NM_006218.4:c.2107_2121dup

PIK3CA · NP_006209.2:p.(Asn703_Glu707dup) · NM_006218.4

GRCh37: chr3:178938863 T>TGAATAGGCAAGTCGA · GRCh38: chr3:179221075 T>TGAATAGGCAAGTCGA

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Asn703_Glu707dup)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

Final determination: Under the VCEP's ACMG/AMP 2015 Table 5 framework, no pathogenic or benign combination threshold is met when no criterion is applied, resulting in a 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, confirmed maternity/paternity, allele-fraction, or cross-tissue evidence is available to evaluate the VCEP PS2 criteria.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3	Not assessed	Not assessed: no variant-specific functional assay, controls, or validated measurements are available to apply the VCEP PS3 acceptability requirements.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS4	Not met	Not met: no affected carrier or case-control observation was identified, so the VCEP Table 2A phenotype score is 0 points.	cspec gnomad_v2 gnomad_v4
PM1	Not met	Not met: p.Asn703_Glu707dup spans residues 703-707, outside all approved PIK3CA domains (31-108, 173-292, 322-483, and 797-1068).	vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Not assessed	Not assessed: the variant is absent from gnomAD, but no available dataset identifies an ethnically matched cohort as required by the VCEP PM2 rule.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the VCEP states PM3 is not applicable because disease-causing variants are heterozygous.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM4	N/A	Not applicable: the VCEP does not use PM4 for these genes, despite this variant being a five-amino-acid in-frame duplication.	cspec pvs1_variant_assessment
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 explicitly assigns confirmed de novo evidence without parental confirmation to PS2 rather than PM6.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1	N/A	Not applicable: the VCEP excludes PP1 because the relevant disease-causing variants are germline mosaic, de novo, or mosaic.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2	N/A	Not applicable: the VCEP PP2 rule is for missense variants with a constraint z-score >3.09, whereas this variant is an in-frame duplication.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3	N/A	Not applicable: the VCEP explicitly excludes PP3 for these gain-of-function variants.	vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4	N/A	Not applicable: the VCEP explicitly accounts for phenotype specificity under PS4 rather than PP4.	cspec
PP5	N/A	Not applicable: the VCEP prohibits use of PP5 under the ClinGen Sequence Variant Interpretation recommendation.	cspec
BA1	Not met	Not met: the variant was absent from all queried gnomAD datasets, 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 all queried gnomAD datasets, rather than exceeding the VCEP BS1 allele-frequency threshold of >0.0185%.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD reports no occurrence of the variant, and no evidence shows the VCEP-required three homozygotes or three well-phenotyped family heterozygotes.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific benign functional study with the VCEP-required controls and quality metrics is available for BS3.	cspec 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 in this disease framework.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1	N/A	Not applicable: the VCEP excludes BP1 for this gene.	cspec
BP2	Not assessed	Not assessed: no cis/trans observation with a known pathogenic PIK3CA variant is documented.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3	N/A	Not applicable: the VCEP states these genes lack exon repetitive regions without known function, the required BP3 context.	cspec pvs1_variant_assessment
BP4	N/A	Not applicable: BP4 is limited to synonymous, noncanonical intronic, or UTR variants, whereas this is an exonic in-frame duplication.	vcep_clingen_brainmalform_acmg_specifications_v1_1
BP5	Not assessed	Not assessed: no case record establishes that the variant occurred with an alternate molecular basis for disease in a different gene.	cspec
BP6	N/A	Not applicable: the VCEP explicitly excludes BP6 from use for this framework.	cspec
BP7	N/A	Not applicable: BP7 is restricted to synonymous, noncanonical intronic, or UTR variants, not this exonic in-frame duplication.	vcep_clingen_brainmalform_acmg_specifications_v1_1

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