PIK3CA c.1214C&gt;A , p.(Ser405Tyr)

PM2 SupportingMet (Supporting): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Details ▾Hide ▴

Reasoning

The exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. This satisfies the applicable PIK3CA Brain Malformations VCEP PM2 rule for an absent/rare variant in a control population sample, with PM2 limited to Supporting strength and a maximum of one person.

Rule

PIK3CA Brain Malformations VCEP PM2: absent/rare from controls in an ethnically matched cohort population sample (>=1); apply at Supporting strength, with one person maximum.

Evidence considered

The governing ClinGen Brain Malformations VCEP specifies PM2 as Supporting for a variant absent/rare in an ethnically matched control cohort population sample, with one person maximum.
The exact variant NM_006218.4:c.1214C>A is reported as absent from gnomAD v2.1.
The exact variant NM_006218.4:c.1214C>A is reported as absent from gnomAD v4.1.
The exact variant NM_006218.4:c.1214C>A is reported as absent from gnomAD-Canada v1.0.

Sources

Not met · 3 · evaluated, threshold not reached

BA1 Not met: the variant is absent from population databases, so no allele frequency exceeds the BA1 threshold of 0.0926%. Details ▾Hide ▴

Reasoning

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; therefore no population allele frequency exceeds the PIK3CA Brain Malformations VCEP BA1 threshold of >0.0926%.

Rule

PIK3CA Brain Malformations VCEP BA1: allele frequency >0.0926% (stand-alone benign evidence).

Evidence considered

The governing ClinGen Brain Malformations VCEP specification sets BA1 at allele frequency >0.0926%.
The exact variant NM_006218.4:c.1214C>A is reported as absent from gnomAD v2.1.
The exact variant NM_006218.4:c.1214C>A is reported as absent from gnomAD v4.1.
The exact variant NM_006218.4:c.1214C>A is reported as absent from gnomAD-Canada v1.0.

Sources

BS1 Not met: the variant is absent from population databases, so no allele frequency exceeds the BS1 threshold of 0.0185%. Details ▾Hide ▴

Reasoning

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; therefore no population allele frequency exceeds the PIK3CA Brain Malformations VCEP BS1 threshold of >0.0185%.

Rule

PIK3CA Brain Malformations VCEP BS1: allele frequency >0.0185% (benign strong evidence).

Evidence considered

The governing ClinGen Brain Malformations VCEP specification sets BS1 at allele frequency >0.0185%.
The exact variant NM_006218.4:c.1214C>A is reported as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so the BS1 frequency threshold is not reached.

Sources

BS2 Not met: the required three homozygotes or qualifying family observations were absent. Details ▾Hide ▴

Reasoning

The VCEP requires at least 3 homozygotes in gnomAD/ExAC or at least 3 heterozygous occurrences in well-phenotyped family members. The variant is absent from the available gnomAD datasets and no qualifying family observations are provided, so the BS2 threshold is not met.

Rule

PIK3CA Brain Malformations VCEP BS2: award Benign Strong only for >=3 gnomAD/ExAC homozygotes or >=3 heterozygous occurrences in well-phenotyped family members.

Evidence considered

The governing ClinGen Brain Malformations VCEP BS2 rule requires at least 3 homozygotes in gnomAD or ExAC, or at least 3 heterozygous occurrences in well-phenotyped family members.
The exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, providing no qualifying homozygous observations in those datasets.
No well-phenotyped family-member observations are present in the case evidence bundle.

Sources

Not assessed · 9 · no assessment recorded

PS1 Not assessed: no pathogenic p.Ser405Tyr comparator was available, so this criterion could not be evaluated. Details ▾Hide ▴

Reasoning

The variant is PIK3CA p.Ser405Tyr. The governing Brain Malformations VCEP retains PS1 at Strong with no modification, requiring the same amino-acid change to have been previously established as pathogenic. The case bundle contains no established pathogenic p.Ser405Tyr comparator; ClinVar contains one single-submitter Uncertain significance record, which cannot establish PS1. Therefore PS1 cannot be assessed as met from the available evidence.

Rule

VCEP PS1 Strong: same amino-acid change as a previously established pathogenic variant; no change.

