0%
PIK3CAc.1258T>CUncertain significance
Print report
Variant interpretation report

PIK3CA c.1258T>C, p.Cys420Arg

NM_006218.4:c.1258T>C NP_006209.2:p.(Cys420Arg) Missense · exon 8 View identifiers
Classification
Uncertain significance

Variant description:

The PIK3CA NM_006218.4:c.1258T>C (NP_006209.2:p.(Cys420Arg)) missense variant has previously been reported in somatic cancers (COSMIC; COSV55874020, n = 261 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: C420R increased lipid kinase activity versus wild type and activated downstream signaling in independent functional assays. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).

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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Supporting
PS3 · supporting

Met at Supporting: C420R increased lipid kinase activity versus wild type and activated downstream signaling in independent functional assays.

PM1Supporting
PM1 · supporting

Met at Supporting: PIK3CA residue 420 lies within the VCEP-approved kinase domain spanning residues 322-483.

PM2Supporting
PM2 · supporting

Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, within the VCEP PM2 limit of one person maximum.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: PS3 (supporting), PM1 (supporting), and PM2 (supporting) do not meet an ACMG/AMP 2015 pathogenic or 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.

No screenshot for this evidence
REVEL score
0.788 recorded score

Recorded REVEL score: 0.788. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
14 reported laboratory submissions

13 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
261 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55874020, n = 261 times).

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: 3 met · 5 not met · 6 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

PM1_Supporting is met because residue C420 lies within the VCEP-approved PIK3CA kinase domain AA 322-483.

PS1 and PM5 remain unassessed without a verified distinct same-amino-acid or same-residue pathogenic comparator.

PP2 remains unassessed without the VCEP-required PIK3CA ExAC/gnomAD missense-constraint z-score; BP1 is explicitly not applicable.

For PS4, the VCEP requires PM2 and phenotype points from Table 2A; PM2 is supported by absence from gnomAD v2.1 and v4.1, but the available C420R evidence does not establish a qualifying human case-control prevalence comparison.

The only conservatively verified Table 2A contribution is one tumor-presence category worth 0.25 points; 0.25 < 0.5, below PS4_Supporting.

PP4, PP5, and BP6 are explicitly not applicable under this VCEP. BP5 remains not assessed because no qualifying alternate molecular basis in a different gene was documented.

Met · 3

PS3 SupportingVCEPMet at Supporting: C420R increased lipid kinase activity versus wild type and activated downstream signaling in independent functional assays. Details ▾Hide ▴
Reasoning

The queried missense variant NM_006218.4:c.1258T>C produces p.Cys420Arg/p.C420R. The governing Brain Malformations VCEP permits Supporting PS3 when a publication provides functional assay evidence. PMID:22949682 directly tested C420R in purified p110alpha/p85alpha complexes using lipid kinase assays, lipid-binding FRET, and HDX-MS; C420R increased basal lipid kinase activity compared with wild type, increased lipid binding, and disrupted the iSH2-C2 interface in a gain-of-function pattern. PMID:15930273 independently tested C420R in vitro and in cells: C420R had greater lipid kinase activity than wild type, elevated Akt and p70S6K phosphorylation, increased focus formation, and anchorage-independent colony formation. These are variant-specific functional results consistent with a damaging gain-of-function effect. The VCEP requires positive and negative validation controls and 8-34 variants for Moderate or 35+ variants for Strong; the available publications do not document the VCEP-defined independent pathogenic/likely pathogenic and benign/likely benign validation controls needed for a strength above Supporting, so Supporting is the calibrated maximum.

VCEP rule
Brain Malformation Recommendation: Award PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP. Quality metrics and minimum validation controls required can be found in Supplementary Document 1. ... Any publication within the spreadsheet can be used as evidence for a supporting level of evidence (PS3). ... Any paper must have validation controls (positive and negative) in order to be used as evidence for a level above supporting. ... 8-34 variants are required for moderate evidence. ... 35+ variants are required for strong evidence.
Evidence considered
  • ClinGen Brain Malformations VCEP Supplemental Document 1, Functional Assay Validation: the four assay classes, including phosphorylation, DEPTOR binding, cell survivability, and cell proliferation, are broadly accepted historically; any publication within the spreadsheet can support PS3 at Supporting level.
  • Burke et al. 2012, PMID:22949682, lipid kinase assay and lipid-binding/HDX-MS study: C420R was one of 11 cancer-linked p110alpha mutants; all cancer-linked mutations increased basal lipid kinase activity compared with WT, and C420R increased lipid binding and disrupted the iSH2-C2 interface.
  • Ikenoue et al. 2005, PMID:15930273, functional analysis of eight PIK3CA mutations: C420R showed greater lipid kinase activity than wild type, elevated Akt and p70S6K phosphorylation, increased focus formation, and anchorage-independent growth.
  • The VCEP's above-Supporting requirements are not documented for these assays: positive controls must be independently P/LP and negative controls independently B/LB; Moderate requires 8-34 variants and Strong requires 35+ variants.
Still missing
  • The available publications do not document the VCEP-defined independent positive and negative validation controls required for PS3 above Supporting, so Moderate or Strong PS3 cannot be assigned.
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this is a gap in the governing file, not evidence that functional evidence is absent.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗PMID:22949682 ↗PMID:15930273 ↗
PM1 SupportingVCEPMet at Supporting: PIK3CA residue 420 lies within the VCEP-approved kinase domain spanning residues 322-483. Details ▾Hide ▴
Reasoning

The queried missense variant changes residue 420 of PIK3CA and is in exon 8. The authoritative vcep_materials.json domain_tables entry lists the PIK3CA kinase domains as residues 322-483 and 797-1068; residue 420 is within 322-483. The governing VCEP permits a supporting point for a variant in an exon within an approved Table 4 functional domain, so PM1_Supporting is met without requiring hotspot recurrence. The governing VCEP file was searched for c.1258T>C, p.Cys420Arg, and p.C420R with no exact variant entry; PM1 is adjudicated from the authoritative Table 4 domain rule and domain membership.

