0%
PIK3CAc.562+14T>GUncertain significance
Print report
Variant interpretation report

PIK3CA c.562+14T>G, p.?

NM_006218.4:c.562+14T>G NP_006209.2:p.? Unknown · intron 3 View identifiers
Classification
Uncertain significance

Variant description:

The PIK3CA NM_006218.4:c.562+14T>G (NP_006209.2:p.?) intronic variant has not previously been reported in somatic cancers (COSMIC). 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: 0 Benign evidence criteria: 0
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: no adjudicated criterion is applied, so the VCEP-based ACMG/AMP 2015 combination rules meet neither a pathogenic nor benign threshold.

02The sources

Evidence at a glance

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

gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.031 maximum delta

Recorded SpliceAI maximum delta score: 0.031. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
No screenshot for this evidence
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
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: 0 met · 2 not met · 10 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

PVS1, PM4, and BP3 are all explicitly not applicable under the governing ClinGen Brain Malformations VCEP specification.

PM3 is not applicable under the VCEP's heterozygous disease model.

BP2 cannot be assessed without documented cis/trans phase with a known pathogenic PIK3CA variant.

Not met · 2 · evaluated, threshold not reached

BA1 VCEPNot met: gnomAD v2.1 and v4.1 both report the variant absent, rather than an allele frequency above the VCEP's >0.0926% BA1 threshold. Details ▾Hide ▴
Reasoning

BA1 is not met. The governing VCEP threshold is allele frequency >0.0926%. The variant was absent from gnomAD v2.1 and gnomAD v4.1, so no observed allele frequency exceeds the BA1 threshold.

VCEP rule
Allele frequency (>0.0926%). An allele frequency (>0.0926%) was approved.
Evidence considered
  • The VCEP BA1 rule specifies: allele frequency (>0.0926%).
  • gnomAD v2.1 (exome; GRCh37 variant 3-178917701-T-G) reports the variant absent.
  • gnomAD v4.1 (GRCh38 variant 3-179199913-T-G) reports the variant absent.
Still missing
  • No c.562+14T>G, p.?, or p.? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; the VCEP rule and population records were available for assessment.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BS1 VCEPNot met: gnomAD v2.1 and v4.1 both report absence, providing no allele frequency above the VCEP's >0.0185% BS1 threshold. Details ▾Hide ▴
Reasoning

BS1 is not met. The governing VCEP threshold is allele frequency >0.0185%. The variant was absent from gnomAD v2.1 and gnomAD v4.1, so no observed allele frequency exceeds the BS1 threshold.

VCEP rule
Allele frequency (>0.0185%). An allele frequency (>0.0185%) was approved. (Supplemental Table 3).
Evidence considered
  • The VCEP BS1 rule specifies: allele frequency (>0.0185%).
  • gnomAD v2.1 (exome; GRCh37 variant 3-178917701-T-G) reports the variant absent.
  • gnomAD v4.1 (GRCh38 variant 3-179199913-T-G) reports the variant absent.
Still missing
  • No c.562+14T>G, p.?, or p.? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; the VCEP rule and population records were available for assessment.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗

Not assessed · 10 · no assessment recorded

PS2 VCEPNot assessed: no documented proband allele fraction, confirmed parental testing, or affected-versus-other-tissue allele-fraction comparison is available for this variant. Details ▾Hide ▴
Reasoning

The VCEP permits PS2 only when the required de novo and tissue allele-fraction evidence is documented. The case evidence contains no proband-level de novo finding, parental maternity/paternity testing, affected-tissue allele fraction, or comparison-tissue allele fraction for NM_006218.4:c.562+14T>G; therefore PS2 cannot be assessed. The governing VCEP file was searched for c.562+14T>G and p.? with no variant-specific entry found.