Evidence considered

The governing VCEP specifies PS1 as Strong, with no change from the original ACMG/AMP rule: same amino-acid change as a previously established pathogenic variant regardless of nucleotide change.
The case variant is NM_006218.4:c.1214C>A, p.Ser405Tyr.
ClinVar variation 3373455 has one single-submitter classification of Uncertain significance and no expert-panel submission; this does not establish a pathogenic same-amino-acid comparator.

Still missing

A previously established pathogenic PIK3CA p.Ser405Tyr variant record with supporting evidence is not available.

Sources

PS2 Not assessed: no proband or parental genotype data, tissue allele fractions, or confirmation of maternity and paternity were available. Details ▾Hide ▴

Reasoning

The applicable PIK3CA Brain Malformations VCEP specification permits PS2_Moderate when the variant is detected in the affected tissue and absent from parental samples with confirmed maternity and paternity, and PS2_Strong only when that parental criterion is also accompanied by detectable affected-tissue presence with absence or lower allelic fraction in another tissue. The consolidated case-evidence bundle contains no proband genotype details, parental test results, maternity or paternity confirmation, tissue-specific allele fractions, or orthogonal confirmation sufficient to evaluate either PS2 rule. Therefore PS2 cannot be awarded from the available evidence.

Rule

VCEP PS2: Strong requires Criteria 1 AND Criteria 2; Moderate requires Criteria 1 OR, if parents are unavailable, Criteria 2.

Evidence considered

The governing Brain Malformations VCEP specification states that PS2_Moderate requires the variant to be detectable in the proband and absent from parental samples with confirmed maternity and paternity, or, when parents are unavailable, detectable in affected tissue under the specified tissue-distribution condition.
The consolidated case-evidence bundle provides no proband-level segregation/de novo observations, parental genotypes, maternity or paternity confirmation, or tissue-specific allele-fraction data.

Still missing

Proband variant detection and assay quality/allele fraction are not documented.
Parental testing results and confirmed maternity and paternity are not documented.
Affected-tissue versus other-tissue variant presence and allelic fractions are not documented.

Sources

PS3 Not assessed: no variant-specific functional assay evidence for p.Ser405Tyr was available. Details ▾Hide ▴

Reasoning

The applicable ClinGen Brain Malformations VCEP specification requires functional assay evidence meeting SVI/BMVCEP quality and validation-control requirements. The case bundle contains no variant-specific functional assay publication or experimental result for PIK3CA NM_006218.4:c.1214C>A (p.Ser405Tyr), so PS3 cannot be assigned at any strength.

Rule

Follow SVI recommendations with BMVCEP specifications for assay quality metrics and minimum validation controls; assign PS3 only when the functional assay meets the specified acceptability criteria.

Evidence considered

The Brain Malformations VCEP specification is applicable to PIK3CA and directs PS3 assessment according to SVI recommendations plus BMVCEP minimum quality metrics and validation controls.
The specification states that supporting-level PS3 requires an eligible functional assay publication, while stronger levels require independent pathogenic/likely pathogenic and benign/likely benign validation controls and specified assay quality metrics.
The consolidated case-evidence bundle reports zero literature PMIDs, an empty fulltext_map.json, and an empty paper_extracts.json; no variant-specific functional assay evidence is present.

Still missing

No variant-specific in vitro or in vivo functional assay result was identified.
No assay methodology, biological readout, positive control, negative control, or replicate documentation was identified.
No publication or paper extraction was available for review.

Sources

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PS4 Not assessed: no affected-individual, phenotype, case-control, or variant-specific literature data were provided. Details ▾Hide ▴

Reasoning

No affected individuals, phenotype descriptions, case-control analysis, or variant-specific literature reports were provided from which to assign the Brain Malformations VCEP PS4 phenotype points.

Rule

Brain Malformations VCEP PS4: assign each reported case only to its highest Table 2A category; sum points and apply Table 2B strength thresholds only if the PM2 prerequisite is met.

Evidence considered

The applicable Brain Malformations VCEP specification uses phenotype points under Table 2A/Table 2B for PS4 and permits their use only when the variant meets PM2; thresholds are Supporting 0.5–1.25, Moderate 1.5–3.25, Strong 3.5–15.75, and Very Strong at least 16 points.
The bundle reports the exact variant absent from gnomAD v2.1 and v4.1, but contains no phenotype-point-eligible affected cases.
The literature packet contains no PMIDs and paper_extracts is empty.