VCEP rule
Brain Malformation Recommendation: A supporting point may be awarded if the variant of interest is located in an exon within one of the below approved functional domains Table 4.
Evidence considered
  • Table 4, PIK3CA kinase domains: AA 322-483 and AA 797-1068.
  • The variant is NP_006209.2:p.(Cys420Arg) and is located in exon 8; residue 420 falls within the approved AA 322-483 domain.
  • The VCEP states that a supporting point may be awarded for a variant in an exon within one of the approved Table 4 functional domains; hotspot recurrence is not required on this domain path.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; the domain-based Table 4 rule was sufficient for PM1.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PM2 SupportingVCEPMet at Supporting: the variant is absent from gnomAD v2.1 and v4.1, within the VCEP PM2 limit of one person maximum. Details ▾Hide ▴
Reasoning

PM2 at Supporting strength is met. The VCEP permits PM2_Supporting for a variant absent or rare in controls in an ethnically matched cohort, with a one-person maximum to account for sequencing and calling artifacts. This variant was absent from gnomAD v2.1 and v4.1 and also absent from the non-cancer gnomAD v2.1 and v3.1 searches, satisfying the available population absence requirement.

VCEP rule
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or ExAC/gnomAD ... Brain Malformation Recommendation:(One person maximum)
Evidence considered
  • ClinGen Brain Malformations VCEP PM2_Supporting rule: the variant must be absent or rare from controls in an ethnically matched cohort population sample, with a one-person maximum recommendation to account for sequencing and calling artifacts.
  • gnomAD v2.1 all-comers search for GRCh37 3-178927980-T-C: absent; no allele count or allele frequency was reported.
  • gnomAD v4.1 all-comers search for GRCh38 3-179210192-T-C: absent; no allele count or allele frequency was reported.
  • gnomAD v2.1 non-cancer and v3.1 non-cancer searches also reported the variant as absent.
Still missing
  • No entry for c.1258T>C, p.Cys420Arg, or p.C420R was found when clingen_brainmalform_acmg_specifications_v1_1.pdf was searched.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗

Not met · 5 · evaluated, threshold not reached

PS4 VCEPNot met: the highest conservatively verified PS4 score is 0.25 tumor-presence points, below the VCEP PS4_Supporting range of 0.5–1.25 points. Details ▾Hide ▴
Reasoning

The VCEP requires phenotype points under Table 2A, only when PM2 is met, with PS4_Supporting requiring 0.5–1.25 points. PM2 is supported because the variant is absent from gnomAD v2.1 and v4.1. The available variant-specific literature reports C420R in tumor or experimental brain-tumor contexts, but does not provide a human affected-versus-unaffected case-control comparison or a count of patients with the VCEP-defined brain-malformation phenotypes. COSMIC reports 261 somatic occurrences, but the available record does not establish the number of distinct eligible primary tumors or exclude normal-tissue records; therefore only one verified tumor-presence category can be conservatively assigned (0.25 points), and the required comparison is 0.25 < 0.5, so PS4_Supporting is not met. The VCEP source text was searched for c.1258T>C, p.Cys420Arg, and p.C420R, with no variant-specific entry found in the governing full-text file.

VCEP rule
Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant meets criteria for (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Supporting = 0.5 – 1.25 points.
Evidence considered
  • ClinGen Brain Malformations VCEP Table 2A: presence of the variant in a tumor sample scores 0.25 points; the source also limits tumor counting and requires avoiding normal-tissue records.
  • ClinGen Brain Malformations VCEP Table 2B: PS4_Supporting is 0.5–1.25 points; explicit comparison: 0.25 < 0.5, therefore the supporting threshold is not reached.
  • The case population data report the variant absent from gnomAD v2.1 and gnomAD v4.1, satisfying the PS4 prerequisite that PM2 be met.
  • COSMIC record COSV55874020 reports 261 somatic occurrences, but the available record does not establish eligible distinct primary tumors for conservative PS4 point assignment.
  • PMID:21266528, cohort of 108 primary endometrial tumors: C420R is listed among exon 1–7 mutations, but the paper does not provide a C420R-specific affected-versus-control comparison.
  • PMID:31996845, mouse glioblastoma and related experimental models: C420R drove tumorigenesis and brain-tumor phenotypes, but this is not a human case-control prevalence comparison for the VCEP phenotype.
Still missing
  • No c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
  • No eligible human case-control counts or VCEP-defined brain-malformation phenotype counts were available for C420R.
  • The COSMIC total of 261 does not identify distinct eligible primary tumors or exclude normal-tissue records, so additional tumor occurrences were not counted.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗cosmic ↗PMID:31996845 ↗PMID:21266528 ↗
BA1 VCEPNot met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BA1 threshold of >0.0926%. Details ▾Hide ▴
Reasoning

BA1 is not met. The Brain Malformations VCEP specifies BA1 when allele frequency is >0.0926%. The variant was absent from gnomAD v2.1 and gnomAD v4.1, with no allele count or frequency reported; the non-cancer gnomAD v2.1 and v3.1 searches also reported absence. Therefore the available population evidence is below the specified BA1 threshold, not above it.