VCEP rule
Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled. ... Criteria 1. The variant is present at a detectable allele fraction but is absent from parental samples with confirmed maternity and paternity. ... Criteria 2. The variant is present at a detectable allele fraction in an affected tissue sample but is absent from or detected at a lower allelic fraction in another tissue (e.g. if present in 5% of brain tissue but absent from the blood or skin this point can be awarded). ... Award the PS2_Moderate point if Criteria 1 is fulfilled, OR if parents are not available but Criteria 2 is fulfilled.
Evidence considered
  • The case bundle reports no literature PMIDs and provides no proband, parental, or tissue-level segregation/de novo observations for NM_006218.4:c.562+14T>G.
  • VCEP PS2 requires detectable variant allele fraction in a proband and absence from parental samples with confirmed maternity and paternity; PS2_Strong additionally requires affected-tissue and comparison-tissue allele-fraction evidence.
  • The VCEP also provides a PS2_Moderate path when Criteria 1 is fulfilled, or when parents are unavailable but Criteria 2 is fulfilled; neither evidence path is documented here.
Still missing
  • No proband-level de novo evidence or parental maternity/paternity testing is available.
  • No affected-tissue and comparison-tissue allele fractions are available.
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PS3 VCEPNot assessed: no variant-specific functional assay results or required validation controls were available to apply the VCEP PS3 requirements. Details ▾Hide ▴
Reasoning

No variant-specific functional assay publication, assay result, control set, validation metrics, or animal-model result was identified in the case evidence. The governing VCEP specification requires PS3 functional assays to meet the acceptability criteria in PMID:31892348 and the BMVCEP Supplementary Document 1; the specification states that any publication in the spreadsheet may support PS3, while evidence above Supporting requires independent pathogenic/likely pathogenic positive controls and benign/likely benign negative controls. Because no assay evidence was available for NM_006218.4:c.562+14T>G / p.? and the governing file contains no entry for this variant, PS3 cannot be assessed at any strength.

VCEP rule
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.
Evidence considered
  • ClinGen Brain Malformations VCEP specification, Supplemental Document 1 (PS3): no variant-specific publication or assay result for NM_006218.4:c.562+14T>G / p.? was available in the case evidence.
  • ClinGen Brain Malformations VCEP specification, Supplemental Document 1 (PS3): above-Supporting evidence requires positive controls classified as pathogenic/likely pathogenic independently of PS3 and negative controls classified as benign/likely benign independently of BS3; neither control set was available for this variant.
Still missing
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
  • Variant-specific functional assay data, assay controls, replicate information, and quality metrics are unavailable in the case evidence.
Sources
cspec ↗
PS4 VCEPNot assessed: controls are absent, but no affected-case phenotype points or case-control counts are available for the VCEP PS4 thresholds. Details ▾Hide ▴
Reasoning

The VCEP requires PS4 phenotype points and permits their use only when the variant meets PM2. The case evidence records the variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, but provides no affected individuals, phenotype assignments, case-control counts, or literature reports from which PS4 points can be calculated. Direct searches of clingen_brainmalform_acmg_specifications_v1_1.pdf.txt found no c.562+14T>G or p.? entry. Therefore PS4 cannot be assessed rather than assigned a strength.

VCEP rule
Brain Malformation Recommendation: For PS4, for cases reported in the literature, we recommend assigning each one to the SINGLE category below that is associated with the highest point value (Table 2A). The total score obtained for all reported cases with a particular variant will determine the strength of PS4 assigned according to the scale (Table 2B).* ... PS4_VeryStrong ≥ 16 points ... PS4_Strong = 3.5-15.75 points ... PS4_Moderate = 1.5-3.25 points ... PS4_Supporting = .5-1.25 points
Evidence considered
  • The case records NM_006218.4:c.562+14T>G as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada; these findings satisfy the VCEP's control rarity prerequisite but do not provide PS4 phenotype points.
  • literature_pass.json reports total_pmids: 0, with no PS4 papers or case reports available for verification.
  • The governing VCEP source assigns each reported case a single Table 2A phenotype category and determines PS4 strength from the total points in Table 2B; no such case data are present.
Still missing
  • No affected-case reports or phenotype point assignments were available for NM_006218.4:c.562+14T>G.
  • No case-control counts or matched-ancestry control frequency comparison were available to calculate an odds ratio and 95% confidence interval.
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PM2 VCEPNot assessed: the variant is absent from gnomAD v2.1 and v4.1, but an ethnically matched control cohort required by the VCEP is not documented. Details ▾Hide ▴
Reasoning

PM2 cannot be fully assessed. The variant is absent from gnomAD v2.1 and v4.1, including the available non-cancer subset records, but the case evidence does not document that either control sample is ethnically matched to the affected population as required by the VCEP rule.

