Variant classification summary

NM_006218.4:c.278G>T

PIK3CA · NP_006209.2:p.(Arg93Leu) · NM_006218.4

GRCh37: chr3:178916891 G>T · GRCh38: chr3:179199103 G>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.(Arg93Leu)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 (Supporting): p.Arg93Leu lies within the approved PI3K adaptor-binding domain (residues 31-108).

2

PM2 (Supporting): the variant is absent from gnomAD v2.1, gnomAD-Canada v1.0, and gnomAD v4.1 (0 of 1,611,098 alleles).

3

Synthesis: PM1 and PM2 at Supporting strength do not meet a pathogenic combination threshold under the generic ACMG/AMP 2015 rules, and no benign criteria apply, yielding a classification of VUS.

Final determination: Under the generic ACMG/AMP 2015 fallback, two supporting pathogenic criteria alone do not meet any pathogenic or likely pathogenic combination and therefore yield 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: p.Arg93Leu is a missense substitution, so no null-variant mechanism such as nonsense-mediated decay is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no ClinVar record or literature documented a previously established pathogenic variant producing the same amino-acid change.	cspec clinvar
PS2	Not assessed	Not assessed: no proband or parental testing evidence was available to establish a de novo occurrence.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay evidence was available to demonstrate a damaging effect.	cspec
PS4	Not assessed	Not assessed: no affected individuals, phenotype, or case-control data were available to establish enrichment.	cspec gnomad_v2 gnomad_v4
PM1	Met	Met (Supporting): residue 93 lies within the approved PI3K adaptor-binding domain (residues 31-108).	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Met	Met (Supporting): absent from gnomAD v2.1, gnomAD-Canada v1.0, and gnomAD v4.1 (0 of 1,611,098 alleles).	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the VCEP restricts PM3 to recessive disease, and PIK3CA variants in this context are heterozygous.	cspec
PM4	N/A	Not applicable: this missense substitution causes no protein length change, so the criterion has nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense change at residue 93 was documented to serve as a comparator.	cspec pm5_candidates
PM6	N/A	Not applicable: the VCEP addresses presumed de novo evidence through PS2 instead.	cspec
PP1	N/A	Not applicable: the VCEP does not use familial cosegregation because PIK3CA disease variants are de novo or mosaic.	cspec
PP2	Not assessed	Not assessed: the PIK3CA missense-constraint z-score was not available to test against the >3.09 threshold.	cspec gnomad_v4 gnomad_v2
PP3	N/A	Not applicable: the VCEP excludes PP3 because PIK3CA disease variants are gain-of-function.	cspec
PP4	N/A	Not applicable: the VCEP incorporates phenotype evidence under PS4.	cspec
PP5	N/A	Not applicable: not used under this VCEP, and the variant has no ClinVar record to evaluate.	cspec clinvar
BA1	Not met	Not met: allele frequency 0.0 in gnomAD v4.1, far below the >0.0926% BA1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: allele frequency 0.0 in gnomAD v4.1, below the >0.0185% BS1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: gnomAD v4.1 reports 0 homozygotes versus the 3 required.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no functional assay evidence was available to show the variant has no damaging effect.	cspec
BS4	N/A	Not applicable: the VCEP does not apply BS4 because these variants arise de novo or as mosaics.	cspec
BP1	N/A	Not applicable: loss of function is not the PIK3CA disease mechanism, so BP1 is excluded.	cspec
BP2	Not assessed	Not assessed: no family, parental, or phase evidence was available to evaluate a second PIK3CA variant.	cspec
BP3	N/A	Not applicable: this missense substitution does not alter protein length within a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: BP4 is limited to synonymous, non-canonical intronic, or UTR variants, not missense.	cspec
BP5	Not assessed	Not assessed: no patient-level workup showing an alternate molecular basis for the phenotype was available.	cspec
BP6	N/A	Not applicable: not used under this VCEP, and the variant has no ClinVar record to evaluate.	cspec clinvar
BP7	N/A	Not applicable: the silent-variant premise does not hold for this missense substitution.	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.