Variant classification summary

NM_006218.4:c.1911+19G>T

PIK3CA · NP_006209.2:p.? · NM_006218.4

GRCh37: chr3:178937542 G>T · GRCh38: chr3:179219754 G>T

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_006218.4:c.1911+19G>T is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at Supporting strength under the Brain Malformations VCEP v1.1.

2

No affected individuals have been reported with this variant; it is absent from ClinVar, COSMIC, and the literature, yielding zero points for PS4 under Table 2A.

3

PVS1, PP3, and BP1 are not applicable under the Brain Malformations VCEP because the PIK3CA disease mechanism for cerebral malformations is gain-of-function.

4

The variant is intronic (c.1911+19) and does not alter an amino acid residue; splice prediction by SpliceAI shows no significant impact (max delta score = 0.01). PS1, PM1, PM5, and PP2 are not applicable because they require amino acid-level changes.

5

BP4 and BP7 could not be fully assessed — BP4 requires two of three splicing tools (only SpliceAI available; missing varSEAK and MaxEntScan) and BP7 requires a PhyloP conservation score (unavailable).

6

Applying the Brain Malformations VCEP Tavtigian point framework: only PM2_Supporting (+1 point) is met. Total score of +1 falls in the VUS range (0-5 points).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is not applicable for PIK3CA under the Brain Malformations VCEP v1.1 because the disease mechanism is gain-of-function, not loss-of-function or haploinsufficiency.	cspec
PS1	N/A	PS1 requires a same amino acid change as a previously established pathogenic variant. NM_006218.4:c.1911+19G>T is intronic and does not produce an amino acid change; no residue is altered.	cspec
PS2	Not met	No de novo observation has been reported for NM_006218.4:c.1911+19G>T. The variant is absent from ClinVar and no literature reports describe de novo occurrence with confirmed maternity and paternity.	clinvar
PS3	Not met	No functional studies have been reported for NM_006218.4:c.1911+19G>T. Zero PMIDs were identified across all evidence sources. The variant has not been directly tested and no systematically characterized range includes this intronic position.
PS4	Not met	PS4 requires phenotype-confirmed cases scored under Table 2A and PM2 must be met first. Although PM2_Supporting is met (variant absent from gnomAD), zero affected individuals have been reported with NM_006218.4:c.1911+19G>T in ClinVar, COSMIC, or the literature, yielding 0 phenotype points.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 framework or in the Brain Malformations VCEP v1.1. The criterion commonly labeled PS5 (reputable source reports variant as pathogenic) is designated as PP5 in the standard framework.
PM1	N/A	PM1 under the Brain Malformations VCEP applies to residues affecting critical functional domains in Table 4 (PIK3CA kinase domains AA 322-483 and AA 797-1068). NM_006218.4:c.1911+19G>T is intronic and does not alter any amino acid residue, so no residue-level domain assessment applies.	cspec
PM2	Met	NM_006218.4:c.1911+19G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under the Brain Malformations VCEP, PM2 is awarded at Supporting strength when the variant is absent or rare (≤1) in ethnically-matched population controls.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	N/A	PM5 applies to novel missense changes at an amino acid residue where a different missense change has been established as pathogenic. NM_006218.4:c.1911+19G>T is intronic and does not produce an amino acid change; no residue for comparator analysis.	cspec pm5_candidates
PM6	N/A	PM6 is designated as Not Applicable by the Brain Malformations VCEP v1.1; assumed de novo without confirmation of maternity/paternity is addressed under PS2 instead.	cspec
PP1	N/A	PP1 is designated as Not Applicable by the Brain Malformations VCEP v1.1; disease-causing variants in PIK3CA-associated brain malformations are germline mosaic, de novo, or mosaic, making co-segregation analysis inappropriate.	cspec
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation (z-score > 3.09). NM_006218.4:c.1911+19G>T is an intronic variant, not a missense variant, and does not fall within the intended scope of this criterion.	cspec
PP3	N/A	PP3 is designated as Not Applicable by the Brain Malformations VCEP v1.1; traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms and are not validated for gain-of-function variants in PIK3CA.	cspec
PP4	N/A	PP4 is designated as Not Applicable by the Brain Malformations VCEP v1.1; patient phenotype specificity is accounted for under the PS4 point-based scoring system instead.	cspec
PP5	N/A	PP5 is designated as Not Applicable by the Brain Malformations VCEP v1.1 per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Additionally, this variant is absent from ClinVar and has no prior classification from any source.	cspec clinvar
BA1	Not met	BA1 requires allele frequency > 0.0926% under the Brain Malformations VCEP. NM_006218.4:c.1911+19G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada; the observed frequency is zero and does not meet the BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	BS1 requires allele frequency > 0.0185% under the Brain Malformations VCEP. NM_006218.4:c.1911+19G>T is absent from all population databases; the observed frequency of zero does not meet the BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	BS2 requires ≥3 homozygotes in gnomAD or ≥3 heterozygous in well-phenotyped family members. NM_006218.4:c.1911+19G>T is absent from gnomAD with zero homozygotes, and no family member phenotype data is available.	gnomad_v2 gnomad_v4 cspec
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. No functional studies have been reported for NM_006218.4:c.1911+19G>T; zero publications were identified.
BS4	N/A	BS4 is designated as Not Applicable by the Brain Malformations VCEP v1.1 because disease-causing variants in PIK3CA-associated brain malformations are de novo, germline mosaic, or post-zygotic mutations, making segregation analysis inappropriate.	cspec
BP1	N/A	BP1 is designated as Not Applicable by the Brain Malformations VCEP v1.1; loss-of-function is not the disease mechanism for PIK3CA, so a missense variant in a gene where primarily truncating variants cause disease is not relevant.	cspec
BP2	Not met	BP2 requires observation of the variant in cis or trans with a known pathogenic variant in the same gene. No phase data or co-occurrence reports are available for NM_006218.4:c.1911+19G>T.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_006218.4:c.1911+19G>T is a substitution, not an in-frame indel.
BP4	Not assessed	BP4 under the Brain Malformations VCEP applies to intronic variants (except canonical splice sites) and requires two of three splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact. SpliceAI predicts no impact (max delta score = 0.01), but varSEAK and MaxEntScan scores are unavailable. Criterion cannot be fully adjudicated with only one of three required tools.	spliceai
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such case has been reported for NM_006218.4:c.1911+19G>T.
BP6	N/A	BP6 is designated as Not Applicable by the Brain Malformations VCEP v1.1 per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Additionally, this variant is absent from ClinVar.	cspec clinvar
BP7	Not assessed	BP7 under the Brain Malformations VCEP applies to intronic positions (except canonical splice sites) and requires the nucleotide to be non-conserved (PhyloP score < 0.1). PhyloP conservation score is not available for this variant position, preventing adjudication.	cspec

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