VCEP rule
Absent/rare from controls in an ethnically-matched cohort population sample ( ≥1).
Evidence considered
  • The VCEP PM2 rule specifies Supporting evidence for a variant absent/rare from controls in an ethnically-matched cohort population sample (≥1).
  • gnomAD v2.1 (exome; GRCh37 variant 3-178917701-T-G) reports the variant absent.
  • gnomAD v4.1 (GRCh38 variant 3-179199913-T-G) reports the variant absent.
  • The available gnomAD v2.1 non-cancer and v3.1 non-cancer records also report the variant absent; their ethnic matching to the affected population is not documented.
Still missing
  • No c.562+14T>G, p.?, or p.? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; the VCEP rule and population records were available for assessment.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BS2 VCEPNot assessed: gnomAD reports no observations, but the required alternative evidence of ≥3 heterozygous occurrences in well-phenotyped family members is unavailable. Details ▾Hide ▴
Reasoning

BS2 cannot be fully assessed. The VCEP requires at least 3 homozygotes in gnomAD or at least 3 heterozygous occurrences in well-phenotyped family members. The variant is absent from gnomAD v2.1 and v4.1, excluding the gnomAD homozygote path, but no family-level phenotype and genotype data are available to evaluate the alternative path.

VCEP rule
Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members. ... Homozygous occurrences in gnomAD or ExAC can also be counted for this point (≥3).
Evidence considered
  • The VCEP BS2 rule requires ≥3 homozygotes in gnomAD or ≥3 heterozygous occurrences in well-phenotyped family members.
  • gnomAD v2.1 (exome; GRCh37 variant 3-178917701-T-G) reports the variant absent, providing no homozygote observations.
  • gnomAD v4.1 (GRCh38 variant 3-179199913-T-G) reports the variant absent, providing no homozygote observations.
  • No qualifying well-phenotyped family-member observations are present in the available case evidence.
Still missing
  • No c.562+14T>G, p.?, or p.? entry was found in clingen_brainmalform_acmg_specifications_v1_1.pdf; no qualifying family-member observations were available.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BS3 VCEPNot assessed: no variant-specific benign functional assay result or VCEP-required quality and validation-control data were available for BS3. Details ▾Hide ▴
Reasoning

No variant-specific functional assay publication, assay result, control set, validation metrics, or animal-model result was identified in the case evidence. The governing VCEP specification defines BS3 as well-established in vitro or in vivo functional studies showing no damaging effect and requires the SVI recommendations together with Brain Malformation Group quality metrics and minimum validation controls. Because no assay evidence was available for NM_006218.4:c.562+14T>G / p.? and the governing file contains no entry for this variant, BS3 cannot be assessed at Strong or Supporting strength.

VCEP rule
BS3 Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. 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
  • ClinGen Brain Malformations VCEP specification, BS3 and BS3_Supporting sections: no variant-specific functional study showing no damaging effect was available for NM_006218.4:c.562+14T>G / p.? in the case evidence.
  • ClinGen Brain Malformations VCEP specification, BS3 section: the required quality metrics and minimum validation controls could not be evaluated because no qualifying assay report was available.
Still missing
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
  • Variant-specific benign functional assay data, assay controls, replicate information, and quality metrics are unavailable in the case evidence.
Sources
cspec ↗
BP2 VCEPNot assessed: no documented cis/trans phase observation with a known pathogenic PIK3CA variant is available for this case. Details ▾Hide ▴
Reasoning

The VCEP permits BP2 when the variant is observed in cis or trans with a known pathogenic variant in the same gene. The available case evidence contains no documented phase result, affected-proband observation, or pathogenic PIK3CA variant in cis or trans, so the rule cannot be evaluated.

