NM_006218.4:c.1407_1409del

PIK3CA · NP_006209.2:p.(Glu469_Thr470delinsAsp) · NM_006218.4

GRCh37: chr3:178928220 AAAC>A · GRCh38: chr3:179210432 AAAC>A

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.(Glu469_Thr470delinsAsp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM1 supporting: residues 469-470 fall within the VCEP-approved PIK3CA kinase domain spanning amino acids 322-483.

PM2 supporting: the variant is absent from the queried gnomAD v2.1 and v4.1 datasets.

Final determination: Under ACMG/AMP 2015 Table 5, two supporting criteria alone do not satisfy any pathogenic, likely pathogenic, benign, or likely benign 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: the VCEP excludes PVS1 for this gene.	cspec
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules cspec
PS2	Not assessed	Not assessed: no proband, parental-testing, maternity/paternity, or tissue allele-fraction evidence is available to evaluate the VCEP PS2 criteria.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay publication, experimental result, or assay-control data are available to evaluate the VCEP PS3 requirements.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PS4	Not assessed	Not assessed: gnomAD absence supports the PM2 prerequisite, but no affected-person phenotype data are available to assign PS4 Table 2A points.	vcep_clingen_brainmalform_acmg_specifications_v1_1 gnomad_v2 gnomad_v4
PM1	Met	Met, Supporting: PIK3CA residues 469-470 fall within the VCEP-approved kinase domain spanning amino acids 322-483.	vcep_clingen_brainmalform_acmg_specifications_v1_1 cspec
PM2	Met	Met at Supporting: the variant was absent from gnomAD v2.1 and v4.1, satisfying the VCEP one-person-maximum rarity rule, pending ancestry-match confirmation.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the VCEP states disease-causing variants are heterozygous.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM4	N/A	Not applicable: the VCEP explicitly does not use PM4 for these genes, including rare in-frame indels that might produce gain of function.	cspec
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules cspec
PM6	N/A	Not applicable: the VCEP states that 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	N/A	Not applicable: PP2 is restricted to missense variants, whereas this variant is an in-frame deletion/indel consequence.	vcep_clingen_brainmalform_acmg_specifications_v1_1 cspec
PP3	N/A	Not applicable: the VCEP excludes PP3 for these gain-of-function PIK3CA variants, regardless of available computational predictor scores.	cspec
PP4	N/A	Not applicable: the VCEP explicitly accounts for phenotype specificity under PS4 rather than PP4.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5	N/A	Not applicable: the VCEP prohibits PP5 use under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BA1 allele-frequency threshold of 0.0926%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP BS1 allele-frequency threshold of 0.0185%.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD contained no variant record and no evidence showed the VCEP-required minimum of 3 homozygotes or 3 well-phenotyped heterozygous relatives.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific benign functional result or assay-control data are available to evaluate the VCEP BS3 requirements or strength.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BS4	N/A	Not applicable: the VCEP excludes BS4 for de novo, germline mosaic, or post-zygotic mutations.	cspec
BP1	N/A	Not applicable: the VCEP excludes BP1 for this gene.	cspec
BP2	Not assessed	Not assessed: no documented cis/trans phase with a known pathogenic PIK3CA variant is available.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3	N/A	Not applicable: the VCEP states these genes lack exon regions that are repetitive and without a known function.	cspec
BP4	N/A	Not applicable: BP4 covers only synonymous, noncanonical intronic, or UTR variants, whereas this is an exonic in-frame deletion.	cspec spliceai
BP5	Not assessed	Not assessed: no affected case with an alternate molecular basis for disease is available to evaluate BP5.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BP6	N/A	Not applicable: the VCEP explicitly prohibits BP6 use under the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7	N/A	Not applicable: BP7 is restricted to synonymous, noncanonical intronic, or UTR variants, while this variant is an exonic in-frame deletion.	cspec

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