Variant classification summary

NM_006218.4:c.268T>C

PIK3CA · NP_006209.2:p.(Cys90Arg) · NM_006218.4

GRCh37: chr3:178916881 T>C · GRCh38: chr3:179199093 T>C

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.(Cys90Arg)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 (Supporting): residue 90 falls in the critical PI3K adaptor-binding domain (amino acids 31-108).

2

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

3

Overall: VUS - two supporting pathogenic criteria (PM1 + PM2) are below the ACMG/AMP 2015 combination threshold for pathogenic or likely pathogenic.

Final determination: Under the generic ACMG/AMP 2015 fallback, two supporting pathogenic criteria alone meet neither a pathogenic nor likely pathogenic combination, so 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 change, so the null-variant mechanisms PVS1 requires (nonsense-mediated decay, truncation, canonical splice disruption) do not apply.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no pathogenic variant causing the same amino-acid change (p.Cys90Arg) has been previously established; the only ClinVar record is of Uncertain significance.	cspec clinvar
PS2	Not assessed	Not assessed: no de novo documentation was available - no parental testing, maternity/paternity confirmation, or tissue comparison - so PS2 could not be awarded.	cspec
PS3	Not assessed	Not assessed: no validated functional assay tested this exact variant; studies of the similar C90Y substitution cannot establish an effect for C90R.	cspec
PS4	Not assessed	Not assessed: no affected cerebral-malformation cases with phenotype-point assignments or case-control enrichment data were available; one somatic cancer occurrence is insufficient.	cspec gnomad_v2 gnomad_v4
PM1	Met	Met (Supporting): residue 90 falls within the PI3K adaptor-binding domain (amino acids 31-108), a critical functional domain in the approved table.	cspec
PM2	Met	Met (Supporting): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: PIK3CA brain-malformation variants are heterozygous, so the recessive in-trans requirement does not apply.	cspec
PM4	N/A	Not applicable: this missense substitution does not change protein length, so there is nothing for PM4 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: the same-residue comparator C90Y was not established as pathogenic; its study reported no increased activity or tumorigenic phenotype.	cspec pm5_candidates PMID:29975751
PM6	N/A	Not applicable: the VCEP addresses de novo evidence through PS2, so PM6 is not used.	cspec
PP1	N/A	Not applicable: disease-causing variants here are germline mosaic or de novo, not evaluated through familial cosegregation.	cspec
PP2	Not assessed	Not assessed: the required missense-constraint z-score (threshold >3.09) was not available.	cspec
PP3	N/A	Not applicable: PIK3CA acts through gain of function, and prediction tools built for loss-of-function mechanisms do not apply.	cspec
PP4	N/A	Not applicable: phenotype specificity is already accounted for under PS4 in this framework.	cspec
PP5	N/A	Not applicable: the VCEP does not use PP5, and the only ClinVar record is a single non-expert Uncertain significance submission.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >0.0926% BA1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from population databases, below the >0.0185% BS1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no gnomAD homozygotes and no heterozygous observations in well-phenotyped family members were available.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no well-established functional study of this exact variant showing a benign effect was available.	cspec
BS4	N/A	Not applicable: these are de novo, germline mosaic, or post-zygotic mutations, so lack of familial segregation is not used as BS4.	cspec
BP1	N/A	Not applicable: loss of function is not the disease mechanism; these brain-malformation disorders follow a gain-of-function mechanism.	cspec
BP2	Not assessed	Not assessed: no cis/trans phase information with a known pathogenic PIK3CA variant was available.	cspec
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame insertion/deletion in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: BP4 is limited to synonymous or non-coding splice-site variants; this is a missense change.	cspec spliceai
BP5	Not assessed	Not assessed: no report shows this variant in a person whose phenotype has an established alternate molecular basis.	cspec
BP6	N/A	Not applicable: the VCEP does not use BP6, and the only ClinVar record is a single non-expert Uncertain significance submission.	cspec clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous silent variant, so the BP7 premise does not hold.	generic_acmg_combination_rules

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