Variant classification summary

NM_006218.2:c.1173A>G

PIK3CA · NP_006209.2:p.(Ile391Met) · NM_006218.2

GRCh37: chr3:178927410 A>G · GRCh38: chr3:179209622 A>G

Gene: PIK3CA Transcript: NM_006218.2

Final call

Benign

BS2 strong PM1 supporting BA1 stand-alone benign BP6 supporting benign BS1 strong

Variant details

Gene

PIK3CA

Transcript

NM_006218.2

Protein

NP_006209.2:p.(Ile391Met)

gnomAD AF

ClinVar

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PIK3CA c.1173A>G (p.Ile391Met) variant has been reported in ClinVar as Benign, including a Benign expert-panel classification from the ClinGen Brain Malformations Variant Curation Expert Panel.

2

This variant is common in population databases, with allele frequency 6.57058% in gnomAD v2.1 and 6.60819% in gnomAD v4.1, greatly exceeding the VCEP BA1 threshold of 0.0926% and BS1 threshold of 0.0185%, and it is also observed in numerous homozygous individuals.

3

Curated literature resources identified functional publications relevant to this variant, but the retrieved evidence did not provide validated variant-specific assay results sufficient to apply either PS3 or BS3.

4

SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, while REVEL is 0.236 and BayesDel is -0.391355; however, PP3 is not applicable and BP4 is restricted to non-missense variants in this VCEP framework.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of -15, which maps to Benign under the specified Tavtigian-style ranges.

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
PS1	Not assessed	No independently verified evidence was identified showing that this variant causes the same amino acid change as a previously established pathogenic PIK3CA variant by a different nucleotide substitution.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS4	N/A	BS4 is not applicable in this VCEP because PIK3CA-related brain malformation cases are typically de novo, germline mosaic, or post-zygotic rather than segregation-based familial presentations.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS2	Met	This variant is present in many apparently healthy population participants, including 1,032 homozygotes in gnomAD v2.1 and 4,921 homozygotes in gnomAD v4.1, which is well above the VCEP BS2 threshold of at least 3 homozygotes.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
PS2	Not assessed	No confirmed de novo evidence with parental testing and tissue-distribution data was identified for this variant, so the VCEP PS2 requirements were not met from the retrieved evidence.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4	N/A	PP4 is not applicable in this VCEP because phenotype specificity is incorporated into the point-based PS4 framework rather than used as an independent criterion.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3	N/A	PP3 is not applicable in this VCEP for PIK3CA gain-of-function disease mechanisms. Computational results were reviewed, including REVEL 0.236, BayesDel -0.391355, and SpliceAI max delta 0.00, but the specification does not use PP3 for these missense gain-of-function variants.	cspec revel bayesdel spliceai vcep_clingen_brainmalform_acmg_specifications_v1_1
PM1	Met	The p.Ile391Met change lies within the PIK3CA amino-acid interval 322-483, which is listed by this VCEP as an approved Table 4 critical functional domain, supporting PM1 at Supporting strength. Cancer Hotspots did not identify a statistically significant hotspot at residue 391, but hotspot recurrence is not required by this VCEP when the variant falls in an approved domain.	cspec hotspots clinvar vcep_clingen_brainmalform_acmg_specifications_v1_1
PS4	Not met	PS4 is not met because this VCEP requires PM2 before phenotype-point assignment, and this variant is common in population databases rather than rare or absent from controls.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
PVS1	N/A	PVS1 is not applicable in this VCEP because PIK3CA-related brain malformations are interpreted under a gain-of-function framework, and this missense variant is also outside the generic null-variant PVS1 categories.	cspec pvs1_variant_assessment vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5	N/A	PP5 is not applicable because this VCEP does not permit use of reputable-source assertions without independent evidence review.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7	N/A	BP7 is not applicable because this is a missense variant, whereas the VCEP restricts BP7 to synonymous, intronic non-canonical splice, and other non-coding variants.	cspec clinvar vcep_clingen_brainmalform_acmg_specifications_v1_1
BP5	Not assessed	No independently verified evidence was identified showing that this variant was found in a case with an alternate molecular basis that explains the reported phenotype.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP4	N/A	BP4 is not applicable because this is a missense variant and the VCEP restricts BP4 to synonymous, intronic non-canonical splice, or UTR variants assessed for splicing impact. Computational results were reviewed, including SpliceAI max delta 0.00, REVEL 0.236, and BayesDel -0.391355, but these do not trigger BP4 for this missense change under the VCEP rule.	cspec spliceai revel bayesdel vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3	N/A	BP3 is not applicable in this VCEP because these genes are not interpreted using BP3 repetitive-region logic.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	No phase data were identified showing that this variant was observed in cis or trans with a known pathogenic PIK3CA variant.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1	N/A	BP1 is not applicable because the disease mechanism for this VCEP is gain of function rather than primarily truncating loss-of-function variation.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS3	Not assessed	Curated literature resources identified functional publications relevant to this variant, but the retrieved evidence did not provide validated variant-specific studies demonstrating a normal or no-damaging effect sufficient for BS3.	oncokb PMID:20530683 PMID:29533785 cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1	Met	This variant exceeds the VCEP BA1 threshold of greater than 0.0926% by a wide margin, with overall allele frequency 6.57058% in gnomAD v2.1 and 6.60819% in gnomAD v4.1.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2	Not assessed	PP2 could be considered for PIK3CA missense variants in this VCEP, but no gene-level missense constraint z-score was provided in the retrieved evidence to compare with the required threshold of greater than 3.09.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1	N/A	PP1 is not applicable in this VCEP because disease-causing variants are typically germline mosaic, de novo, or post-zygotic rather than segregation-based familial findings.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM5	Not assessed	No independently verified evidence was identified showing that a different missense change at residue Ile391 has been established as pathogenic.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM4	N/A	PM4 is not applicable in this VCEP.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM3	N/A	PM3 is not applicable because this disorder framework does not use recessive trans observations for PIK3CA-associated disease.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Not met	PM2 is not met because this variant is not rare in population databases. Its overall allele frequency is 6.57058% in gnomAD v2.1 and 6.60819% in gnomAD v4.1, far above a one-person maximum or rare-control expectation.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3	Not assessed	Curated literature resources identified functional publications relevant to this variant, but the retrieved evidence did not provide validated variant-specific assay results sufficient to support a damaging effect under the VCEP PS3 requirements.	oncokb PMID:20530683 PMID:29533785 cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP6	Met	Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Benign.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 clinvar
BS1	Met	This variant exceeds the VCEP BS1 threshold of greater than 0.0185%, with overall allele frequency 6.57058% in gnomAD v2.1 and 6.60819% in gnomAD v4.1, which is far above the maximum expected frequency for a disease-causing PIK3CA brain malformation variant.	cspec gnomad_v2 gnomad_v4 vcep_clingen_brainmalform_acmg_specifications_v1_1
PM6	N/A	PM6 is not applicable in this VCEP because de novo evidence is handled through the PS2 framework instead.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1

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