Variant classification summary

NM_006218.4:c.1624G>A

PIK3CA · NP_006209.2:p.(Glu542Lys) · NM_006218.4

GRCh37: chr3:178936082 G>A · GRCh38: chr3:179218294 G>A

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PS3 supporting PS4 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Glu542Lys)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Supporting: p.E542K increased PI3K-alpha enzymatic activity, supporting a damaging gain-of-function effect.

2

PS4 Supporting: one hemimegalencephaly point plus 0.25 tumor-occurrence points totals 1.25 VCEP points.

Final determination: Under ACMG/AMP 2015 Table 5, two Supporting pathogenic criteria alone do not meet a Pathogenic or Likely Pathogenic rule, and no benign rule is met, so the result 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 met	Not met: the pathogenic record is the same c.1624G>A variant, with no alternate-nucleotide Glu542Lys record identified for PS1.	vcep_clingen_brainmalform_acmg_specifications_v1_1 clinvar
PS2	Not assessed	Not assessed: HME-3 had mosaic E542K at 28% alternate allele frequency, but confirmed parental absence and the required cross-tissue comparison were not reported.	vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:25599672
PS3	Met	Met at Supporting: p.E542K increased PI3Kα enzymatic activity to a magnitude similar to activation by physiological effectors, but stronger calibration controls are undocumented.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:20593314
PS4	Met	Met at Supporting: 1.25 VCEP phenotype points (1.0 hemimegalencephaly case plus 0.25 tumor occurrence) fall within the 0.5-1.25 PS4 Supporting range.	cspec gnomad_v2 gnomad_v4 PMID:25599672 cosmic
PM1	Not met	Not met: residue 542 is outside every approved PIK3CA domain interval, including 322-483 and 797-1068.	vcep_clingen_brainmalform_acmg_specifications_v1_1 cspec PMID:20593314
PM2	Not assessed	Not assessed: the variant is absent from four gnomAD datasets, but the available evidence does not establish an ethnically matched cohort as required by the VCEP PM2 rule.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the VCEP excludes PM3 because disease-causing variants in this framework are heterozygous.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM4	N/A	Not applicable: the VCEP excludes PM4 for this gene.	cspec
PM5	Not assessed	Not assessed: the comparator search found 0 same-residue candidates but ended with HTTP 429, so absence of a qualifying PM5 variant is unconfirmed.	vcep_clingen_brainmalform_acmg_specifications_v1_1 pm5_candidates
PM6	N/A	Not applicable: the VCEP states that PM6 is addressed according to PS2 and will not be used.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1	N/A	Not applicable: the VCEP excludes PP1 because disease-causing variants are germline mosaic, de novo, or mosaic.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2	Not assessed	Not assessed: the required ExAC/gnomAD missense-constraint z-score is unavailable, so it cannot be compared with the >3.09 threshold.	cspec
PP3	N/A	Not applicable: the VCEP excludes PP3 for gain-of-function PIK3CA variants, including this missense p.E542K substitution.	cspec
PP4	N/A	Not applicable: the VCEP explicitly accounts for this phenotype evidence under PS4.	cspec
PP5	Met	Not applicable: the VCEP prohibits use of PP5 for this framework.	cspec clinvar
BA1	Not met	Not met: the variant was absent from gnomAD v2.1, v4.1, v2.1 non-cancer, and v3.1 non-cancer, rather than exceeding the >0.0926% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant was absent from gnomAD v2.1, v4.1, v2.1 non-cancer, and v3.1 non-cancer, rather than exceeding the >0.0185% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD reported the variant absent with no homozygote count, and no qualifying set of at least 3 well-phenotyped family observations is available.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: the available p.E542K assay reports increased PI3Kα activity, not a validated absence of damaging effect on protein function.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:20593314
BS4	N/A	Not applicable: the VCEP states that BS4 does not apply because disease-causing variants are de novo, germline mosaic, or mosaic.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1	N/A	Not applicable: the VCEP excludes BP1 because loss of function is not the disease mechanism.	vcep_clingen_brainmalform_acmg_specifications_v1_1 cspec
BP2	Not assessed	Not assessed: p.E542K is reported in HME-3, but no cis/trans phase or pathogenic same-gene partner is documented.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:25599672
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 p.E542K is a coding missense substitution.	cspec
BP5	Not assessed	Not assessed: the reported HME-3 case lacks documented evidence of an alternate disease-causing variant in a different gene.	cspec PMID:25599672
BP6	N/A	Not applicable: the VCEP explicitly excludes BP6.	cspec
BP7	N/A	Not applicable: BP7 requires a synonymous, non-canonical intronic, or UTR variant, but p.E542K is a coding missense substitution.	cspec

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