VCEP rule
Observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
  • The case evidence does not document cis/trans phase, a paired pathogenic PIK3CA variant, or an affected-proband observation relevant to BP2.
  • ClinGen Brain Malformations VCEP BP2 entry, page 4/page 11: 'Observed in cis or trans with a known pathogenic variant in the same gene.'
Still missing
  • No phase-resolved observation linking c.562+14T>G to a known pathogenic PIK3CA variant in cis or trans was available in the case evidence.
  • No entry for c.562+14T>G, p.?, or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PIK3CA/fulltext/clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this search result is not evidence that the variant-specific evidence is absent.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BP4 VCEPNot assessed: The intronic variant has one named no-impact result, SpliceAI max delta 0.031, but two of three tools are required and varSEAK/MaxEntScan results are unavailable. Details ▾Hide ▴
Reasoning

The variant is an intronic position outside the canonical splice sites, so it lies within BP4's stated scope. The VCEP requires no-impact predictions from at least two of three named tools: varSEAK, spliceAI, and MaxEntScan. Only SpliceAI is available here (maximum delta score 0.031); no varSEAK or MaxEntScan result is available. Therefore the two-of-three requirement cannot be evaluated and BP4 is not assessed, rather than not met.

VCEP rule
Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function. Not applicable for any variant type except 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
  • The VCEP limits BP4 to synonymous, intronic noncanonical-splice-site, and UTR variants and requires two of three named splicing tools to predict no splicing change: varSEAK, spliceAI, and MaxEntScan.
  • VariantValidator places NM_006218.4:c.562+14T>G in intron 3i; it is not a canonical splice-site variant.
  • SpliceAI reports DS_AG 0.001, DS_AL 0.001, DS_DG 0.031, DS_DL 0.002, with maximum delta score 0.031 and an evidence sentence describing no significant splice impact.
  • The available case evidence contains no varSEAK or MaxEntScan result, so the VCEP two-of-three condition cannot be determined.
Still missing
  • No varSEAK prediction is available for NM_006218.4:c.562+14T>G.
  • No MaxEntScan prediction is available for NM_006218.4:c.562+14T>G.
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this file contains the governing rule but no variant-specific BP4 assignment.
Sources
cspec ↗spliceai ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BP5 VCEPNot assessed: no case with an alternate molecular basis for disease in a different gene is documented for this variant. Details ▾Hide ▴
Reasoning

The VCEP retains BP5 for a variant observed in a case with an alternate molecular basis for disease in a different gene. The available case evidence contains no affected-case report, alternate-diagnosis information, or molecular finding in another gene for this variant, so the criterion cannot be evaluated.

VCEP rule
Variant found in a case with an alternate molecular basis for disease ... Observed in a case with an alternate molecular basis for disease in a different gene
Evidence considered
  • The VCEP's BP5 recommendation is limited to an alternate molecular basis for disease in a different gene; the case bundle contains no such finding.
  • literature_pass.json reports total_pmids: 0, so no variant-specific case report was available to verify BP5.
Still missing
  • No affected-case phenotype record identifies an alternate molecular basis for disease in a different gene.
  • No alternate-gene molecular result or case report was available for NM_006218.4:c.562+14T>G.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BP7 VCEPNot assessed: The variant is noncanonical intronic, but no VCEP-required conservation result, including PhyloP <0.1, is available. Details ▾Hide ▴
Reasoning

The variant is an intronic position outside the canonical splice sites, so it lies within the VCEP's BP7 variant-location scope. The VCEP requires the nucleotide to be non-conserved, defined as absent from all vertebrae or having a PhyloP score below 0.1. No vertebrate-conservation result or PhyloP score is available. The criterion therefore cannot be assessed.

VCEP rule
For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1).
Evidence considered
  • The VCEP applies BP7 to synonymous, intronic noncanonical-splice-site, and UTR variants when the nucleotide is non-conserved.
  • The VCEP defines non-conserved as the same nucleotide not being present in all vertebrae or a PhyloP score below 0.1.
  • VariantValidator places NM_006218.4:c.562+14T>G in intron 3i and confirms it is not at a canonical splice site.
  • No PhyloP score or all-vertebrae conservation result is present for this variant.
Still missing
  • No PhyloP score is available for NM_006218.4:c.562+14T>G.
  • No result showing that the nucleotide is absent from all vertebrae is available.
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this file contains the governing rule but no variant-specific BP7 assignment.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable: the VCEP states that brain-malformation disease in these genes is gain of function, so PVS1 is not used regardless of this intronic variant's p.? consequence. Details ▾Hide ▴
Reasoning

PVS1 is not applicable under the Brain Malformations VCEP specification because loss of function is not an established disease mechanism for these brain malformations; the VCEP identifies gain of function as the mechanism. The variant is intronic at NM_006218.4:c.562+14T>G in exon 3i, with predicted protein consequence p.?, but these consequence details do not override the VCEP-level applicability restriction.

VCEP rule
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).
Evidence considered
  • ClinGen Brain Malformations VCEP PVS1 entry: PVS1 is marked Not Applicable for this VCEP because LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms and the disease mechanism is GOF.
  • Variant assessment: NM_006218.4:c.562+14T>G, exon 3i, intronic/other consequence classification, canonical_splice_consensus=false, predicted protein consequence NP_006209.2:p.?.
Still missing
  • No exact entry for c.562+14T>G or p.? was found when searching clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this does not alter the explicit VCEP applicability rule.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗pvs1_variant_assessment
PS1 N/ANot applicable: c.562+14T>G is intronic with protein consequence p.?, so no amino-acid change exists for PS1 comparison. Details ▾Hide ▴
Reasoning

PS1 is not applicable because the variant is intronic and has normalized protein consequence NP_006209.2:p.?, so there is no amino-acid change to compare with a previously established pathogenic variant. Searches of the governing VCEP full-text file found no entry for c.562+14T>G or p.?.

Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Evidence considered
  • Normalization reports NM_006218.4:c.562+14T>G with NP_006209.2:p.? and exon 3i; no amino-acid residue or alternate amino acid is defined.
  • The governing VCEP full-text file was searched for c.562+14T>G and p.?; no variant-specific entry was found.
Still missing
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; the file is a criterion specification, not a variant-level catalog.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PM1 N/ANot applicable: the variant is intronic with no residue, while PM1 requires location in an approved functional-domain exon. Details ▾Hide ▴
Reasoning

PM1 is not applicable because the VCEP route requires the variant to be located in an approved functional domain exon, while this variant is intronic and has no protein residue. The authoritative PIK3CA domain list was checked: 173-292, 322-483, 797-1068, and 31-108. Searches of the governing VCEP full-text file found no entry for c.562+14T>G or p.? .

VCEP rule
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
  • The authoritative vcep_materials.json domain_tables entry for PIK3CA lists Kinase Ras-binding domain 173-292, kinase domains 322-483 and 797-1068, and adaptor binding domain 31-108; no residue can be assigned for this p.? intronic variant.
  • The governing VCEP full-text file was searched for c.562+14T>G and p.?; no variant-specific entry was found.
Still missing
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; the file is a criterion specification, not a variant-level catalog.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PM3 VCEPNot applicable: the VCEP states that PM3 is not applicable because disease-causing variants are heterozygous. Details ▾Hide ▴
Reasoning

PM3 is not applicable under the Brain Malformations VCEP specification because the disease-causing variants in this framework are heterozygous; therefore recessive phase evidence cannot activate PM3.

VCEP rule
Not applicable since disease-causing variants are heterozygous.
Evidence considered
  • ClinGen Brain Malformations VCEP PM3 entry: the criterion is marked Not Applicable, with the instruction 'Not applicable since disease-causing variants are heterozygous.'
  • The VCEP specification's PM3 table entry describes PM3 as N/A for this framework.
Still missing
  • No entry for c.562+14T>G, p.?, or p.? was found in /Users/gs_agent/LYFESCI_HERMES_v11/vcep_db/PIK3CA/fulltext/clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this search result is not evidence that the variant-specific evidence is absent.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PM4 VCEPNot applicable: the VCEP does not use PM4 for these genes, and c.562+14T>G is intronic rather than an in-frame indel or stop-loss variant. Details ▾Hide ▴
Reasoning

PM4 is explicitly not applicable for this VCEP. The governing specification says the criterion will not be used for these genes because reported in-frame deletion/insertions are exceptionally rare and most insertion/deletions are associated with a loss-of-function mechanism, even though a gain-of-function in-frame indel is theoretically possible. This variant is intronic c.562+14T>G, not an in-frame deletion/insertion or stop-loss variant.