Still missing

Variant-specific affected-case reports with phenotype details sufficient for Table 2A point assignment are needed.
A PS4 assessment also requires confirmation that the PM2 prerequisite is met before phenotype points can be used.

Sources

PM5 Not assessed: no pathogenic missense variant at residue 405 was identified for comparison. Details ▾Hide ▴

Reasoning

The governing VCEP retains PM5 at Moderate with no change, requiring a different pathogenic missense change at the same amino-acid residue. The collected PM5 candidate artifact identified zero same-residue candidates and no expert-panel or non-expert-majority pathogenic/likely pathogenic comparator. No paper records were available. PM5 therefore cannot be assessed as met.

Rule

VCEP PM5 Moderate: different missense change at the same amino-acid residue determined to be pathogenic; no change.

Evidence considered

The governing VCEP specifies PM5 at Moderate strength with no change: a missense change at an amino-acid residue where a different missense change determined to be pathogenic has been seen before.
The PM5 candidate collection reports zero same-residue candidates, zero expert-panel pathogenic/likely pathogenic candidates, and zero non-expert-majority pathogenic/likely pathogenic candidates.
The PM5 candidate collection reports an HTTP 429 rate-limit error and explicitly states that it does not adjudicate PM5 automatically.

Still missing

A different PIK3CA missense variant at residue Ser405 established as pathogenic or likely pathogenic with auditable supporting evidence is not available.
The same-residue comparator search ended with an HTTP 429 rate-limit error, so additional comparator retrieval may be needed.

Sources

cspec ↗pm5_candidates

PP2 Not assessed: the required PIK3CA missense-constraint z-score (>3.09) was not available. Details ▾Hide ▴

Reasoning

The governing VCEP permits PP2 at Supporting strength for PIK3CA when the ExAC/gnomAD missense-constraint z-score is greater than 3.09. The case bundle does not provide the required PIK3CA missense-constraint z-score, so the criterion cannot be assessed.

Rule

VCEP PP2 Supporting: award if the ExAC/gnomAD missense-constraint z-score is >3.09; applicable to PIK3CA.

Evidence considered

The governing VCEP specifies PP2 at Supporting strength for PIK3CA when the missense-constraint z-score computed in ExAC/gnomAD is greater than 3.09.
No ExAC/gnomAD missense-constraint z-score for PIK3CA is present in the case bundle.

Still missing

The PIK3CA ExAC/gnomAD missense-constraint z-score is not available in the case evidence bundle.

Sources

BS3 Not assessed: no variant-specific benign functional assay evidence was available. Details ▾Hide ▴

Reasoning

The applicable ClinGen Brain Malformations VCEP specification requires well-established functional evidence showing no damaging effect and adherence to SVI/BMVCEP assay quality and validation-control requirements. No variant-specific benign functional assay result is present in the case bundle, so BS3 cannot be assigned at any strength.

Rule

Follow SVI recommendations with Brain Malformation Group specifications for assay quality metrics and minimum validation controls; assign BS3 only when well-established functional studies show no damaging effect.

Evidence considered

The Brain Malformations VCEP specification defines BS3 as well-established in vitro or in vivo functional evidence showing no damaging effect and requires the SVI/BMVCEP quality and validation-control recommendations.
The consolidated case-evidence bundle reports zero literature PMIDs, an empty fulltext_map.json, and an empty paper_extracts.json; no variant-specific benign functional assay evidence is present.

Still missing

No variant-specific functional assay demonstrating preserved protein function or normal splicing was identified.
No assay methodology, biological relevance, negative-effect result, controls, or replicate documentation was identified.
No publication or paper extraction was available for review.

Sources

BP2 Not assessed: no data showed this variant in cis or trans with a known pathogenic PIK3CA variant. Details ▾Hide ▴

Reasoning

The governing VCEP permits BP2 at Supporting strength when the variant is observed in cis or trans with a known pathogenic variant in the same gene. The available case bundle contains no affected-proband, family, parental, phase, or second-variant data demonstrating that NM_006218.4:c.1214C>A (p.Ser405Tyr) is in cis or trans with a known pathogenic PIK3CA variant.

Rule

Supporting: observed in cis or trans with a known pathogenic variant in the same gene.

