Variant classification summary

NM_006218.4:c.1346C>T

PIK3CA · NP_006209.2:p.(Pro449Leu) · NM_006218.4

GRCh37: chr3:178928068 C>T · GRCh38: chr3:179210280 C>T

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM1 supporting PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Pro449Leu)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 (Supporting): residue 449 lies in the VCEP-approved PIK3CA kinase-domain interval (AA 322-483).

2

PM2 (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

3

Overall: VUS - PM1 and PM2 at Supporting strength are the only met criteria, and two supporting pathogenic criteria do not satisfy the ACMG/AMP 2015 Likely Pathogenic combination.

Final determination: Under the generic ACMG/AMP 2015 fallback, two supporting pathogenic criteria alone meet no benign, likely benign, likely pathogenic, or pathogenic combination threshold; therefore the classification 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: this is a missense substitution (p.Pro449Leu), so no null-variant mechanism such as nonsense-mediated decay applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: the known same-residue variant is p.Pro449Thr, a different amino-acid change from this p.Pro449Leu.	PMID:20530683
PS2	Not assessed	Not assessed: no proband assay details, parental genotypes, or allele-fraction data were available to confirm a de novo origin.	cspec
PS3	Not assessed	Not assessed: the functional paper tested p.Pro449Thr, not p.Pro449Leu, so its gain-of-function result cannot be transferred to this variant.	cspec PMID:20530683
PS4	Not met	Not met: tumor observations contribute only 0.25 point per category, below the 0.5-point PS4 supporting threshold.	cspec gnomad_v2 gnomad_v4
PM1	Met	Met (Supporting): residue 449 lies in the PIK3CA kinase-domain interval AA 322-483 approved in the VCEP specification.	cspec
PM2	Met	Met (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the VCEP rarity threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: a recessive criterion, but PIK3CA disease variants here are heterozygous.	cspec
PM4	N/A	Not applicable: missense substitution causes no protein-length change, so there is nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: p.Pro449Thr is not established as a pathogenic clinical variant, and no qualifying same-residue candidate was found.	PMID:20530683 pm5_candidates
PM6	N/A	Not applicable: the VCEP designates PM6 not applicable, with this evidence addressed under PS2.	cspec
PP1	N/A	Not applicable: the VCEP excludes segregation evidence because these variants are typically de novo or mosaic.	cspec
PP2	Not assessed	Not assessed: no PIK3CA missense-constraint z-score was available to test the >3.09 requirement.	cspec
PP3	N/A	Not applicable: the VCEP excludes prediction tools because the PIK3CA disease mechanism is gain of function.	cspec
PP4	N/A	Not applicable: phenotype specificity is already accounted for under the PS4 point-based framework.	cspec
PP5	N/A	Not applicable: the VCEP disallows PP5, and the ClinVar record contains no expert-panel submission.	cspec clinvar
BA1	Not met	Not met: absent from gnomAD, so allele frequency is far below the >0.0926% BA1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD, so allele frequency is far below the >0.0185% BS1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no homozygotes or well-phenotyped family-member observations meet the required three occurrences.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no assay directly testing p.Pro449Leu demonstrated a benign effect; the available study tested p.Pro449Thr.	cspec PMID:20530683
BS4	N/A	Not applicable: the VCEP excludes BS4 for these de novo, germline-mosaic, or post-zygotic mutations.	cspec
BP1	N/A	Not applicable: loss of function is not the disease mechanism for PIK3CA, which acts by gain of function.	cspec
BP2	Not assessed	Not assessed: no second pathogenic PIK3CA variant or phase information was available to establish co-occurrence.	cspec clinvar
BP3	N/A	Not applicable: missense substitution does not alter protein length within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: BP4 is restricted to synonymous, intronic, or UTR variants, and this is a missense change.	cspec spliceai
BP5	Not assessed	Not assessed: no evidence of an alternate molecular diagnosis explaining the presenting disease was available.	cspec
BP6	N/A	Not applicable: the VCEP disallows BP6, and no expert-panel benign assertion exists in the ClinVar record.	cspec clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this missense change alters the protein sequence.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.