VCEP rule
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.
Evidence considered
  • ClinGen Brain Malformations VCEP PM4 entry: PM4 is marked Not Applicable for this VCEP, with the stated restriction that the point will still not be used for these genes.
  • Variant assessment: NM_006218.4:c.562+14T>G is intronic in exon 3i with predicted protein consequence p.?, not an in-frame deletion/insertion or stop-loss variant.
Still missing
  • No exact entry for c.562+14T>G or p.? was found when searching clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this does not alter the explicit VCEP applicability rule.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗pvs1_variant_assessment
PM5 N/ANot applicable: c.562+14T>G is intronic with protein consequence p.?, not a novel missense change at an amino-acid residue. Details ▾Hide ▴
Reasoning

PM5 is not applicable because the VCEP criterion requires a novel missense change at an amino-acid residue, whereas this variant is intronic with normalized protein consequence p.? and no residue. No same-residue comparator can therefore be evaluated. Searches of the governing VCEP full-text file found no entry for c.562+14T>G or p.? .

Rule
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Evidence considered
  • Normalization reports NP_006209.2:p.? with no reference amino acid, position, or observed alternate amino acid; pm5_candidates.json consequently records no same-residue candidates and an ineligible non-missense consequence.
  • The governing VCEP full-text file was searched for c.562+14T>G and p.?; no variant-specific entry was found.
Still missing
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; the file is a criterion specification, not a variant-level catalog.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PM6 VCEPNot applicable: the VCEP directs that assumed de novo evidence without confirmed maternity and paternity is addressed under PS2 and PM6 will not be used. Details ▾Hide ▴
Reasoning

PM6 is explicitly not used by the Brain Malformations VCEP because assumed de novo evidence without confirmed maternity and paternity is addressed through PS2. The governing VCEP file was searched for c.562+14T>G and p.? with no variant-specific entry found.

VCEP rule
Assumed de novo, but without confirmation of paternity and maternity. ... Brain Malformation Recommendation: This point is addressed according to PS2 and will not be used.
Evidence considered
  • The VCEP states that PM6 is addressed according to PS2 and will not be used.
Still missing
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PP1 VCEPNot applicable: the VCEP excludes family co-segregation because disease-causing variants are germline mosaic, de novo, or mosaic. Details ▾Hide ▴
Reasoning

PP1 is explicitly not applicable under the Brain Malformations VCEP because the disease-causing variants are germline mosaic, de novo, or mosaic, so family co-segregation is not used for this framework. The governing VCEP file was searched for c.562+14T>G and p.? with no variant-specific entry found.

VCEP rule
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease ... Brain Malformation Recommendation: Not applicable since disease-causing variants are germline mosaic, de novo or mosaic.
Evidence considered
  • The VCEP marks PP1 not applicable since disease-causing variants are germline mosaic, de novo or mosaic.
Still missing
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PP2 N/ANot applicable: PP2 is restricted to missense variants, but c.562+14T>G is intronic with protein consequence p.?. Details ▾Hide ▴
Reasoning

PP2 is not applicable because the VCEP criterion is restricted to missense variants, while this variant is intronic with protein consequence p.?; no missense constraint z-score can establish PP2 for this variant. The governing VCEP file contains no variant-specific entry for c.562+14T>G or p.? .

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 VCEP normalization data classify the variant as intronic at exon 3i with NP_006209.2:p.?; PP2's missense z-score condition therefore does not apply.
  • The governing VCEP full-text file was searched for c.562+14T>G and p.?; no variant-specific entry was found.
Still missing
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; the file is a criterion specification, not a variant-level catalog.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PP3 VCEPNot applicable: The VCEP excludes PP3 for these gain-of-function variants because traditional pathogenicity algorithms focus on loss-of-function mechanisms. Details ▾Hide ▴
Reasoning

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. The variant is intronic with an uncertain protein consequence, and the available SpliceAI result (maximum delta score 0.031) cannot override the VCEP's explicit exclusion. No PP3 evidence is assigned.

