LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-29
Case ID: NM_006218.4_c.1633G_A_20261029_051528
Framework: ACMG/AMP 2015
Variant classification summary

NM_006218.4:c.1633G>A

PIK3CA  · NP_006209.2:p.(Glu545Lys)  · NM_006218.4
GRCh37: chr3:178936091 G>A  ·  GRCh38: chr3:179218303 G>A
Gene: PIK3CA Transcript: NM_006218.4
Final call
Likely Pathogenic
PS3 supporting PS4 strong PM2 supporting BP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PIK3CA
Transcript
NM_006218.4
Protein
NP_006209.2:p.(Glu545Lys)
gnomAD AF
4.032420662123472e-06 (v2.1)
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic evidence: functional assays show increased E545K activity and abnormal AKT-related endothelial phenotypes.
2
Pathogenic evidence: 8.5 VCEP phenotype points meet the PS4 Strong range across brain, vascular-malformation, and tumor cases.
3
Pathogenic evidence: the variant is present at only 1/247,990 alleles in gnomAD v2.1.
4
Benign-context evidence: E545K co-occurred with a second PIK3CA mutation in two tumors, supporting BP5 without meeting a benign classification rule.
Final determination: Under ACMG/AMP 2015 Table 5, one Strong pathogenic criterion plus at least two Supporting pathogenic criteria supports Likely Pathogenic; the applied BP5 Supporting criterion alone does not satisfy a benign rule.
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 Not applicable: the VCEP excludes PVS1 for this gene.
cspec
PS1 Not assessed Not assessed: no independent BMVCEP-pathogenic same-amino-acid comparator with a different nucleotide change was documented.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PS2 Not assessed Not assessed: affected-brain detection and absent matched blood support tissue mosaicism, but parental availability and confirmed maternity/paternity are not documented for the VCEP PS2 rule.
cspec PMID:22729223
PS3 Met Met at supporting: E545K showed increased lipid-kinase and transforming activity, while p.Glu545Lys activated AKT and caused abnormal endothelial phenotypes in functional assays.
cspec PMID:15930273 PMID:26637981
PS4 Met Met at Strong: 8.5 VCEP phenotype points (4.0 brain, 3.0 vascular-malformation, 1.5 tumor) falls within the 3.5-15.75 PS4_Strong range.
cspec gnomad_v2 gnomad_v4 PMID:22729223 PMID:26637981 PMID:15608678
PM1 Not met Not met: residue 545 lies outside all approved PIK3CA PM1 domains, including kinase intervals 322-483 and 797-1068.
vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:15930273 PMID:26637981
PM2 Met Met at Supporting: gnomAD v2.1 exomes has 1 alternate allele among 247,990 (AF 4.03242e-06), within the VCEP one-person maximum.
cspec gnomad_v2 gnomad_v4
PM3 N/A Not applicable: the VCEP excludes PM3 because disease-causing variants in these disorders are heterozygous.
cspec
PM4 N/A Not applicable: the VCEP excludes PM4 for this gene.
cspec
PM5 Not assessed Not assessed: no qualifying different missense comparator at residue 545 was available, and the candidate search ended with an HTTP 429 error.
vcep_clingen_brainmalform_acmg_specifications_v1_1 pm5_candidates
PM6 N/A Not applicable: the Brain Malformations VCEP explicitly addresses PM6 through PS2 and will not use PM6.
cspec
PP1 N/A Not applicable: the VCEP excludes PP1 because disease-causing PIK3CA variants are germline mosaic, de novo, or mosaic.
cspec
PP2 Not assessed Not assessed: the required PIK3CA ExAC/gnomAD missense-constraint z-score is unavailable, with the VCEP threshold set at >3.09.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3 N/A Not applicable: the Brain Malformations VCEP explicitly designates PP3 as N/A, so no computational predictor can establish PP3 for this variant.
cspec
PP4 N/A Not applicable: the VCEP states PP4 is accounted for under PS4, so no separate phenotype-specificity criterion is awarded.
cspec
PP5 N/A Not applicable: the VCEP excludes PP5 from use, regardless of available pathogenic classifications from reputable sources.
cspec
BA1 Not met Not met: gnomAD v2.1 AF is 0.000403%, far below the VCEP BA1 threshold of >0.0926%, with gnomAD v4.1 also absent.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: gnomAD v2.1 AF is 0.000403%, below the VCEP BS1 threshold of >0.0185%, and gnomAD v4.1 is absent.
cspec gnomad_v2 gnomad_v4
BS2 Not met Not met: gnomAD v2.1 records 0 homozygotes, below the VCEP requirement of at least 3, with no qualifying family observations available.
cspec gnomad_v2
BS3 Not assessed Not assessed: reviewed assays report increased E545K activity and abnormal endothelial phenotypes, with no benign functional result establishing absence of damage.
cspec PMID:15930273 PMID:26637981
BS4 N/A Not applicable: the VCEP excludes BS4 for de novo, germline mosaic, or post-zygotic mutations.
cspec
BP1 N/A Not applicable: the VCEP excludes BP1 because loss of function is not the PIK3CA disease mechanism.
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2 Not assessed Not assessed: two tumors had a second PIK3CA mutation, but phase and pathogenicity of that partner variant were not established.
cspec PMID:15608678 PMID:22729223 vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3 N/A Not applicable: the VCEP excludes BP3 for this gene.
cspec
BP4 N/A Not applicable: BP4 covers only synonymous, noncanonical intronic, or UTR variants, whereas c.1633G>A is a missense change.
cspec
BP5 Met Met at Supporting: PMID:15608678 reports E545K with a second PIK3CA mutation in two tumors, providing an alternate molecular basis for disease.
cspec PMID:15608678
BP6 N/A Not applicable: the VCEP excludes BP6 from use, so benign-source reports cannot generate this criterion.
cspec
BP7 N/A Not applicable: BP7 is restricted to synonymous, noncanonical intronic, or UTR variants, while c.1633G>A is a missense substitution.
cspec
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