used.
Evidence considered
  • The Brain Malformations VCEP marks PM6 not applicable and states: 'This point is addressed according to PS2 and will not be used.'
  • The governing VCEP full-text file was searched for c.3G>A, p.Met1?, and p.M1?; no variant-specific entry was found.
Still missing
  • No variant-specific c.3G>A, p.Met1?, or p.M1? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt after searching all three notations.
Sources
cspec ↗
PP1 VCEPNot applicable: the VCEP excludes PP1 for this disorder because its disease-causing variants are de novo or mosaic. Details ▾Hide ▴
Reasoning

The governing Brain Malformations VCEP explicitly marks PP1 as not applicable because disease-causing variants are germline mosaic, de novo, or mosaic, and provides no PP1 strength rule. The VCEP full-text file was searched for c.3G>A, p.Met1?, and p.M1?; no variant-specific entry was found.

VCEP rule
PP1 is not applicable since disease-causing variants are germline mosaic, de novo, or mosaic.
Evidence considered
  • The Brain Malformations VCEP marks PP1 not applicable because disease-causing variants are germline mosaic, de novo, or mosaic.
  • The governing VCEP full-text file was searched for c.3G>A, p.Met1?, and p.M1?; no variant-specific entry was found.
Still missing
  • No variant-specific c.3G>A, p.Met1?, or p.M1? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt after searching all three notations.
Sources
cspec ↗
PP2 N/APP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_006218.4:c.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: initiation_loss (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PP3 VCEPNot applicable: initiation-loss variant p.(Met1?) is outside the VCEP's PP3 scope, which excludes this gain-of-function consequence. Details ▾Hide ▴
Reasoning

PP3 is not applicable. The case consequence is initiation_loss for NM_006218.4:c.3G>A, represented as NP_006209.2:p.(Met1?), rather than a missense or splice-region consequence. The governing ClinGen Brain Malformations VCEP specification explicitly states that PP3 is not applicable for this gain-of-function framework because traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms. Therefore, no REVEL, SpliceAI, or other computational predictor is evaluated for PP3.

VCEP rule
PP3 is not applicable for this VCEP because these variants are gain-of-function and traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms.
Evidence considered
  • The case normalization identifies NM_006218.4:c.3G>A as NP_006209.2:p.(Met1?) with consequence_class initiation_loss.
  • The ClinGen Brain Malformations VCEP specification states that PP3 is not applicable because these PIK3CA brain-malformation variants are gain-of-function and traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms.
Still missing
  • No direct c.3G>A, p.Met1?, or p.M1? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; this does not affect the explicit PP3 scope determination.
Sources
cspec ↗
PP4 VCEPNot applicable: the Brain Malformations VCEP explicitly accounts for phenotype-specific evidence under PS4 rather than PP4. Details ▾Hide ▴
Reasoning

The governing Brain Malformations VCEP specification explicitly states that PP4 is not applicable because phenotype-specific evidence is accounted for under PS4.

VCEP rule
PP4 is not applicable for this VCEP because phenotype-specific evidence is accounted for under PS4.
Evidence considered
  • The governing specification states under PP4: "Not applicable since this criterion is accounted for under PS4."
Sources
cspec ↗
BS4 VCEPNot applicable: the VCEP excludes BS4 because this disorder is evaluated using de novo, germline-mosaic, or post-zygotic mechanisms. Details ▾Hide ▴
Reasoning

The governing Brain Malformations VCEP explicitly marks BS4 as not applicable because these are de novo, germline mosaic, or post-zygotic mutations; consequently, lack of segregation in affected family members is not used for this framework. The VCEP full-text file was searched for c.3G>A, p.Met1?, and p.M1?; no variant-specific entry was found.

VCEP rule
BS4 is not applicable as these are de novo, germline mosaic, or post-zygotic mutations.
Evidence considered
  • The Brain Malformations VCEP marks BS4 not applicable and states that these are de novo, germline mosaic, or post-zygotic mutations.
  • The governing VCEP full-text file was searched for c.3G>A, p.Met1?, and p.M1?; no variant-specific entry was found.
Still missing
  • No variant-specific c.3G>A, p.Met1?, or p.M1? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt after searching all three notations.
Sources
cspec ↗
BP1 VCEPBP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_006218.4:c.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
VCEP rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: initiation_loss (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP3 VCEPBP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_006218.4:c.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
VCEP rule
deterministic_prefilter: requires_repeat_region_indel
Evidence considered
  • Deterministic consequence classification: initiation_loss (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
BP4 N/ANot applicable: initiation-loss variant p.(Met1?) is neither synonymous, intronic, nor UTR, the VCEP-defined BP4 scope. Details ▾Hide ▴
Reasoning

BP4 is not applicable. The case consequence is initiation_loss for NM_006218.4:c.3G>A, represented as NP_006209.2:p.(Met1?), and is not synonymous, intronic, or a non-coding UTR variant. The governing ClinGen Brain Malformations VCEP specification restricts BP4 to synonymous, intronic positions except canonical splice sites, and non-coding UTR variants evaluated with splicing prediction tools. Therefore, the available SpliceAI score is not evaluated for BP4.

