Variant classification summary

NM_006218.4:c.1258T>C

PIK3CA · NP_006209.2:p.(Cys420Arg) · NM_006218.4

GRCh37: chr3:178927980 T>C · GRCh38: chr3:179210192 T>C

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PS3 supporting PM1 supporting PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Cys420Arg)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PS3 Supporting reflects increased C420R lipid kinase activity and downstream signaling in functional assays.

2

VUS: PM1 Supporting reflects C420R localization within the VCEP-approved PIK3CA kinase domain at amino acids 322-483.

3

VUS: PM2 Supporting reflects absence of the variant from gnomAD v2.1 and v4.1.

Final determination: Under ACMG/AMP 2015 Table 5, three Supporting pathogenic criteria alone do not satisfy any Pathogenic or Likely Pathogenic rule, and no benign criterion satisfies a benign rule; therefore 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: no distinct alternate nucleotide change producing the same pathogenic p.Cys420Arg amino-acid change was identified for comparison.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS2	Not assessed	Not assessed: no human proband allele fraction, confirmed maternity/paternity, parental testing, or affected-tissue comparative allele-fraction data are available.	cspec
PS3	Met	Met at Supporting: C420R increased lipid kinase activity versus wild type and activated downstream signaling in independent functional assays.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:22949682 PMID:15930273
PS4	Not met	Not met: the highest conservatively verified PS4 score is 0.25 tumor-presence points, below the VCEP PS4_Supporting range of 0.5–1.25 points.	cspec gnomad_v2 gnomad_v4 cosmic PMID:31996845 PMID:21266528
PM1	Met	Met at Supporting: PIK3CA residue 420 lies within the VCEP-approved kinase domain spanning residues 322-483.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, within the VCEP PM2 limit of one person maximum.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
PM3	N/A	Not applicable: the VCEP excludes PM3 because disease-causing PIK3CA variants are heterozygous.	cspec
PM4	N/A	Not applicable: the VCEP excludes PM4 for this gene.	cspec
PM5	Not assessed	Not assessed: the comparator collection found 0 same-residue candidates at PIK3CA C420, but retrieval was incomplete.	cspec pm5_candidates vcep_clingen_brainmalform_acmg_specifications_v1_1
PM6	N/A	Not applicable: the VCEP states PM6 is addressed according to PS2 and will not be used.	cspec
PP1	N/A	Not applicable: the VCEP excludes PP1 because disease-causing variants are germline mosaic, de novo, or mosaic.	cspec
PP2	Not assessed	Not assessed: the VCEP requires a PIK3CA ExAC/gnomAD missense-constraint z-score >3.09, but that z-score is unavailable.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3	N/A	Not applicable: the VCEP excludes PP3 for these gain-of-function variants, regardless of available computational predictor scores.	cspec
PP4	N/A	Not applicable: the VCEP explicitly accounts for phenotype specificity under PS4 rather than applying PP4 separately.	cspec
PP5	N/A	Not applicable: the VCEP explicitly marks PP5 as not applicable, regardless of available pathogenic assertions.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BA1 threshold of >0.0926%.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BS1 threshold of >0.0185%.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
BS2	Not met	Not met: gnomAD v2.1 and v4.1 report no variant, so the required ≥3 homozygotes or ≥3 well-phenotyped family observations are not documented.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
BS3	Not met	Not met: C420R increased lipid kinase activity and downstream Akt/p70S6K activation rather than showing no damaging effect.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:22949682 PMID:15930273
BS4	N/A	Not applicable: the VCEP excludes BS4 because these mutations are de novo, germline mosaic, or post-zygotic.	cspec
BP1	N/A	Not applicable: the VCEP excludes BP1 because loss of function is not the disease mechanism.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	Not assessed: no documented cis/trans pathogenic PIK3CA variant or phase result is available for this case.	cspec
BP3	N/A	Not applicable: the VCEP excludes BP3 for this gene.	cspec
BP4	N/A	Not applicable: BP4 is restricted to synonymous, non-canonical intronic, or UTR variants, whereas this variant is missense.	cspec
BP5	Not assessed	Not assessed: no qualifying case documents C420R with an alternate molecular diagnosis in a different gene under the VCEP BP5 rule.	cspec
BP6	N/A	Not applicable: the VCEP prohibits BP6 use under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	Not applicable: BP7 is limited to synonymous, non-canonical intronic, or UTR variants, whereas this variant is missense.	cspec

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