Variant classification summary

NM_006218.4:c.1037T>G

PIK3CA · NP_006209.2:p.(Val346Gly) · NM_006218.4

GRCh37: chr3:178921555 T>G · GRCh38: chr3:179203767 T>G

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PS4 supporting PM1 supporting PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Val346Gly)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS4 Supporting: two COSMIC tumor occurrences contribute the VCEP threshold score of 0.50 points.

2

PM1 Supporting: p.Val346Gly affects residue 346 within the VCEP-approved PIK3CA kinase domain at residues 322-483.

3

PM2 Supporting: the variant is absent from the available gnomAD and non-cancer control datasets.

Final determination: Under ACMG/AMP 2015 Table 5, three Supporting criteria alone satisfy none of the Pathogenic, Likely Pathogenic, Benign, or Likely Benign combinations, 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 assessed	Not assessed: no independently established pathogenic same-amino-acid comparator with a different nucleotide change was available.	vcep_clingen_brainmalform_acmg_specifications_v1_1 clinvar
PS2	Not assessed	Not assessed: proband allele fraction, parental maternity/paternity testing, and affected-versus-other-tissue allele fractions are unavailable for the required PS2 criteria.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3	Not assessed	Not assessed: no variant-specific functional assay or qualifying validation-control data were available to satisfy the VCEP PS3 acceptability criteria.	vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:27631024
PS4	Met	Met at Supporting: two COSMIC occurrences contribute 0.50 points, and 0.50 >= 0.5 satisfies the VCEP PS4_Supporting range after PM2.	cspec gnomad_v2 gnomad_v4 cosmic vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:23946963 PMID:27631024
PM1	Met	Met, Supporting: residue 346 falls within the VCEP-approved PIK3CA kinase-domain interval 322-483.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Met	Met at Supporting: the variant was absent from gnomAD v2.1, v4.1, and both available non-cancer subsets, satisfying the VCEP's absent-or-rare controls requirement.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the VCEP states that PM3 is not applicable because disease-causing PIK3CA variants 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: no qualifying pathogenic different-missense comparator at residue Val346 was established, and candidate retrieval was incomplete.	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.	cspec 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.	cspec 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 3.09.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3	N/A	Not applicable: the VCEP excludes PP3 for these gain-of-function disorders because traditional pathogenicity predictors focus on loss-of-function mechanisms.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4	N/A	Not applicable: the VCEP states that PP4 phenotype specificity is accounted for under PS4.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5	N/A	Not applicable: the VCEP prohibits PP5 use for this framework, regardless of the ClinVar pathogenic submission.	cspec clinvar vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1	Not met	Not met: the variant was absent from gnomAD v2.1, v4.1, and non-cancer subsets, rather than exceeding the VCEP's >0.0926% allele-frequency threshold.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant was absent from gnomAD v2.1, v4.1, and non-cancer subsets, rather than exceeding the VCEP's >0.0185% allele-frequency threshold.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD reported no variant observation, so there are not the VCEP-required ≥3 homozygotes and no qualifying family-member count is available.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific benign functional result or qualifying validation-control data were available under the VCEP BS3 requirements.	vcep_clingen_brainmalform_acmg_specifications_v1_1 PMID:27631024
BS4	N/A	Not applicable: the VCEP excludes BS4 for de novo, germline mosaic, or post-zygotic mutations.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1	N/A	Not applicable: the VCEP states BP1 is unavailable because loss of function is not the disease mechanism.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	Not assessed: no documented cis/trans phase relationship with a known pathogenic PIK3CA variant is available for this variant.	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 covers synonymous, noncanonical intronic, or UTR variants, while this variant is a missense coding substitution.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP5	Not assessed	Not assessed: no documented exact-variant case has an alternate molecular basis in a different gene.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP6	N/A	Not applicable: the VCEP prohibits BP6 use for this framework, regardless of any benign-source report.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7	N/A	Not applicable: BP7 is restricted to synonymous, noncanonical intronic, or noncoding UTR variants, not missense coding substitutions.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1

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