Analysis in progress
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PIK3CA
Final classification
VUS
PIK3CA c.1911+19G>T · p.?
PIK3CA

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.

Gene
PIK3CA
Transcript
NM_006218.4
HGVS · transcript:coding
NM_006218.4:c.1911+19G>T
Consequence
N/A
GRCh38
chr3:179219754 G>T
GRCh37
chr3:178937542 G>T
Basis ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 v1.1 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 v1.1 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2 VUS
PIK3CA c.1911+19G>T

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 v1.1.1 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.2 PVS1, PP3, and BP1 are not applicable under the Brain Malformations VCEP because the PIK3CA disease mechanism for cerebral malformations is gain-of-function.3 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.4 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).5 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).6

PM2 VUS
Gene diagram · NM_006218.4 · variants mapped to exon structure
PIK3CA NM_006218.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 11 assessed
Applied · 1
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
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.
Absent from gnomAD v2.1 (exomes). Absent from gnomAD v4.1 (exomes). Absent from gnomAD-Canada v1.0 (genomes). VCEP PM2 rule: Supporting strength when absent/rare (≤1).
Assessed · not applied
Pathogenic
PS2 No de novo observation has been reported for NM_006218.4:c.1911+19G>T.
PS3 No functional studies have been reported for NM_006218.4:c.1911+19G>T.
PS4 PS4 requires phenotype-confirmed cases scored under Table 2A and PM2 must be met first.
Benign
BA1 BA1 requires allele frequency > 0.0926% under the Brain Malformations VCEP.
BS1 BS1 requires allele frequency > 0.0185% under the Brain Malformations VCEP.
BS2 BS2 requires ≥3 homozygotes in gnomAD or ≥3 heterozygous in well-phenotyped family members.
BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect.
BP2 BP2 requires observation of the variant in cis or trans with a known pathogenic variant in the same gene.
BP4 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.
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease.
BP7 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).
N/A · 14 PVS1 · PS1 · PM1 · PM5 · PM6 · PP1 · PP2 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3 · BP6
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
COSMIC ↗
Sources & reference links
8Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC