Variant classification summary

NM_006218.4:c.1214C>A

PIK3CA · NP_006209.2:p.(Ser405Tyr) · NM_006218.4

GRCh37: chr3:178927451 C>A · GRCh38: chr3:179209663 C>A

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.(Ser405Tyr)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 (Supporting): residue 405 falls within the PIK3CA kinase domain (residues 322-483).

2

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

3

Final classification: VUS — two supporting pathogenic criteria do not reach any pathogenic or likely pathogenic combination threshold under the applied ACMG/AMP 2015 combination rules.

Final determination: Under the generic ACMG/AMP 2015 fallback, two supporting pathogenic criteria alone do not meet a pathogenic or likely pathogenic combination; in the absence of qualifying benign evidence, 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 missense variant causes no loss-of-function mechanism such as nonsense-mediated decay or truncation.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no pathogenic p.Ser405Tyr comparator was available, so this criterion could not be evaluated.	cspec clinvar
PS2	Not assessed	Not assessed: no proband or parental genotype data, tissue allele fractions, or confirmation of maternity and paternity were available.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay evidence for p.Ser405Tyr was available.	cspec
PS4	Not assessed	Not assessed: no affected-individual, phenotype, case-control, or variant-specific literature data were provided.	cspec gnomad_v2 gnomad_v4
PM1	Met	Met (Supporting): residue 405 falls within the PIK3CA kinase domain (residues 322-483).	cspec
PM2	Met	Met (Supporting): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: PM3 applies to recessive disorders with a pathogenic variant in trans; PIK3CA disease variants are heterozygous.	cspec
PM4	N/A	Not applicable: no protein length change occurs, since this is a missense substitution, not an insertion, deletion, or stop-loss.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no pathogenic missense variant at residue 405 was identified for comparison.	cspec pm5_candidates
PM6	N/A	Not applicable: the VCEP handles assumed de novo evidence under PS2 rather than PM6.	cspec
PP1	N/A	Not applicable: familial co-segregation evidence does not apply to de novo or mosaic disease variants under the VCEP.	cspec
PP2	Not assessed	Not assessed: the required PIK3CA missense-constraint z-score (>3.09) was not available.	cspec
PP3	N/A	Not applicable: PIK3CA brain-malformation variants act through gain of function, which computational predictors do not capture.	cspec
PP4	N/A	Not applicable: phenotype evidence is already accounted for under PS4.	cspec
PP5	N/A	Not applicable: the VCEP does not permit PP5, and ClinVar holds only one non-expert uncertain-significance submission.	cspec clinvar
BA1	Not met	Not met: the variant is absent from population databases, so no allele frequency exceeds the BA1 threshold of 0.0926%.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from population databases, so no allele frequency exceeds the BS1 threshold of 0.0185%.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: the required three homozygotes or qualifying family observations were absent.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no variant-specific benign functional assay evidence was available.	cspec
BS4	N/A	Not applicable: lack of segregation does not apply to de novo or mosaic disease variants under the VCEP.	cspec
BP1	N/A	Not applicable: BP1 targets truncating loss-of-function disorders, whereas PIK3CA acts through gain of function.	cspec
BP2	Not assessed	Not assessed: no data showed this variant in cis or trans with a known pathogenic PIK3CA variant.	cspec clinvar
BP3	N/A	Not applicable: the variant is a missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: BP4 is restricted to synonymous, intronic, or UTR variants; this variant is missense.	cspec
BP5	Not assessed	Not assessed: no alternate molecular diagnosis explaining the phenotype was identified.	cspec
BP6	N/A	Not applicable: the VCEP does not permit BP6, and no expert benign ClinVar assertion exists.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants only; this missense variant 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.