VCEP rule
Brain Malformation Recommendation: An allele frequency (>0.0926%) was approved. ... Note: this was adjusted from ACMG Guidelines due to maintaining the 5x threshold for benign (consistent with previously established guidelines)
Evidence considered
  • ClinGen Brain Malformations VCEP BA1 rule: allele frequency >0.0926% is required; the specification notes that this threshold was adjusted from ACMG Guidelines to maintain the 5x threshold for benign evidence.
  • gnomAD v2.1 all-comers search for GRCh37 3-178927980-T-C: absent; no allele count or allele frequency was reported.
  • gnomAD v4.1 all-comers search for GRCh38 3-179210192-T-C: absent; no allele count or allele frequency was reported.
  • gnomAD v2.1 non-cancer and v3.1 non-cancer searches also reported the variant as absent.
Still missing
  • No entry for c.1258T>C, p.Cys420Arg, or p.C420R was found when clingen_brainmalform_acmg_specifications_v1_1.pdf was searched.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BS1 VCEPNot met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BS1 threshold of >0.0185%. Details ▾Hide ▴
Reasoning

BS1 is not met. The Brain Malformations VCEP specifies BS1 when allele frequency is >0.0185%. The variant was absent from gnomAD v2.1 and gnomAD v4.1, with no allele count or frequency reported; the non-cancer gnomAD v2.1 and v3.1 searches also reported absence. The available population evidence therefore does not exceed the VCEP BS1 threshold.

VCEP rule
Brain Malformation Recommendation: An allele frequency (>0.0185%) was approved. (Supplemental Table 3)
Evidence considered
  • ClinGen Brain Malformations VCEP BS1 rule: allele frequency >0.0185% is required, as approved in Supplemental Table 3.
  • gnomAD v2.1 all-comers search for GRCh37 3-178927980-T-C: absent; no allele count or allele frequency was reported.
  • gnomAD v4.1 all-comers search for GRCh38 3-179210192-T-C: absent; no allele count or allele frequency was reported.
  • gnomAD v2.1 non-cancer and v3.1 non-cancer searches also reported the variant as absent.
Still missing
  • No entry for c.1258T>C, p.Cys420Arg, or p.C420R was found when clingen_brainmalform_acmg_specifications_v1_1.pdf was searched.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BS2 VCEPNot met: gnomAD v2.1 and v4.1 report no variant, so the required ≥3 homozygotes or ≥3 well-phenotyped family observations are not documented. Details ▾Hide ▴
Reasoning

BS2 is not met. The VCEP requires at least three homozygotes in gnomAD or ExAC, or at least three heterozygous observations in well-phenotyped family members. The variant is absent from gnomAD v2.1 and v4.1, so no qualifying gnomAD homozygotes are present; the case evidence also documents no qualifying family observations.

VCEP rule
Brain Malformation Recommendation: Clinical laboratories are encouraged to accumulate more than 2 (≥3) instances of well phenotyped family members before applying this strong criterion. To be considered for this point, the variant should be either germline (most common), or somatic in a relevant tissue. Homozygous occurrences in gnomAD or ExAC can also be counted for this point (≥3)
Evidence considered
  • ClinGen Brain Malformations VCEP BS2 rule: clinical laboratories are encouraged to accumulate at least three well-phenotyped family-member instances; homozygous occurrences in gnomAD or ExAC can also be counted at ≥3.
  • gnomAD v2.1 all-comers search for GRCh37 3-178927980-T-C: absent, therefore no homozygote count is reported.
  • gnomAD v4.1 all-comers search for GRCh38 3-179210192-T-C: absent, therefore no homozygote count is reported.
  • No qualifying well-phenotyped family-member heterozygote series is documented in the available case evidence.
Still missing
  • No entry for c.1258T>C, p.Cys420Arg, or p.C420R was found when clingen_brainmalform_acmg_specifications_v1_1.pdf was searched.
  • No qualifying set of at least three heterozygous observations in well-phenotyped family members is documented.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BS3 VCEPNot met: C420R increased lipid kinase activity and downstream Akt/p70S6K activation rather than showing no damaging effect. Details ▾Hide ▴
Reasoning

BS3 requires well-established functional studies showing no damaging effect on protein function. The available variant-specific studies instead show damaging gain-of-function findings for p.Cys420Arg/p.C420R: PMID:22949682 reports increased basal lipid kinase activity and lipid binding, while PMID:15930273 reports increased lipid kinase activity, Akt and p70S6K activation, focus formation, and anchorage-independent growth compared with wild type. Therefore the available functional evidence contradicts, rather than meets, BS3.

