LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-03
Case ID: NM_006218.4_c.3140A_T_20261103_101525
Framework: ACMG/AMP 2015
Variant classification summary

NM_006218.4:c.3140A>T

PIK3CA  · NP_006209.2:p.(His1047Leu)  · NM_006218.4
GRCh37: chr3:178952085 A>T  ·  GRCh38: chr3:179234297 A>T
Gene: PIK3CA Transcript: NM_006218.4
Final call
VUS
PS3 supporting PS4 supporting 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.(His1047Leu)
gnomAD AF
4.027807986337675e-06 (v2.1)
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: PS3 Supporting reflects increased lipid binding and gain-of-function activity for exact H1047L.
2
VUS: PS4 Supporting reflects four exact H1047L tumor occurrences totaling 1.00 VCEP point.
3
VUS: PM2 Supporting reflects one gnomAD v2.1 allele, within the VCEP control-frequency limit.
Final determination: Under the VCEP's ACMG/AMP 2015 base rules, three Supporting pathogenic criteria do not satisfy any Pathogenic or Likely Pathogenic rule, and no benign criterion is applied, 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: H1047L is reported clinically and functionally, but no independent BMVCEP pathogenic assessment satisfies the VCEP prerequisite for PS1.
cspec PMID:15520168 PMID:22120714 PMID:26627007 PMID:17376864 clinvar
PS2 Not assessed Not assessed: parental maternity/paternity results and the VCEP-required affected-tissue versus other-tissue allele-fraction comparison are not documented for this variant.
vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:15520168 PMID:26627007 PMID:22120714 PMID:17376864
PS3 Met Met at Supporting: H1047L showed lipid binding several-fold higher than activated wild-type PIK3CA in a recombinant biochemical assay.
cspec PMID:22120714 PMID:17376864 PMID:26627007
PS4 Met Met at Supporting: four exact H1047L tumor samples contribute 1.00 VCEP point, within the 0.5-1.25 PS4_Supporting range.
vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4 PMID:15520168
PM1 Not met Not met: His1047 lies within kinase-domain AA 797-1068, but the VCEP excludes recurrent gain-of-function residues from PM1.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:15520168 PMID:22120714 PMID:17376864 cosmic
PM2 Met Met at Supporting: gnomAD v2.1 shows 1 allele among 248274, within the VCEP PM2 limit of ≤1 allele in an ethnically matched control sample.
vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
PM3 N/A Not applicable: the VCEP states disease-causing variants are heterozygous, excluding its recessive in-trans PM3 criterion.
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: H1047R is documented, but no alternate His1047 missense variant has an independent BMVCEP pathogenic assessment in the available evidence.
cspec PMID:20593314 PMID:22120714
PM6 N/A Not applicable: the VCEP explicitly directs that PM6 is addressed through PS2 and will not be used.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1 N/A Not applicable: the VCEP excludes PP1 because disease-causing variants are germline mosaic, de novo, or mosaic.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2 Not assessed Not assessed: the VCEP requires a PIK3CA missense-constraint z-score greater than 3.09, but no z-score is available.
cspec
PP3 N/A Not applicable: the VCEP excludes PP3 for gain-of-function variants because traditional pathogenicity algorithms focus on loss-of-function mechanisms.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4 N/A Not applicable: the VCEP states that phenotype specificity is accounted for under PS4 rather than PP4.
vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5 N/A Not applicable: the Brain Malformations VCEP explicitly marks PP5 as not applicable for this framework.
vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1 Not met Not met: the highest gnomAD v2.1 frequency was 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 gnomAD v2.1 frequency was 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 v2.1 reports 0 homozygotes, versus the VCEP requirement for at least 3 homozygotes or 3 qualifying family heterozygotes.
vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
BS3 Not met Not met: H1047L increased lipid binding, transformation, and growth-promoting activity rather than showing no damaging effect in functional assays.
cspec PMID:22120714 PMID:17376864 PMID:26627007
BS4 N/A Not applicable: the VCEP lists BS4, lack of segregation in affected family members, as N/A.
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1 N/A Not applicable: the VCEP states BP1 cannot be used because loss of function is not the disease mechanism.
cspec
BP2 Not assessed Not assessed: no documented cis/trans phase links c.3140A>T to another known pathogenic PIK3CA variant.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:15520168 PMID:26627007 PMID:22120714 PMID:17376864
BP3 N/A Not applicable: the VCEP excludes BP3 for this gene.
cspec
BP4 N/A Not applicable: BP4 covers synonymous, noncanonical intronic, or UTR variants, whereas c.3140A>T is a missense variant.
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP5 Not assessed Not assessed: no reviewed exact-variant report documents an alternate pathogenic molecular basis in a different gene, as BP5 requires.
vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:15520168
BP6 N/A Not applicable: the Brain Malformations VCEP explicitly marks BP6 as not applicable for this framework.
vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7 N/A Not applicable: BP7 covers synonymous, noncanonical intronic, or UTR variants, whereas c.3140A>T is a missense variant.
vcep_clingen_brainmalform_acmg_specifications_v1_1
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