Rule
Award BP4 only for synonymous, intronic positions except canonical splice sites, or non-coding UTR variants when two of three specified splicing prediction tools predict no impact; otherwise BP4 is not applicable.
Evidence considered
  • The case normalization identifies NM_006218.4:c.3G>A as NP_006209.2:p.(Met1?) with consequence_class initiation_loss.
  • The ClinGen Brain Malformations VCEP specification states that BP4 is not applicable except for synonymous, intronic positions excluding canonical splice sites, and non-coding UTR variants; its specified tools are varSEAK, SpliceAI, and MaxEntScan.
Still missing
  • No direct c.3G>A, p.Met1?, or p.M1? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; this does not affect the explicit BP4 scope determination.
Sources
cspec ↗
BP7 N/ABP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006218.4:c.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: initiation_loss (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules

Identifiers

Gene
PIK3CA
Transcript
NM_006218.4
Coding (HGVS c.)
NM_006218.4:c.3G>A
Protein (HGVS p.)
NP_006209.2:p.(Met1?)
GRCh38
chr3:179198828 G>A
GRCh37
chr3:178916616 G>A
Location and type
Exon 2 · initiation loss

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 0 / 1,513,740 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,513,740 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1513740 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/71510 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -12 bp
0.000
SpliceAI acceptor gainat +213 bp
0.001
SpliceAI donor lossat +207 bp
0.014
SpliceAI donor gainat +359 bp
0.000
Pangolin splice lossmagnitude shown
-0.008
Pangolin splice gain
0.004

Other predictors

REVEL
0.650
BayesDel
0.660

How the predictions were used

PP3 VCEPNot applicable: initiation-loss variant p.(Met1?) is outside the VCEP's PP3 scope, which excludes this gain-of-function consequence. Details ▾Hide ▴
Reasoning

PP3 is not applicable. The case consequence is initiation_loss for NM_006218.4:c.3G>A, represented as NP_006209.2:p.(Met1?), rather than a missense or splice-region consequence. The governing ClinGen Brain Malformations VCEP specification explicitly states that PP3 is not applicable for this gain-of-function framework because traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms. Therefore, no REVEL, SpliceAI, or other computational predictor is evaluated for PP3.

VCEP rule
PP3 is not applicable for this VCEP because these variants are gain-of-function and traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms.
Evidence considered
  • The case normalization identifies NM_006218.4:c.3G>A as NP_006209.2:p.(Met1?) with consequence_class initiation_loss.
  • The ClinGen Brain Malformations VCEP specification states that PP3 is not applicable because these PIK3CA brain-malformation variants are gain-of-function and traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms.
Still missing
  • No direct c.3G>A, p.Met1?, or p.M1? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; this does not affect the explicit PP3 scope determination.
Sources
cspec ↗
BP4 N/ANot applicable: initiation-loss variant p.(Met1?) is neither synonymous, intronic, nor UTR, the VCEP-defined BP4 scope. Details ▾Hide ▴
Reasoning

BP4 is not applicable. The case consequence is initiation_loss for NM_006218.4:c.3G>A, represented as NP_006209.2:p.(Met1?), and is not synonymous, intronic, or a non-coding UTR variant. The governing ClinGen Brain Malformations VCEP specification restricts BP4 to synonymous, intronic positions except canonical splice sites, and non-coding UTR variants evaluated with splicing prediction tools. Therefore, the available SpliceAI score is not evaluated for BP4.

Rule
Award BP4 only for synonymous, intronic positions except canonical splice sites, or non-coding UTR variants when two of three specified splicing prediction tools predict no impact; otherwise BP4 is not applicable.
Evidence considered
  • The case normalization identifies NM_006218.4:c.3G>A as NP_006209.2:p.(Met1?) with consequence_class initiation_loss.
  • The ClinGen Brain Malformations VCEP specification states that BP4 is not applicable except for synonymous, intronic positions excluding canonical splice sites, and non-coding UTR variants; its specified tools are varSEAK, SpliceAI, and MaxEntScan.
Still missing
  • No direct c.3G>A, p.Met1?, or p.M1? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; this does not affect the explicit BP4 scope determination.
Sources
cspec ↗
BP7 N/ABP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006218.4:c.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: initiation_loss (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.65. BayesDel score = 0.66.

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Systematic Functional Annotation of Somatic Mutations in Cancer.
    The paper does not mention PIK3CA c.3G>A or NP_006209.2:p.(M1?). It reports functional screening of other PIK3CA mutations using Ba/F3 and MCF10A cell models, including parallel pooled and individual testing of 29 PIK3CA mutants.
    Does not name this variant
    PMID 29533785 ↗
    Quoted passage
    To examine whether screening individual mutations can overcome the potential masking effect of highly active driver mutations in the pooled format, we carried out parallel pooled and individual screens of 29 PIK3CA mutants and wild-type PIK3CA in the Ba/F3 cell line under both in vivo and in vitro settings (Figure S1).

    Results, Development of a Versatile Functional Genomic Platform

  • PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis.
    The paper does not mention PIK3CA c.3G>A or NP_006209.2:p.(M1?). It investigates other PIK3CA variants in glioma using an in vivo mouse complementation and screening system, including E545K, H1047R, R88Q, and C420R.
    Does not name this variant
    PMID 31996845 ↗
    Quoted passage
    Using this system, we identified several new driver variants of PIK3CA that are active in glioma.

    Discussion

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 0 / 1,513,740 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.014 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

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1513740 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/71510 alleles, homozygotes = 0).

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). REVEL score = 0.65. BayesDel score = 0.66.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.

Somatic

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

Cancer Hotspots

This variant lies in a statistically significant hotspot.