VCEP rule
Brain Malformation Recommendation: Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required (PMID: 31892348) (Supplementary Document 1)
Evidence considered
  • The VCEP BS3 rule requires functional studies showing no damaging effect on protein function and directs reviewers to the SVI recommendations plus Brain Malformation Group quality metrics and minimum validation controls.
  • Burke et al. 2012, PMID:22949682: C420R was included in lipid kinase and lipid-binding assays and showed increased activity/binding relative to WT, findings inconsistent with no damaging effect.
  • Ikenoue et al. 2005, PMID:15930273: C420R increased lipid kinase activity, Akt and p70S6K phosphorylation, focus formation, and soft-agar colony formation relative to wild type, findings inconsistent with BS3.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this is a gap in the governing file, not evidence that benign functional evidence is absent.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗PMID:22949682 ↗PMID:15930273 ↗

Not assessed · 6 · no assessment recorded

PS1 ACMG_2015Not assessed: no distinct alternate nucleotide change producing the same pathogenic p.Cys420Arg amino-acid change was identified for comparison. Details ▾Hide ▴
Reasoning

The Brain Malformations VCEP applies PS1 as originally described: the queried PIK3CA p.Cys420Arg variant must be compared with a previously established pathogenic variant producing the same amino-acid change, regardless of nucleotide change. The available records identify the queried c.1258T>C / p.C420R variant itself, but no alternate nucleotide change producing p.C420R was identified. The governing VCEP file was searched for c.1258T>C, p.Cys420Arg, and p.C420R with no exact variant entry; the available evidence therefore does not establish the required distinct nucleotide-level comparator.

Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
  • The queried variant is NM_006218.4:c.1258T>C, NP_006209.2:p.(Cys420Arg) / p.(C420R).
  • The VCEP governing file was searched under c.1258T>C, p.Cys420Arg, and p.C420R; no exact variant entry was found.
  • No distinct alternate-nucleotide p.C420R comparator was present in the reviewed case evidence.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
  • A verified alternate-nucleotide p.C420R comparator is needed to evaluate PS1.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PS2 VCEPNot assessed: no human proband allele fraction, confirmed maternity/paternity, parental testing, or affected-tissue comparative allele-fraction data are available. Details ▾Hide ▴
Reasoning

The VCEP permits PS2_Moderate when the variant is present at a detectable allele fraction but absent from parental samples with confirmed maternity and paternity, or when parents are unavailable but the affected-tissue criterion is fulfilled. The available evidence does not provide a human proband's allele fraction, confirmed parental testing, maternity/paternity, affected tissue, or comparative tissue allele fraction for NM_006218.4:c.1258T>C. PMID:31996845 reports C420R in mouse glioblastoma models and does not establish human de novo or parental evidence. Therefore PS2 cannot be assessed.

VCEP rule
Award the PS2_Moderate point if Criteria 1 is fulfilled, OR if parents are not available but Criteria 2 is fulfilled. ... Criteria 1. The variant is present at a detectable allele fraction but is absent from parental samples with confirmed maternity and paternity.
Evidence considered
  • No case-level human proband, parental-testing, maternity/paternity, or tissue allele-fraction evidence was identified for NM_006218.4:c.1258T>C.
  • PMID:31996845 studied PIK3CA C420R in mouse glioblastoma models; its reported mouse tumor and neural phenotypes do not establish human de novo status or parental absence.
  • The governing VCEP rule requires PS2_Moderate when Criteria 1 is fulfilled, or when parents are unavailable but Criteria 2 is fulfilled; neither pathway can be evaluated from the available evidence.
Still missing
  • Human proband-level de novo documentation is unavailable, including detectable allele fraction and confirmed maternity and paternity.
  • Affected-tissue and comparison-tissue allele fractions are unavailable.
  • No entry for c.1258T>C, p.Cys420Arg, or p.C420R was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗PMID:31996845 ↗
PM5 ACMG_2015Not assessed: the comparator collection found 0 same-residue candidates at PIK3CA C420, but retrieval was incomplete. Details ▾Hide ▴
Reasoning

PM5 requires a different missense change at the same amino-acid residue that has been determined to be pathogenic. The case's PM5 comparator collection found three candidates overall but zero same-residue candidates at PIK3CA residue 420, and the retrieval reported an HTTP 429 failure. Because the available search result cannot establish that no pathogenic C420 alternate exists, PM5 is not assessed rather than treated as absent or not met. The governing VCEP file was searched for c.1258T>C, p.Cys420Arg, and p.C420R with no exact variant entry.

Rule
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Evidence considered
  • The governing PM5 rule requires a different missense change at the same amino-acid residue determined to be pathogenic.
  • pm5_candidates.json reports total_candidates_seen = 3, same_residue_candidates = 0, and HTTP Error 429: Too Many Requests.
  • The VCEP governing file was searched under c.1258T>C, p.Cys420Arg, and p.C420R; no exact variant entry was found.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
  • A complete, verified search for a different pathogenic missense substitution at residue C420 is still required; the available comparator retrieval ended with HTTP 429.
Sources
cspec ↗pm5_candidatesvcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PP2 VCEPNot assessed: the VCEP requires a PIK3CA ExAC/gnomAD missense-constraint z-score >3.09, but that z-score is unavailable. Details ▾Hide ▴
Reasoning

The VCEP specifies PP2 for PIK3CA when the ExAC/gnomAD missense-constraint z-score is greater than 3.09. The case evidence does not provide the applicable PIK3CA missense-constraint z-score, so the threshold cannot be evaluated and PP2 is not assessed. The available REVEL and BayesDel values are not the VCEP-specified metric and were not substituted.

VCEP rule
Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09. (applicable to MTOR, PIK3CA and AKT3 but not PIK3R2).
Evidence considered
  • The governing PP2 rule specifies ExAC/gnomAD missense constraint and a z-score threshold of >3.09 for PIK3CA.
  • No PIK3CA missense-constraint z-score is present in the reviewed case evidence; REVEL 0.788 and BayesDel 0.24502 are different metrics and were not used.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
  • The PIK3CA ExAC/gnomAD missense-constraint z-score is not available in the case evidence.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BP2 ACMG_2015Not assessed: no documented cis/trans pathogenic PIK3CA variant or phase result is available for this case. Details ▾Hide ▴
Reasoning

The VCEP permits BP2 at Supporting strength when this 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 second pathogenic PIK3CA variant, affected-proband phase, or inheritance result for NM_006218.4:c.1258T>C (p.Cys420Arg), so BP2 cannot be assessed. The governing file clingen_brainmalform_acmg_specifications_v1_1.pdf was searched for c.1258T>C, p.Cys420Arg, and p.C420R; no variant-specific entry was found.

Rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Evidence considered
  • ClinGen Brain Malformations VCEP BP2 rule: the variant must be observed in cis or trans with a known pathogenic variant in the same gene.
  • Case evidence reviewed: no phased second pathogenic PIK3CA variant, parental phase, or inheritance result is documented for NM_006218.4:c.1258T>C (p.Cys420Arg).
  • The governing file clingen_brainmalform_acmg_specifications_v1_1.pdf was searched under c.1258T>C, p.Cys420Arg, and p.C420R; no variant-specific entry was found.
Still missing
  • No documented phase or inheritance result linking NM_006218.4:c.1258T>C (p.Cys420Arg) to a known pathogenic variant in PIK3CA.
  • No entry for c.1258T>C, p.Cys420Arg, or p.C420R was found when clingen_brainmalform_acmg_specifications_v1_1.pdf was searched.
Sources
cspec ↗
BP5 VCEPNot assessed: no qualifying case documents C420R with an alternate molecular diagnosis in a different gene under the VCEP BP5 rule. Details ▾Hide ▴
Reasoning

The VCEP defines BP5 as a variant observed in a case with an alternate molecular basis for disease, specifically an alternate cause in a different gene. The available case materials do not document C420R in a qualifying case with a confirmed alternate molecular diagnosis, so BP5 cannot be evaluated as met or not met. The VCEP source text was searched for c.1258T>C, p.Cys420Arg, and p.C420R, with no variant-specific entry found in the governing full-text file.

VCEP rule
Variant found in a case with an alternate molecular basis for disease. Brain Malformation Recommendation: Observed in a case with an alternate molecular basis for disease in a different gene
Evidence considered
  • The VCEP BP5 recommendation requires observation in a case with an alternate molecular basis for disease in a different gene; no such qualifying case was documented in the reviewed materials.
Still missing
  • No c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
  • A confirmed alternate molecular diagnosis in a different gene for a C420R-positive case was not available.
Sources
cspec ↗
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable: the VCEP excludes PVS1 for this gene. Details ▾Hide ▴
Reasoning

The ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 marks PVS1 as not applicable. The VCEP states: "LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF)." NM_006218.4:c.1258T>C in PIK3CA is a missense substitution predicted to produce NP_006209.2:p.(Cys420Arg). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.

VCEP rule
deterministic_prefilter: vcep_not_applicable
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
  • VCEP criterion policy: vcep_not_applicable
Sources
cspec ↗
PM3 VCEPNot applicable: the VCEP excludes PM3 because disease-causing PIK3CA variants are heterozygous. Details ▾Hide ▴
Reasoning

PM3 is not applicable under the ClinGen Brain Malformations VCEP specification because the disease-causing variants are heterozygous. The VCEP explicitly excludes this recessive-allelic criterion, so phase and affected-proband observations cannot activate PM3 in this framework.

VCEP rule
Not applicable since disease-causing variants are heterozygous.
Evidence considered
  • ClinGen Brain Malformations VCEP criterion specification: PM3 is marked Not Applicable, with the reason that disease-causing variants are heterozygous.
  • Variant normalization: NM_006218.4:c.1258T>C produces the missense change NP_006209.2:p.(Cys420Arg).
Still missing
  • No entry for c.1258T>C, p.Cys420Arg, or p.C420R was found when clingen_brainmalform_acmg_specifications_v1_1.pdf was searched; this does not alter the explicit PM3 not-applicable rule.
Sources
cspec ↗
PM4 VCEPNot applicable: the VCEP excludes PM4 for this gene. Details ▾Hide ▴
Reasoning

The ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 marks PM4 as not applicable. The VCEP states: "Although there have been reported in-frame deletion/insertions in these genes which cause the overgrowth phenotype, they are exceptionally rare. Most insertion/deletions are associated with a LoF disease mechanism and so this point will still not be used even though we recognize that it is possible that a variant is an in-frame indel that results in a GoF mechanism." NM_006218.4:c.1258T>C in PIK3CA is a missense substitution predicted to produce NP_006209.2:p.(Cys420Arg). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.

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

The VCEP explicitly states that PM6, assumed de novo without confirmation of paternity and maternity, is addressed according to PS2 and will not be used. PM6 is therefore not applicable under this VCEP specification.