VCEP rule
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 states that PP3 is not applicable because these variants are gain-of-function and traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms.
  • The case variant is NM_006218.4:c.562+14T>G, an intronic noncanonical-splice-site variant with predicted protein consequence NP_006209.2:p.?.
  • SpliceAI is available and reports maximum delta score 0.031, but this result does not alter the VCEP's explicit PP3 inapplicability.
Still missing
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this file contains the governing rule but no variant-specific PP3 assignment.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PP4 VCEPNot applicable: the VCEP explicitly accounts for phenotype specificity under PS4 rather than PP4. Details ▾Hide ▴
Reasoning

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

VCEP rule
Phenotype specific for disease with single genetic etiology. This criterion is accounted for under PS4.
Evidence considered
  • ClinGen Brain Malformations VCEP specification, supporting-criteria table: PP4, phenotype specific for disease with single genetic etiology; specification: this criterion is accounted for under PS4.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PP5 VCEPNot applicable: the VCEP prohibits PP5 use under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Reasoning

The Brain Malformations VCEP marks PP5 as not applicable and states that it is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The VCEP criteria entry for PP5 is marked Not Applicable for this VCEP and says the criterion is not for use.
  • ClinVar has no result for this variant, and literature_pass.json contains no publications, but those observations are not needed because PP5 is VCEP-inapplicable.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BS4 VCEPNot applicable: the VCEP excludes lack-of-segregation evidence for de novo, germline mosaic, or post-zygotic mutations. Details ▾Hide ▴
Reasoning

BS4 is explicitly not applicable under the Brain Malformations VCEP because these are de novo, germline mosaic, or post-zygotic mutations; lack of segregation in affected family members is therefore not used. The governing VCEP file was searched for c.562+14T>G and p.? with no variant-specific entry found.

VCEP rule
Lack of segregation in affected members of a family ... Brain Malformation Recommendation: Not applicable as these are de novo, germline mosaic or post-zygotic mutations.
Evidence considered
  • The VCEP states that BS4 is not applicable as these are de novo, germline mosaic or post-zygotic mutations.
Still missing
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BP1 VCEPNot applicable: the VCEP explicitly excludes BP1 because loss of function is not the disease mechanism. Details ▾Hide ▴
Reasoning

BP1 is explicitly not applicable under this VCEP because loss of function is not the disease mechanism. This conclusion does not depend on the variant's intronic consequence.

VCEP rule
Not applicable as LOF is not the disease mechanism.
Evidence considered
  • The governing VCEP full-text file states that BP1 is not applicable because LOF is not the disease mechanism.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BP3 VCEPNot applicable: the VCEP states that these genes lack qualifying nonfunctional repetitive exon regions, and this variant is intronic rather than an in-frame indel. Details ▾Hide ▴
Reasoning

BP3 is explicitly not applicable for the genes covered by this VCEP because their exon regions do not have repetitive regions without a known function. The variant is intronic and is not an in-frame deletion or insertion, so it also does not meet the original BP3 variant-type definition.

VCEP rule
This is not applicable for the genes specified since the exon regions do not have repetitive regions without a known function.
Evidence considered
  • ClinGen Brain Malformations VCEP BP3 entry: BP3 is marked Not Applicable for this VCEP because the exon regions do not have repetitive regions without a known function.
  • Variant assessment: NM_006218.4:c.562+14T>G is intronic in exon 3i with predicted protein consequence p.?, not an in-frame deletion/insertion.
Still missing
  • No exact entry for c.562+14T>G or p.? was found when searching clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this does not alter the explicit VCEP applicability rule.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗pvs1_variant_assessment
BP6 VCEPNot applicable: the VCEP explicitly excludes BP6 for this framework. Details ▾Hide ▴
Reasoning

The Brain Malformations VCEP explicitly marks BP6 as not applicable.

VCEP rule
Brain Malformation Recommendation: Not applicable
Evidence considered
  • The VCEP criteria entry for BP6 is marked Not Applicable for this VCEP, regardless of whether a reputable benign classification source exists.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗

Identifiers

Gene
PIK3CA
Transcript
NM_006218.4
Coding (HGVS c.)
NM_006218.4:c.562+14T>G
Protein (HGVS p.)
NP_006209.2:p.?
GRCh38
chr3:179199913 T>G
GRCh37
chr3:178917701 T>G
Location and type
Intron 3 · unknown

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

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -223 bp
0.001
SpliceAI acceptor gainat -202 bp
0.001
SpliceAI donor lossat -14 bp
0.002
SpliceAI donor gainat -85 bp
0.031
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.004

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 VCEPNot assessed: The intronic variant has one named no-impact result, SpliceAI max delta 0.031, but two of three tools are required and varSEAK/MaxEntScan results are unavailable. Details ▾Hide ▴
Reasoning

The variant is an intronic position outside the canonical splice sites, so it lies within BP4's stated scope. The VCEP requires no-impact predictions from at least two of three named tools: varSEAK, spliceAI, and MaxEntScan. Only SpliceAI is available here (maximum delta score 0.031); no varSEAK or MaxEntScan result is available. Therefore the two-of-three requirement cannot be evaluated and BP4 is not assessed, rather than not met.

VCEP rule
Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function. Not applicable for any variant type except 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
  • The VCEP limits BP4 to synonymous, intronic noncanonical-splice-site, and UTR variants and requires two of three named splicing tools to predict no splicing change: varSEAK, spliceAI, and MaxEntScan.
  • VariantValidator places NM_006218.4:c.562+14T>G in intron 3i; it is not a canonical splice-site variant.
  • SpliceAI reports DS_AG 0.001, DS_AL 0.001, DS_DG 0.031, DS_DL 0.002, with maximum delta score 0.031 and an evidence sentence describing no significant splice impact.
  • The available case evidence contains no varSEAK or MaxEntScan result, so the VCEP two-of-three condition cannot be determined.
Still missing
  • No varSEAK prediction is available for NM_006218.4:c.562+14T>G.
  • No MaxEntScan prediction is available for NM_006218.4:c.562+14T>G.
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this file contains the governing rule but no variant-specific BP4 assignment.
Sources
cspec ↗spliceai ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
BP7 VCEPNot assessed: The variant is noncanonical intronic, but no VCEP-required conservation result, including PhyloP <0.1, is available. Details ▾Hide ▴
Reasoning

The variant is an intronic position outside the canonical splice sites, so it lies within the VCEP's BP7 variant-location scope. The VCEP requires the nucleotide to be non-conserved, defined as absent from all vertebrae or having a PhyloP score below 0.1. No vertebrate-conservation result or PhyloP score is available. The criterion therefore cannot be assessed.

VCEP rule
For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1).
Evidence considered
  • The VCEP applies BP7 to synonymous, intronic noncanonical-splice-site, and UTR variants when the nucleotide is non-conserved.
  • The VCEP defines non-conserved as the same nucleotide not being present in all vertebrae or a PhyloP score below 0.1.
  • VariantValidator places NM_006218.4:c.562+14T>G in intron 3i and confirms it is not at a canonical splice site.
  • No PhyloP score or all-vertebrae conservation result is present for this variant.
Still missing
  • No PhyloP score is available for NM_006218.4:c.562+14T>G.
  • No result showing that the nucleotide is absent from all vertebrae is available.
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this file contains the governing rule but no variant-specific BP7 assignment.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗
PP3 VCEPNot applicable: The VCEP excludes PP3 for these gain-of-function variants because traditional pathogenicity algorithms focus on loss-of-function mechanisms. Details ▾Hide ▴
Reasoning

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. The variant is intronic with an uncertain protein consequence, and the available SpliceAI result (maximum delta score 0.031) cannot override the VCEP's explicit exclusion. No PP3 evidence is assigned.

VCEP rule
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 states that PP3 is not applicable because these variants are gain-of-function and traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms.
  • The case variant is NM_006218.4:c.562+14T>G, an intronic noncanonical-splice-site variant with predicted protein consequence NP_006209.2:p.?.
  • SpliceAI is available and reports maximum delta score 0.031, but this result does not alter the VCEP's explicit PP3 inapplicability.
Still missing
  • No entry for c.562+14T>G or p.? was found in clingen_brainmalform_acmg_specifications_v1_1.pdf.txt; this file contains the governing rule but no variant-specific PP3 assignment.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1 ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.031 Open source ↗
COSMIC Captured COSMIC 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

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 = 0.03).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).