Variant classification summary

NM_006218.4:c.2171A>G

PIK3CA · NP_006209.2:p.(Lys724Arg) · NM_006218.4

GRCh37: chr3:178938929 A>G · GRCh38: chr3:179221141 A>G

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Lys724Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PIK3CA c.2171A>G (p.Lys724Arg; p.K724R) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at Supporting strength under the Brain Malformations VCEP rarity rule.

3

Under the Brain Malformations VCEP specification, Lys724 is outside the approved PIK3CA PM1 domains at amino acids 322-483 and 797-1068, so PM1 is not met.

4

Computational results were reviewed, but PP3 is not applicable for PIK3CA gain-of-function missense variants in this VCEP; SpliceAI predicts no significant splice effect with a max delta score of 0.02, REVEL is 0.399, and BayesDel is -0.142828.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of 1, which maps to VUS 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 evidence was identified that this nucleotide change results in the same amino acid substitution as a previously established pathogenic PIK3CA variant, so PS1 cannot be applied from the available data.	clinvar cspec
BS4	N/A	BS4 is not applicable under the Brain Malformations VCEP because disease-associated variants in this setting are typically de novo, germline mosaic, or post-zygotic rather than evaluated through lack of segregation.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS2	Not met	This variant is absent from gnomAD, so the VCEP threshold for BS2 of at least 3 homozygotes in population data is not met, and no well-phenotyped unaffected family observations were identified.	gnomad_v2 gnomad_v4 cspec
PS2	Not assessed	No case-level data were identified showing this variant in an affected tissue sample with absence from parental samples and tissue-comparison evidence required by the Brain Malformations VCEP, so PS2 cannot be applied from the available evidence.	clinvar cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4	N/A	PP4 is not applicable under the Brain Malformations VCEP because phenotype specificity is accounted for within the VCEP PS4 framework.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3	N/A	PP3 is not applicable under the Brain Malformations VCEP for PIK3CA gain-of-function variants. Computational results were reviewed, including SpliceAI max delta 0.02, REVEL 0.399, and BayesDel -0.142828, but they do not override the VCEP rule excluding PP3 for this variant class.	cspec spliceai revel bayesdel
PM1	Not met	Under the Brain Malformations VCEP, PM1 for PIK3CA is limited to Supporting strength for variants in approved Table 4 domains. Lys724 is outside the listed kinase-domain intervals of amino acids 322-483 and 797-1068, so PM1 is not met.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS4	Not assessed	This variant meets the rarity prerequisite for PS4 because it is absent from gnomAD, but no affected-case evidence or phenotype-point total was identified to support PS4 under the Brain Malformations VCEP point system.	gnomad_v2 gnomad_v4 clinvar cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PVS1	N/A	PVS1 is not applicable under the Brain Malformations VCEP because the disease mechanism for PIK3CA in this framework is gain of function, and this variant is a missense substitution rather than a null variant.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 pvs1_variant_assessment
PP5	N/A	PP5 is not used under current ClinGen VCEP recommendations, so it is not applicable for this review.	cspec
BP7	N/A	BP7 is restricted to synonymous, intronic, or certain non-coding variants. This is a missense variant, so BP7 is not applicable.	cspec spliceai
BP5	Not assessed	No evidence was identified that this variant was found in a case with an alternate molecular basis for disease, so BP5 cannot be applied from the available data.	clinvar cspec
BP4	N/A	BP4 under the Brain Malformations VCEP applies only to synonymous, intronic, or non-coding variants evaluated for splicing. This missense variant is therefore not eligible for BP4, although SpliceAI predicts no significant splice impact with a max delta score of 0.02.	cspec spliceai
BP3	N/A	BP3 is not applicable under the Brain Malformations VCEP for these genes.	cspec
BP2	Not assessed	No phase data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 cannot be applied from the available evidence.	clinvar cspec
BP1	N/A	BP1 is not applicable under the Brain Malformations VCEP because loss of function is not the disease mechanism for PIK3CA in this setting.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BS3	Not assessed	No well-established functional studies were identified showing no damaging effect for this variant, so BS3 cannot be applied from the available evidence.	oncokb cspec
BA1	Not met	This variant is absent from gnomAD and therefore far below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%, so BA1 is not met.	gnomad_v2 gnomad_v4 cspec
PP2	Not assessed	PP2 may be used by this VCEP for PIK3CA when the missense constraint z-score exceeds 3.09, but no qualifying missense-constraint evidence was provided in the available materials, so PP2 was not applied.	cspec
PP1	N/A	PP1 is not applicable under the Brain Malformations VCEP because disease-causing variants in this setting are typically de novo, germline mosaic, or post-zygotic rather than assessed through segregation.	cspec
PM5	Not assessed	No evidence was identified that a different missense change at Lys724 has already been established as pathogenic, so PM5 cannot be applied from the available data.	clinvar cspec
PM4	N/A	PM4 is not applicable under the Brain Malformations VCEP and this variant is not an in-frame insertion, deletion, or stop-loss change.	cspec
PM3	N/A	PM3 is not applicable under the Brain Malformations VCEP because PIK3CA-related disease in this framework is not interpreted as a recessive condition requiring trans observations.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which satisfies the Brain Malformations VCEP PM2 rarity requirement and supports PM2 at Supporting strength.	gnomad_v2 gnomad_v4 cspec
PS3	Not assessed	No validated functional assay evidence was identified for this exact variant showing an abnormal gain-of-function effect under the Brain Malformations VCEP framework, so PS3 cannot be applied from the available evidence.	oncokb cspec
BP6	N/A	BP6 is not used under current ClinGen VCEP recommendations, so it is not applicable for this review.	cspec
BS1	Not met	This variant is absent from gnomAD and therefore below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%, so BS1 is not met.	gnomad_v2 gnomad_v4 cspec
PM6	N/A	PM6 is not applicable under the Brain Malformations VCEP because de novo and mosaic evidence is addressed through the PS2 framework.	cspec

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