VCEP rule
Brain Malformation Recommendation: This point is addressed according to PS2 and will not be used.
Evidence considered
  • The VCEP specification classifies PM6 as addressed according to PS2 and not used; no PM6 evidence was applied.
Still missing
  • No entry for c.1258T>C, p.Cys420Arg, or p.C420R was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗
PP1 VCEPNot applicable: the VCEP excludes PP1 because disease-causing variants are germline mosaic, de novo, or mosaic. Details ▾Hide ▴
Reasoning

The VCEP marks PP1 as not applicable because disease-causing variants in this disease context are germline mosaic, de novo, or mosaic. PP1 is therefore not applicable under this VCEP specification.

VCEP rule
Brain Malformation Recommendation: Not applicable since disease-causing variants are germline mosaic, de novo or mosaic.
Evidence considered
  • The VCEP specification states that PP1 is not applicable for this disease context; segregation evidence was not used for PP1.
Still missing
  • No entry for c.1258T>C, p.Cys420Arg, or p.C420R was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗
PP3 VCEPNot applicable: the VCEP excludes PP3 for these gain-of-function variants, regardless of available computational predictor scores. Details ▾Hide ▴
Reasoning

The queried variant is the missense substitution NM_006218.4:c.1258T>C (p.Cys420Arg/p.C420R). The VCEP explicitly makes PP3 not applicable for these gain-of-function variants because traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms. No protein-impact or splice-prediction score is used for PP3, and the VCEP file contains no exact variant-specific entry under c.1258T>C, p.Cys420Arg, or p.C420R.

VCEP rule
Brain Malformation Recommendation: This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms. Use of this criterion can be revisited if there emerges additional published experience with predictive algorithms specifically designed to detect gain of function mutations.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, PP3: the variant is a missense change (p.Cys420Arg/p.C420R), and the VCEP states that PP3 is not applicable for these gain-of-function variants.
  • The governing VCEP full-text file was searched for c.1258T>C, p.Cys420Arg, and p.C420R; no exact variant-specific entry was found.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this does not alter the VCEP-defined not-applicable scope.
Sources
cspec ↗
PP4 VCEPNot applicable: the VCEP explicitly accounts for phenotype specificity under PS4 rather than applying PP4 separately. Details ▾Hide ▴
Reasoning

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

VCEP rule
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Brain Malformation Recommendation: Not applicable since this criterion is accounted for under PS4.
Evidence considered
  • The governing VCEP specification states that PP4 is not applicable because this criterion is accounted for under PS4.
Sources
cspec ↗
PP5 VCEPNot applicable: the VCEP explicitly marks PP5 as not applicable, regardless of available pathogenic assertions. Details ▾Hide ▴
Reasoning

The Brain Malformations VCEP explicitly marks PP5 not applicable; therefore reputable-source pathogenic assertions are not converted into PP5 in this VCEP framework.

VCEP rule
Brain Malformation Recommendation: Not Applicable
Evidence considered
  • The governing VCEP specification lists PP5 as not applicable. ClinVar contains pathogenic submissions, but those assertions cannot be used for PP5 under this VCEP rule.
Sources
cspec ↗
BS4 VCEPNot applicable: the VCEP excludes BS4 because these mutations are de novo, germline mosaic, or post-zygotic. Details ▾Hide ▴
Reasoning

The VCEP marks BS4, lack of segregation in affected family members, as not applicable because these are de novo, germline mosaic, or post-zygotic mutations. BS4 is therefore not applicable under this VCEP specification.

VCEP rule
Brain Malformation Recommendation: Not applicable as these are de novo, germline mosaic or post-zygotic mutations.
Evidence considered
  • The VCEP specification states that BS4 is not applicable for de novo, germline mosaic, or post-zygotic mutations; no non-segregation evidence was used for BS4.
Still missing
  • No entry for c.1258T>C, p.Cys420Arg, or p.C420R was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗
BP1 VCEPNot applicable: the VCEP excludes BP1 because loss of function is not the disease mechanism. Details ▾Hide ▴
Reasoning

The Brain Malformations VCEP explicitly marks BP1 as not applicable because loss of function is not the disease mechanism for this framework. The queried variant is missense, but the VCEP applicability rule independently excludes BP1, so no benign evidence assessment is needed.

VCEP rule
Not applicable as LOF is not the disease mechanism.
Evidence considered
  • The VCEP applicability instruction states: Not applicable as LOF is not the disease mechanism.
  • The case normalization identifies the queried variant as a missense change, but BP1 remains excluded by the VCEP rule.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this does not affect the explicit BP1 applicability decision.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BP3 VCEPNot applicable: the VCEP excludes BP3 for this gene. Details ▾Hide ▴
Reasoning

The ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 marks BP3 as not applicable. The VCEP states: "This is not applicable for the genes specified since the exon regions do not have repetitive regions without a known function." NM_006218.4:c.1258T>C in PIK3CA is a missense substitution predicted to produce NP_006209.2:p.(Cys420Arg). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.

VCEP rule
deterministic_prefilter: vcep_not_applicable
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
  • VCEP criterion policy: vcep_not_applicable
Sources
cspec ↗
BP4 N/ANot applicable: BP4 is restricted to synonymous, non-canonical intronic, or UTR variants, whereas this variant is missense. Details ▾Hide ▴
Reasoning

The queried variant is a missense substitution in exon 8, not a synonymous, intronic, or UTR variant. The VCEP limits BP4 to synonymous variants, non-canonical intronic positions, and UTR variants, requiring two of varSEAK, SpliceAI, and MaxEntScan to predict no splice change. Therefore the available SpliceAI result is outside BP4's governing scope and cannot establish BP4.