Evidence considered

The governing VCEP rule for BP2 is: observed in cis or trans with a known pathogenic variant in the same gene.
The consolidated case bundle identifies only the target PIK3CA variant and reports one ClinVar submission as uncertain significance for a condition not provided; it contains no partner-variant or phase information.
No literature PMIDs or paper extractions were available for this case, so no publication documents an affected proband with a phased pathogenic PIK3CA allele.

Still missing

No documented pathogenic PIK3CA variant in the same individual or family was provided.
No parental testing, segregation data, or other phasing evidence was provided to establish cis or trans configuration.
A clinically interpretable source confirming the partner variant as pathogenic is absent.

Sources

BP5 Not assessed: no alternate molecular diagnosis explaining the phenotype was identified. Details ▾Hide ▴

Reasoning

BP5 remains applicable as originally described by the VCEP, but the bundle contains no affected case with a confirmed alternate molecular diagnosis explaining the phenotype.

Rule

Brain Malformations VCEP BP5: applicable as originally described for a variant found in a case with an alternate molecular basis for disease.

Evidence considered

The Brain Malformations VCEP retains BP5 without modification: a variant found in a case with an alternate molecular basis for disease.
No individual-level phenotype, co-diagnosis, or alternate molecular finding is present in the consolidated evidence bundle.

Still missing

A variant-bearing affected individual with a documented alternate molecular diagnosis sufficient to explain the presenting phenotype is needed.

Sources

Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 VCEPNot applicable: this missense variant causes no loss-of-function mechanism such as nonsense-mediated decay or truncation. Details ▾Hide ▴

Reasoning

PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_006218.4:c.1214C>A in PIK3CA is a missense substitution predicted to produce NP_006209.2:p.(Ser405Tyr). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

VCEP rule

deterministic_prefilter: requires_null_variant_class

Evidence considered

Deterministic consequence classification: missense (prefetch.json normalized protein consequence)

Sources

pvs1_generic_framework ↗generic_acmg_combination_rules

PM3 VCEPNot applicable: PM3 applies to recessive disorders with a pathogenic variant in trans; PIK3CA disease variants are heterozygous. Details ▾Hide ▴

Reasoning

The ClinGen Brain Malformations VCEP specification marks PM3 as not applicable for PIK3CA because disease-causing variants are heterozygous; PM3 is intended for recessive disorders with a pathogenic variant confirmed in trans.

VCEP rule

Not applicable for this VCEP because disease-causing variants are heterozygous.

Evidence considered

The governing PIK3CA Brain Malformations VCEP specification states that PM3 is not applicable because disease-causing variants are heterozygous.
The case variant is NM_006218.4:c.1214C>A, p.(Ser405Tyr), a missense variant; no recessive/biallelic interpretation is applicable under this VCEP framework.

Sources

PM4 VCEPNot applicable: no protein length change occurs, since this is a missense substitution, not an insertion, deletion, or stop-loss. Details ▾Hide ▴

Reasoning

PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_006218.4:c.1214C>A in PIK3CA is a missense substitution predicted to produce NP_006209.2:p.(Ser405Tyr). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

VCEP rule

deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel

Evidence considered

Deterministic consequence classification: missense (prefetch.json normalized protein consequence)

Sources

pvs1_generic_framework ↗generic_acmg_combination_rules

PM6 VCEPNot applicable: the VCEP handles assumed de novo evidence under PS2 rather than PM6. Details ▾Hide ▴

Reasoning

The PIK3CA Brain Malformations VCEP specification designates PM6 as not applicable and explicitly states that assumed de novo evidence without confirmation of paternity and maternity is addressed according to PS2. PM6 is therefore not used independently in this framework.

VCEP rule

VCEP PM6: Not applicable; addressed by PS2.

Evidence considered

The governing VCEP specification lists PM6 as not applicable, states that it is addressed by PS2, and defines PM6 as assumed de novo without confirmation of paternity and maternity.

Sources

PP1 VCEPNot applicable: familial co-segregation evidence does not apply to de novo or mosaic disease variants under the VCEP. Details ▾Hide ▴

Reasoning

The PIK3CA Brain Malformations VCEP specification designates PP1 as not applicable because disease-causing variants in this context are germline mosaic, de novo, or mosaic. Classical familial co-segregation evidence is therefore not used for PP1 under the governing framework.

VCEP rule

VCEP PP1: Not applicable for this VCEP.

Evidence considered

The governing VCEP specification lists PP1 as not applicable and explains that it is not applicable because disease-causing variants are germline mosaic, de novo, or mosaic.

