Variant classification summary

NM_006218.4:c.1035T>A

PIK3CA · NP_006209.2:p.(Asn345Lys) · NM_006218.4

GRCh37: chr3:178921553 T>A · GRCh38: chr3:179203765 T>A

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PS3 supporting PM1 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Asn345Lys)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: p.N345K increased lipid kinase activity and oncogenic signaling in variant-specific functional studies.

2

PM1 supporting: residue 345 lies within the VCEP-approved PIK3CA kinase domain at amino acids 322-483.

Final determination: Under ACMG/AMP 2015 Table 5, PS3 supporting plus PM1 supporting does not satisfy any pathogenic, likely pathogenic, benign, or likely benign combination, resulting in 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: no distinct nucleotide change producing p.Asn345Lys was established as pathogenic under the BMVCEP criteria required for PS1.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 clinvar PMID:20593314 PMID:17376864 PMID:22949682
PS2	Not assessed	Not assessed: no proband allele fraction, parental testing, maternity or paternity confirmation, or affected-versus-other-tissue allele-fraction comparison is documented.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3	Met	Met at supporting: N345K increased basal lipid kinase activity versus wild type and was the second most potent activator in the 11-mutant assay panel.	cspec PMID:22949682 PMID:17376864
PS4	Not assessed	Not assessed: COSMIC reports 293 occurrences, but eligible separate primary tumors and the capped PS4 tumor-sample count cannot be verified.	cspec gnomad_v2 gnomad_v4 cosmic
PM1	Met	Met at supporting strength: residue 345 lies within the VCEP-approved PIK3CA kinase-domain interval 322-483.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Not assessed	Not assessed: the variant is absent from gnomAD v2.1 and v4.1, but the required ethnically matched cohort cannot be confirmed from available evidence.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: The VCEP excludes PM3 because disease-causing PIK3CA variants are heterozygous, regardless of any available phase observations.	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: no qualifying alternate missense change at residue 345 was available, and the comparator search was incomplete after an HTTP 429 error.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 pm5_candidates PMID:20593314 PMID:17376864 PMID:22949682
PM6	N/A	Not applicable: the VCEP directs that PM6 de novo evidence without confirmed maternity and paternity is addressed by PS2 and not used.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1	N/A	Not applicable: the VCEP excludes PP1 co-segregation evidence because these disease-causing variants are germline mosaic, de novo, or mosaic.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2	Not assessed	Not assessed: the required PIK3CA ExAC/gnomAD missense-constraint z-score is unavailable for comparison with the >3.09 threshold.	cspec
PP3	N/A	Not applicable: the VCEP excludes PP3 for these gain-of-function variants, including this PIK3CA missense variant.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4	N/A	Not applicable: the VCEP states that PP4 phenotype evidence is accounted for under PS4.	cspec
PP5	N/A	Not applicable: the VCEP prohibits PP5 use, regardless of the pathogenic ClinVar submissions.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its allele frequency is below the VCEP BA1 threshold of >0.0926%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its allele frequency is below the VCEP BS1 threshold of >0.0185%.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 report no variant observations, and no qualifying set of three well-phenotyped family heterozygotes is documented.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: N345K increased lipid kinase activity and oncogenic signaling, rather than showing the VCEP-required absence of damaging functional effects.	cspec PMID:22949682 PMID:17376864
BS4	N/A	Not applicable: the VCEP excludes BS4 lack-of-segregation evidence for de novo, germline mosaic, or post-zygotic mutations.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1	N/A	Not applicable: the VCEP excludes BP1 because PIK3CA brain-malformation disease is attributed to gain of function, not loss of function.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	Not assessed: No documented phase-tested pathogenic PIK3CA variant is reported in trans for a fully penetrant dominant disorder or in cis in any inheritance pattern.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3	N/A	Not applicable: the VCEP excludes BP3 for this gene.	cspec
BP4	N/A	Not applicable: BP4 is limited to synonymous, eligible intronic, or UTR variants, whereas this variant is missense.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 spliceai
BP5	Not assessed	Not assessed: no patient-level case shows this variant with an alternate molecular basis for disease in a different gene.	cspec clinvar cosmic
BP6	N/A	Not applicable: the VCEP prohibits BP6 use for this framework.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous, eligible intronic, or UTR variants, but this variant changes the PIK3CA protein to p.Asn345Lys.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1

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