VCEP rule
Brain Malformation Recommendation: Not applicable for any variant type except for For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs,. This criterion can be applied when two of three splicing prediction tools predict no splicing change. The splicing prediction tools used are: varSEAK, spliceAI and MaxEntScan.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, BP4: BP4 applies only to synonymous, non-canonical intronic, and UTR variants, with two of three named splice tools predicting no splicing change.
  • The case normalization identifies NM_006218.4:c.1258T>C as the missense p.Cys420Arg/p.C420R substitution; the available SpliceAI score is therefore not evidence for BP4 under this VCEP rule.
  • The governing VCEP full-text file was searched for c.1258T>C, p.Cys420Arg, and p.C420R; no exact variant-specific entry was found.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this does not alter the VCEP-defined not-applicable scope.
Sources
cspec ↗
BP6 VCEPNot applicable: the VCEP prohibits BP6 use under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Reasoning

The Brain Malformations VCEP explicitly marks BP6 not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

VCEP rule
Brain Malformation Recommendation: Not applicable
Evidence considered
  • The governing VCEP specification marks BP6 not applicable and states that it is not for use.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is limited to synonymous, non-canonical intronic, or UTR variants, whereas this variant is missense. Details ▾Hide ▴
Reasoning

The queried variant is a missense substitution, not a synonymous, intronic, or UTR variant. The VCEP's BP7 scope is limited to synonymous variants, non-canonical intronic positions, and UTR variants with a non-conserved nucleotide; the BP7 rule therefore does not apply, regardless of splice or conservation data.

VCEP rule
Brain Malformation Recommendation: For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point. Not conserved is defined as the same nucleotide NOT present in all vertebrae or PhyloP score <0.1.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, BP7: the criterion is limited to synonymous, non-canonical intronic, and UTR variants, with a non-conserved nucleotide.
  • The case normalization identifies NM_006218.4:c.1258T>C as the missense p.Cys420Arg/p.C420R substitution, outside BP7's specified variant classes.
  • The governing VCEP full-text file was searched for c.1258T>C, p.Cys420Arg, and p.C420R; no exact variant-specific entry was found.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this does not alter the VCEP-defined not-applicable scope.
Sources
cspec ↗

Identifiers

Gene
PIK3CA
Transcript
NM_006218.4
Coding (HGVS c.)
NM_006218.4:c.1258T>C
Protein (HGVS p.)
NP_006209.2:p.(Cys420Arg)
GRCh38
chr3:179210192 T>C
GRCh37
chr3:178927980 T>C
Location and type
Exon 8 · missense
ClinVar
31945
COSMIC
COSV55874020

Gene diagram

Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.4. Select a row to find it on the plot.

PIK3CANM_006218.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +43 bp
0.166
SpliceAI acceptor gainat +220 bp
0.016
SpliceAI donor lossat +283 bp
0.000
SpliceAI donor gainat +151 bp
0.004
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.025

Other predictors

REVEL
0.788
BayesDel
0.245

How the predictions were used

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

The queried variant is the missense substitution NM_006218.4:c.1258T>C (p.Cys420Arg/p.C420R). The VCEP explicitly makes PP3 not applicable for these gain-of-function variants because traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms. No protein-impact or splice-prediction score is used for PP3, and the VCEP file contains no exact variant-specific entry under c.1258T>C, p.Cys420Arg, or p.C420R.

VCEP rule
Brain Malformation Recommendation: This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms. Use of this criterion can be revisited if there emerges additional published experience with predictive algorithms specifically designed to detect gain of function mutations.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, PP3: the variant is a missense change (p.Cys420Arg/p.C420R), and the VCEP states that PP3 is not applicable for these gain-of-function variants.
  • The governing VCEP full-text file was searched for c.1258T>C, p.Cys420Arg, and p.C420R; no exact variant-specific entry was found.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this does not alter the VCEP-defined not-applicable scope.
Sources
cspec ↗
BP4 N/ANot applicable: BP4 is restricted to synonymous, non-canonical intronic, or UTR variants, whereas this variant is missense. Details ▾Hide ▴
Reasoning

The queried variant is a missense substitution in exon 8, not a synonymous, intronic, or UTR variant. The VCEP limits BP4 to synonymous variants, non-canonical intronic positions, and UTR variants, requiring two of varSEAK, SpliceAI, and MaxEntScan to predict no splice change. Therefore the available SpliceAI result is outside BP4's governing scope and cannot establish BP4.

VCEP rule
Brain Malformation Recommendation: Not applicable for any variant type except for For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs,. This criterion can be applied when two of three splicing prediction tools predict no splicing change. The splicing prediction tools used are: varSEAK, spliceAI and MaxEntScan.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, BP4: BP4 applies only to synonymous, non-canonical intronic, and UTR variants, with two of three named splice tools predicting no splicing change.
  • The case normalization identifies NM_006218.4:c.1258T>C as the missense p.Cys420Arg/p.C420R substitution; the available SpliceAI score is therefore not evidence for BP4 under this VCEP rule.
  • The governing VCEP full-text file was searched for c.1258T>C, p.Cys420Arg, and p.C420R; no exact variant-specific entry was found.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this does not alter the VCEP-defined not-applicable scope.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is limited to synonymous, non-canonical intronic, or UTR variants, whereas this variant is missense. Details ▾Hide ▴
Reasoning

The queried variant is a missense substitution, not a synonymous, intronic, or UTR variant. The VCEP's BP7 scope is limited to synonymous variants, non-canonical intronic positions, and UTR variants with a non-conserved nucleotide; the BP7 rule therefore does not apply, regardless of splice or conservation data.

VCEP rule
Brain Malformation Recommendation: For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point. Not conserved is defined as the same nucleotide NOT present in all vertebrae or PhyloP score <0.1.
Evidence considered
  • ClinGen Brain Malformations VCEP specification v1.1, BP7: the criterion is limited to synonymous, non-canonical intronic, and UTR variants, with a non-conserved nucleotide.
  • The case normalization identifies NM_006218.4:c.1258T>C as the missense p.Cys420Arg/p.C420R substitution, outside BP7's specified variant classes.
  • The governing VCEP full-text file was searched for c.1258T>C, p.Cys420Arg, and p.C420R; no exact variant-specific entry was found.
Still missing
  • No exact c.1258T>C, p.Cys420Arg, or p.C420R entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this does not alter the VCEP-defined not-applicable scope.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). REVEL score = 0.788. BayesDel score = 0.24502.

5 paper records listed. 2 cited in the classification.

Cited in the classification

  • Functional analysis of PIK3CA gene mutations in human colorectal cancer.
    Ikenoue T et al. · 2005 Jun 1
    The study constructed and tested C420R among eight cancer-associated PIK3CA mutants. C420R showed greater in vitro lipid kinase activity than wild type, increased Akt and p70S6K phosphorylation in cells, increased focus formation, and anchorage-independent growth.
    → PS3 · supporting Names this variant
    PMID 15930273 ↗
    Source detail
    Although the lipid kinase activities of all the cancer-associated p110a mutants examined in this study were not as high as that of iSH2p110a, they all had greater lipid kinase activities than wild-type p110a. These results suggested that all the cancer-associated PIK3CA mutations examined in this study act as gain-of-function mutations.

    Location Results, ‘In vitro lipid kinase activity of p110alpha mutants’; subsequent sections ‘Activation of Akt and p70S6K in vivo by p110alpha mutants,’ ‘Focus formation activity induced by p110alpha mutants,’ and ‘Anchorage-independent growth induced by p110alpha mutants.’

    Context HEK293T immunoprecipitated p110alpha lipid kinase assays; NIH 3T3 stable-expression phospho-Akt/phospho-p70S6K assays; focus-formation and soft-agar transformation assays; eight cancer-associated mutants compared with wild type and constitutively active controls.

  • Oncogenic mutations mimic and enhance dynamic events in the natural activation o
    The study examined 11 cancer-linked p110alpha mutants, including C420R, using lipid kinase activity assays, lipid-binding FRET, and HDX-MS. C420R was associated with increased basal lipid kinase activity, increased lipid binding, and disruption of the iSH2-C2 interface, supporting an activating gain-of-function effect.
    → PS3 · supporting Names this variant
    PMID 22949682 ↗
    Source detail
    All cancer-linked mutations, including mutants in the ABD and ABD–RBD linker, increased basal lipid kinase activity compared with WT, with H1047R acting as the most potent activator, followed by N345K and E545K.

    Location Results, ‘Lipid Kinase Activity of Cancer-Linked Mutations’; Fig. 1C and the paragraph describing C2 domain mutants; Fig. 5B for lipid-binding FRET.

    Context Purified full-length p110alpha/p85alpha complexes; 11 cancer-linked mutants; lipid kinase assays, protein-lipid FRET, and hydrogen/deuterium exchange mass spectrometry, with WT comparison and duplicate or triplicate assay reporting as described.

Other recorded publications

  • Comprehensive analysis of oncogenic effects of PIK3CA mutations in human mammary
    No paper-specific finding is recorded.
    PMID 18074223 ↗
  • PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis.
    The paper explicitly studied PIK3CA C420R in mouse glioblastoma models and patient-derived xenograft models, showing tumorigenic and neural phenotypes; it does not provide human proband, parental, de novo, or family-segregation data for this variant.
    Names this variant
    PMID 31996845 ↗
    Quoted passage
    This analysis demonstrated that established hotspots (E545K and H1047R) are enriched along with other variants (R88Q and C420R) that have not been characterized in glioma (Fig. 1c). To confirm driver function of these variants, we individually expressed them in the 2xCr model, finding that they all complement loss of PTEN and drive tumorigenesis, while also pathologically resembling GBM (Fig. 1d, Extended Data Figs. 1a–b, 3, Extended Data Table).

    Results, ‘Identifying PIK3CA driver variants,’ paragraph describing the pooled screen and individual validation

  • A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endomet
    The paper reports C420R among mutations identified by resequencing 108 primary endometrial tumors and describes it as a known gain-of-function mutant, but it does not give a C420R-specific affected-versus-control prevalence comparison.
    Names this variant
    PMID 21266528 ↗
    Quoted passage
    Five of 20 unique mutations, namely R88Q, K111N, R108H, E365K, and C420R, are known to encode gain-of-function mutants of p110α (33, 37).

    Results, ‘Mutations in exons 1–7 of PIK3CA,’ paragraph 3; Discussion, paragraph on the C2 domain

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.166 Open source ↗
ClinVar 13 Pathogenic · 1 Likely pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 31945)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). REVEL score = 0.788. BayesDel score = 0.24502.

Functional

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

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55874020, n = 261 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.