Variant classification summary

NM_006218.4:c.562+14T>G

PIK3CA · NP_006209.2:p.? · NM_006218.4

GRCh37: chr3:178917701 T>G · GRCh38: chr3:179199913 T>G

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1, PM4, and BP3 are all explicitly not applicable under the governing ClinGen Brain Malformations VCEP specification.

2

PM3 is not applicable under the VCEP's heterozygous disease model.

3

BP2 cannot be assessed without documented cis/trans phase with a known pathogenic PIK3CA variant.

Final determination: Under the VCEP's ACMG/AMP 2015 Table 5 framework, criteria that meet neither a pathogenic nor benign combination result in a Variant of Uncertain Significance.

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 states that brain-malformation disease in these genes is gain of function, so PVS1 is not used regardless of this intronic variant's p.? consequence.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 pvs1_variant_assessment
PS1	N/A	Not applicable: c.562+14T>G is intronic with protein consequence p.?, so no amino-acid change exists for PS1 comparison.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS2	Not assessed	Not assessed: no documented proband allele fraction, confirmed parental testing, or affected-versus-other-tissue allele-fraction comparison is available for this variant.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3	Not assessed	Not assessed: no variant-specific functional assay results or required validation controls were available to apply the VCEP PS3 requirements.	cspec
PS4	Not assessed	Not assessed: controls are absent, but no affected-case phenotype points or case-control counts are available for the VCEP PS4 thresholds.	cspec gnomad_v2 gnomad_v4 gnomad_canada vcep_clingen_brainmalform_acmg_specifications_v1_1
PM1	N/A	Not applicable: the variant is intronic with no residue, while PM1 requires location in an approved functional-domain exon.	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 an ethnically matched control cohort required by the VCEP is not documented.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
PM3	N/A	Not applicable: the VCEP states that 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, and c.562+14T>G is intronic rather than an in-frame indel or stop-loss variant.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 pvs1_variant_assessment
PM5	N/A	Not applicable: c.562+14T>G is intronic with protein consequence p.?, not a novel missense change at an amino-acid residue.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM6	N/A	Not applicable: the VCEP directs that assumed de novo evidence without confirmed maternity and paternity is addressed under PS2 and PM6 will not be used.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1	N/A	Not applicable: the VCEP excludes family co-segregation because disease-causing variants are germline mosaic, de novo, or mosaic.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2	N/A	Not applicable: PP2 is restricted to missense variants, but c.562+14T>G is intronic with protein consequence p.?.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3	N/A	Not applicable: The VCEP excludes PP3 for these gain-of-function variants because traditional pathogenicity algorithms focus on loss-of-function mechanisms.	cspec 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 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.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1	Not met	Not met: gnomAD v2.1 and v4.1 both report the variant absent, rather than an allele frequency above the VCEP's >0.0926% BA1 threshold.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
BS1	Not met	Not met: gnomAD v2.1 and v4.1 both report absence, providing no allele frequency above the VCEP's >0.0185% BS1 threshold.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
BS2	Not assessed	Not assessed: gnomAD reports no observations, but the required alternative evidence of ≥3 heterozygous occurrences in well-phenotyped family members is unavailable.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
BS3	Not assessed	Not assessed: no variant-specific benign functional assay result or VCEP-required quality and validation-control data were available for BS3.	cspec
BS4	N/A	Not applicable: the VCEP excludes lack-of-segregation evidence for de novo, germline mosaic, or post-zygotic mutations.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1	N/A	Not applicable: the VCEP explicitly excludes BP1 because loss of function is not the disease mechanism.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	Not assessed: no documented cis/trans phase observation with a known pathogenic PIK3CA variant is available for this case.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3	N/A	Not applicable: the VCEP states that these genes lack qualifying nonfunctional repetitive exon regions, and this variant is intronic rather than an in-frame indel.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 pvs1_variant_assessment
BP4	Not assessed	Not assessed: The intronic variant has one named no-impact result, SpliceAI max delta 0.031, but two of three tools are required and varSEAK/MaxEntScan results are unavailable.	cspec spliceai vcep_clingen_brainmalform_acmg_specifications_v1_1
BP5	Not assessed	Not assessed: no case with an alternate molecular basis for disease in a different gene is documented for this variant.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP6	N/A	Not applicable: the VCEP explicitly excludes BP6 for this framework.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7	Not assessed	Not assessed: The variant is noncanonical intronic, but no VCEP-required conservation result, including PhyloP <0.1, is available.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1

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