Sources

PP3 VCEPNot applicable: PIK3CA brain-malformation variants act through gain of function, which computational predictors do not capture. Details ▾Hide ▴

Reasoning

Not applicable under the governing ClinGen Brain Malformations VCEP specification because PIK3CA brain-malformation variants act through gain of function and traditional computational pathogenicity predictors focus on loss-of-function mechanisms.

VCEP rule

ClinGen Brain Malformations VCEP v1.1: PP3 is not applicable for gain-of-function variants; it may be revisited only with published experience for predictors specifically designed to detect gain-of-function mutations.

Evidence considered

The governing ClinGen Brain Malformations VCEP specification explicitly states that PP3 is not applicable for this VCEP because these variants are gain of function and traditional mutation-pathogenicity prediction algorithms focus on loss-of-function mechanisms.
The case is a missense variant, NM_006218.4:c.1214C>A (p.Ser405Tyr). Its available REVEL score (0.827) and BayesDel score (0.337221) do not override the VCEP non-applicability determination; BayesDel has no verified calibrated threshold supplied for this evaluation.

Sources

PP4 VCEPNot applicable: phenotype evidence is already accounted for under PS4. Details ▾Hide ▴

Reasoning

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

VCEP rule

Brain Malformations VCEP: PP4 is not applicable; phenotype specificity is evaluated through PS4.

Evidence considered

The VCEP specification states: 'Not applicable since this criterion is accounted for under PS4.'

Sources

PP5 VCEPNot applicable: the VCEP does not permit PP5, and ClinVar holds only one non-expert uncertain-significance submission. Details ▾Hide ▴

Reasoning

The governing VCEP specification does not permit PP5. Independently, the exact ClinVar record has only one non-expert GeneDx submission classified as uncertain significance and no expert-panel Pathogenic/Likely pathogenic assertion.

VCEP rule

PP5 is not applicable under the Brain Malformations VCEP; in addition, an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic assertion would be required for the specified PP5 use case.

Evidence considered

The VCEP specification states that PP5 is not for use as recommended by the ClinGen SVI VCEP Review Committee.
ClinVar variation 3373455 exactly matches NM_006218.4:c.1214C>A (p.Ser405Tyr) and has one GeneDx clinical-testing submission, classified as uncertain significance; the audit identifies zero expert-panel submissions.

Sources

BS4 VCEPNot applicable: lack of segregation does not apply to de novo or mosaic disease variants under the VCEP. Details ▾Hide ▴

Reasoning

The PIK3CA Brain Malformations VCEP specification designates BS4 as not applicable because the relevant disease-causing variants are de novo, germline mosaic, or post-zygotic mutations. Lack of segregation in affected family members is consequently not used as BS4 in this framework.

VCEP rule

VCEP BS4: Not applicable for this VCEP.

Evidence considered

The governing VCEP specification lists BS4 as not applicable and states that it is not applicable because these are de novo, germline mosaic, or post-zygotic mutations.

Sources

BP1 VCEPNot applicable: BP1 targets truncating loss-of-function disorders, whereas PIK3CA acts through gain of function. Details ▾Hide ▴

Reasoning

BP1 is explicitly not applicable under the governing Brain Malformations VCEP because the disease mechanism for these genes is gain of function rather than a disorder primarily caused by truncating loss-of-function variants.

VCEP rule

VCEP BP1: Not Applicable for this VCEP because LOF is not the disease mechanism.

Evidence considered

The governing VCEP marks BP1 as not applicable and states: not applicable as LOF is not the disease mechanism.
The VCEP framework identifies the disease mechanism for the specified genes, including PIK3CA in this context, as gain of function.

Sources

BP3 VCEPNot applicable: the variant is a missense substitution, not an in-frame indel in a repetitive region. Details ▾Hide ▴

Reasoning

BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_006218.4:c.1214C>A in PIK3CA is a missense substitution predicted to produce NP_006209.2:p.(Ser405Tyr). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

VCEP rule

deterministic_prefilter: requires_repeat_region_indel

Evidence considered

Deterministic consequence classification: missense (prefetch.json normalized protein consequence)

Sources

pvs1_generic_framework ↗generic_acmg_combination_rules

BP4 N/ANot applicable: BP4 is restricted to synonymous, intronic, or UTR variants; this variant is missense. Details ▾Hide ▴

Reasoning

Not applicable under the governing ClinGen Brain Malformations VCEP specification because this is a missense variant. The VCEP restricts BP4 to synonymous, non-canonical intronic, or UTR variants and requires two of varSEAK, SpliceAI, and MaxEntScan to predict no splicing impact.

