LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-06
Case ID: NM_006218.4_c.1634A_G_20261106_101751
Framework: ACMG/AMP 2015
Variant classification summary

NM_006218.4:c.1634A>G

PIK3CA  · NP_006209.2:p.(Glu545Gly)  · NM_006218.4
GRCh37: chr3:178936092 A>G  ·  GRCh38: chr3:179218304 A>G
Gene: PIK3CA Transcript: NM_006218.4
Final call
VUS
PS2 moderate PS4 moderate PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PIK3CA
Transcript
NM_006218.4
Protein
NP_006209.2:p.(Glu545Gly)
gnomAD AF
0.0 (v2.1)
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS2 Moderate: E545G was detected in nine epidermal nevi and absent from tested unaffected tissue or leukocyte DNA.
2
PS4 Moderate: the VCEP-capped COSMIC count produces 2.25 points, within the Moderate range.
3
PM2 Supporting: the variant is absent from gnomAD v4.1 and has zero observed alleles in gnomAD v2.1 exomes.
Final determination: Under ACMG/AMP 2015 Table 5, two Moderate pathogenic criteria plus one Supporting pathogenic criterion satisfy no Pathogenic or Likely Pathogenic rule, while no benign rule is satisfied, yielding VUS.
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: exact E545G reports were found, but no independently BMVCEP-established pathogenic same-amino-acid comparator with a different nucleotide was available.
vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:15520168 PMID:17673550
PS2 Met Met at Moderate: E545G was detected heterozygously in nine epidermal nevi and absent from unaffected tissue or leukocyte DNA, satisfying the VCEP's tissue-distribution pathway.
cspec PMID:17673550 vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3 Not assessed Not assessed: PMID:17376864 is flagged as a possible E545G functional study, but assay controls and variant-specific results cannot be independently verified.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PS4 Met Met at Moderate: the VCEP-capped COSMIC count yields 2.25 points, and 1.5 <= 2.25 <= 3.25 satisfies the PS4_Moderate range.
vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4 cosmic PMID:15520168 PMID:17673550
PM1 Not met Not met: residue 545 lies outside all approved PIK3CA domains, including kinase domains 322-483 and 797-1068.
vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:20593314
PM2 Met Met at Supporting: the variant has AF 0% and 0 homozygotes in gnomAD v2.1 exomes and is absent from gnomAD v4.1.
cspec gnomad_v2 gnomad_v4
PM3 N/A Not applicable: the VCEP explicitly excludes PM3 because disease-causing PIK3CA variants are heterozygous.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM4 N/A Not applicable: the VCEP excludes PM4 for this gene.
cspec
PM5 Not assessed Not assessed: no independently BMVCEP-pathogenic different missense substitution at PIK3CA residue 545 was available as a comparator.
vcep_clingen_brainmalform_acmg_specifications_v1_1 pm5_candidates PMID:20593314 PMID:26627007
PM6 N/A Not applicable: the VCEP explicitly directs that PM6 is addressed through PS2 and will not be used.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1 N/A Not applicable: the VCEP excludes PP1 because disease-causing variants in this context are germline mosaic, de novo, or mosaic.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2 Not assessed Not assessed: the required PIK3CA ExAC/gnomAD missense-constraint z-score is unavailable, so comparison with 3.09 cannot be made.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3 N/A Not applicable: the VCEP excludes PP3 for these gain-of-function PIK3CA variants, regardless of available REVEL 0.737 or SpliceAI maximum delta 0.001.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4 N/A Not applicable: the VCEP explicitly states that PP4 is accounted for under PS4.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5 N/A Not applicable: the VCEP marks PP5 not applicable, regardless of available pathogenic reports.
vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1 Not met Not met: gnomAD allele frequency is 0% (0/247,982), below the VCEP BA1 threshold of >0.0926%.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: gnomAD allele frequency is 0% (0/247,982), below the VCEP BS1 threshold of >0.0185%.
cspec gnomad_v2 gnomad_v4
BS2 Not met Not met: gnomAD reports 0 homozygotes, short of the VCEP requirement for at least 3 homozygotes.
cspec gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no independently verifiable benign or neutral functional assay showing no damaging effect was available for E545G.
vcep_clingen_brainmalform_acmg_specifications_v1_1
BS4 N/A Not applicable: the VCEP excludes BS4 for these de novo, germline mosaic, or post-zygotic mutations.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1 N/A Not applicable: the VCEP excludes BP1 because loss of function is not the disease mechanism for these genes.
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2 Not assessed Not assessed: no documented cis/trans phase with a known pathogenic PIK3CA variant is available for E545G.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:15520168 PMID:17673550
BP3 N/A Not applicable: the VCEP excludes BP3 for this gene.
cspec
BP4 N/A Not applicable: BP4 is restricted to synonymous, noncanonical intronic, or UTR variants, whereas c.1634A>G is missense p.Glu545Gly.
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP5 Not assessed Not assessed: exact E545G reports lack the case-level alternate molecular diagnosis required to determine BP5.
vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:15520168 PMID:17673550
BP6 N/A Not applicable: the VCEP marks BP6 not applicable regardless of whether a benign source is identified.
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7 N/A Not applicable: BP7 requires a synonymous, noncanonical intronic, or UTR variant with a non-conserved nucleotide, but c.1634A>G is missense.
vcep_clingen_brainmalform_acmg_specifications_v1_1
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