LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-29
Case ID: NM_006218.4_c.3140A_G_20261029_191532
Framework: ACMG/AMP 2015
Variant classification summary

NM_006218.4:c.3140A>G

PIK3CA  · NP_006209.2:p.(His1047Arg)  · NM_006218.4
GRCh37: chr3:178952085 A>G  ·  GRCh38: chr3:179234297 A>G
Gene: PIK3CA Transcript: NM_006218.4
Final call
VUS
PS3 supporting PS4 moderate PM2 supporting PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PIK3CA
Transcript
NM_006218.4
Protein
NP_006209.2:p.(His1047Arg)
gnomAD AF
4.027807986337675e-06 (v2.1)
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 Supporting: exact H1047R assays showed 2.5- to 3.5-fold higher PI3K activity and concordant oncogenic phenotypes.
2
PS4 Moderate: nine capped COSMIC tumor occurrences yielded 2.25 points, within the VCEP Moderate range.
3
PM2 Supporting: one gnomAD v2.1 allele was observed and the variant was absent from gnomAD v4.1.
4
PP5 Supporting: the ClinGen Brain Malformations Expert Panel classified the variant as pathogenic.
Final determination: Under ACMG/AMP 2015 Table 5, one Moderate criterion plus three Supporting criteria does not meet a pathogenic, likely pathogenic, benign, or likely benign rule, so the call is 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: no alternate-nucleotide variant producing His1047Arg was available to satisfy the VCEP's PS1 requirement.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PS2 Not assessed Not assessed: a de novo annotation lacks the VCEP-required confirmed maternity/paternity, detectable allele fractions, and affected-versus-other-tissue comparison.
cspec clinvar vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3 Met Met at supporting: exact H1047R assays showed 2.5- to 3.5-fold higher PI3K activity than wild type and concordant oncogenic phenotypes across cell and animal models.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:16322248 PMID:15016963 PMID:17376864 PMID:16432179 PMID:19029981
PS4 Met Met at moderate strength: nine allowable COSMIC tumor occurrences contribute 2.25 points, satisfying the VCEP PS4_Moderate range of 1.5-3.25 points.
cspec cosmic gnomad_v2 gnomad_v4 PMID:15016963 PMID:15520168 PMID:15608678
PM1 Not met Not met: residue 1047 lies within kinase domain 797-1068 but is a recurrent gain-of-function residue excluded from PM1 by the VCEP.
vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:15520168 PMID:15608678
PM2 Met Met at Supporting: gnomAD v2.1 shows 1 allele among 248274 exome alleles and 0 homozygotes, while gnomAD v4.1 is absent.
vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
PM3 N/A Not applicable: the VCEP specifies that disease-causing PIK3CA variants are heterozygous, so recessive in-trans evidence is excluded.
cspec
PM4 N/A Not applicable: the VCEP excludes PM4 for this gene.
cspec
PM5 Not assessed Not assessed: no independently pathogenic alternate missense change at His1047 was available for the VCEP's PM5 comparison.
vcep_clingen_brainmalform_acmg_specifications_v1_1 pm5_candidates
PM6 N/A Not applicable: the VCEP explicitly states that assumed de novo evidence without confirmed parentage is addressed by PS2 and will not be used for PM6.
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, which must exceed 3.09, is unavailable.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3 N/A Not applicable: the VCEP excludes PP3 for PIK3CA gain-of-function variants because traditional pathogenicity predictors focus on loss-of-function mechanisms.
cspec
PP4 N/A Not applicable: the VCEP states that phenotype-specific evidence is accounted for under PS4.
cspec
PP5 Met Not applicable: the governing VCEP explicitly marks PP5 as not applicable.
cspec clinvar
BA1 Not met Not met: the highest observed gnomAD frequency is 0.00089098%, below the VCEP BA1 threshold of 0.0926%.
vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
BS1 Not met Not met: the highest observed gnomAD frequency is 0.00089098%, below the VCEP BS1 threshold of 0.0185%.
vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
BS2 Not met Not met: gnomAD reports 0 homozygotes, and no qualifying set of at least 3 well-phenotyped family heterozygotes is documented.
vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
BS3 Not met Not met: exact H1047R studies showed increased PI3K activity, including 2.5- to 3.5-fold above wild type, rather than no damaging effect.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:16322248 PMID:15016963 PMID:16432179 PMID:19029981
BS4 N/A Not applicable: the VCEP excludes BS4 because these mutations are de novo, germline mosaic, or post-zygotic rather than familial segregating variants.
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 in this specification.
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2 Not assessed Not assessed: H1047R and E545K co-occurred in one tumor, but phase was not established as cis or trans.
cspec PMID:15608678
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.3140A>G is a missense coding variant.
cspec spliceai
BP5 Not assessed Not assessed: no reviewed case establishes PIK3CA H1047R alongside an alternate disease-causing molecular basis in a different gene.
cspec PMID:15520168 PMID:15608678
BP6 N/A Not applicable: the governing VCEP explicitly marks BP6 as not applicable.
cspec
BP7 N/A Not applicable: BP7 covers synonymous, noncanonical intronic, or UTR variants, but c.3140A>G is a missense coding substitution.
cspec
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