Rule

ClinGen Brain Malformations VCEP v1.1: BP4 applies only to synonymous, non-canonical intronic, or UTR variants when two of three specified splice predictors (varSEAK, SpliceAI, MaxEntScan) predict no splicing change.

Evidence considered

NM_006218.4:c.1214C>A is an exonic missense variant predicting p.Ser405Tyr.
The governing VCEP BP4 rule limits use to synonymous, non-canonical intronic, and UTR variants when at least two of varSEAK, SpliceAI, and MaxEntScan predict no splice impact.

Sources

BP6 VCEPNot applicable: the VCEP does not permit BP6, and no expert benign ClinVar assertion exists. Details ▾Hide ▴

Reasoning

The governing VCEP specification does not permit BP6. Independently, no exact-variant ClinVar expert-panel Benign/Likely benign assertion is present; the only submission is a non-expert uncertain-significance assertion.

VCEP rule

BP6 is not applicable under the Brain Malformations VCEP; in addition, an exact-variant ClinVar expert-panel Benign/Likely benign assertion would be required for the specified BP6 use case.

Evidence considered

The VCEP specification states that BP6 is not for use as recommended by the ClinGen SVI VCEP Review Committee.
ClinVar variation 3373455 exactly matches the assessed variant; its sole GeneDx submission is uncertain significance and is not an expert-panel assertion.

Sources

BP7 N/ANot applicable: BP7 applies to synonymous variants only; this missense variant alters the protein sequence. Details ▾Hide ▴

Reasoning

BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006218.4:c.1214C>A in PIK3CA is a missense substitution predicted to produce NP_006209.2:p.(Ser405Tyr). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.

Rule

deterministic_prefilter: requires_synonymous

Evidence considered

Deterministic consequence classification: missense (prefetch.json normalized protein consequence)

Sources

generic_acmg_combination_rules

Identifiers

Gene: PIK3CA
Transcript: NM_006218.4
Coding (HGVS c.): NM_006218.4:c.1214C>A
Protein (HGVS p.): NP_006209.2:p.(Ser405Tyr)
GRCh38: chr3:179209663 C>A
GRCh37: chr3:178927451 C>A
Location and type: Exon 7 · missense
ClinVar: 3373455

Gene diagram

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

PIK3CANM_006218.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in PIK3CA — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

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.

Other predictors

REVEL: 0.827
BayesDel: 0.337

How the predictions were used

PP3 VCEPNot applicable: PIK3CA brain-malformation variants act through gain of function, which computational predictors do not capture. Details ▾Hide ▴

Reasoning

VCEP rule

ClinGen Brain Malformations VCEP v1.1: PP3 is not applicable for gain-of-function variants; it may be revisited only with published experience for predictors specifically designed to detect gain-of-function mutations.

Evidence considered

The governing ClinGen Brain Malformations VCEP specification explicitly states that PP3 is not applicable for this VCEP because these variants are gain of function and traditional mutation-pathogenicity prediction algorithms focus on loss-of-function mechanisms.
The case is a missense variant, NM_006218.4:c.1214C>A (p.Ser405Tyr). Its available REVEL score (0.827) and BayesDel score (0.337221) do not override the VCEP non-applicability determination; BayesDel has no verified calibrated threshold supplied for this evaluation.

Sources

BP4 N/ANot applicable: BP4 is restricted to synonymous, intronic, or UTR variants; this variant is missense. Details ▾Hide ▴

Reasoning

Rule

ClinGen Brain Malformations VCEP v1.1: BP4 applies only to synonymous, non-canonical intronic, or UTR variants when two of three specified splice predictors (varSEAK, SpliceAI, MaxEntScan) predict no splicing change.

Evidence considered

NM_006218.4:c.1214C>A is an exonic missense variant predicting p.Ser405Tyr.
The governing VCEP BP4 rule limits use to synonymous, non-canonical intronic, and UTR variants when at least two of varSEAK, SpliceAI, and MaxEntScan predict no splice impact.

Sources