Variant classification summary

NM_006218.2:c.2198A>G

PIK3CA · NP_006209.2:p.(Lys733Arg) · NM_006218.2

GRCh37: chr3:178941879 A>G · GRCh38: chr3:179224091 A>G

Gene: PIK3CA Transcript: NM_006218.2

Final call

Benign

BA1 stand-alone benign BS1 strong BP6 supporting benign

Variant details

Gene

PIK3CA

Transcript

NM_006218.2

Protein

NP_006209.2:p.(Lys733Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PIK3CA c.2198A>G (p.Lys733Arg) variant has been reported in ClinVar as Benign, including an expert-panel benign classification from the ClinGen Brain Malformations Variant Curation Expert Panel.

2

This variant is present in population databases at a frequency above the Brain Malformations VCEP benign thresholds, with East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1, exceeding both the BS1 threshold of 0.0185% and the BA1 threshold of 0.0926%.

3

In silico review does not support a splice-disrupting effect, with SpliceAI max delta score 0.12; REVEL was 0.269 and BayesDel was -0.264459, although PP3 and BP4 are not applicable to this missense gain-of-function interpretation under the Brain Malformations VCEP.

Final determination: Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework yields a total score of -12, 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 evidence was identified showing that this exact amino acid change has been established as pathogenic through a different nucleotide change at the same codon.	cspec
PS2	Not assessed	No confirmed de novo or tissue-mosaic evidence was identified for this variant, so the Brain Malformations VCEP requirements for PS2 were not met from the available data.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3	Not assessed	No validated functional study for p.Lys733Arg demonstrating an abnormal gain-of-function effect at a level specified by the Brain Malformations VCEP was identified.	cspec oncokb
PS4	Not met	This variant does not meet PM2 because it is present in gnomAD above the VCEP rarity threshold, including East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1; under the Brain Malformations VCEP, PS4 phenotype points can only be used if PM2 is met.	cspec gnomad_v2 gnomad_v4 clinvar
PM1	Not met	The Brain Malformations VCEP allows PM1 at Supporting strength for PIK3CA variants in approved Table 4 domains at amino acids 322-483 or 797-1068. Lys733 falls outside these approved intervals, so PM1 is not met.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Not met	This variant is not absent or rare enough for PM2 because it is present in gnomAD, with East Asian AF 0.56428% in v2.1 and 0.25756% in v4.1, which are well above the VCEP one-person rarity allowance for PM2_Supporting.	cspec gnomad_v2 gnomad_v4
PM5	Not assessed	No reviewed evidence was identified showing a different missense change at Lys733 that is already established as pathogenic for this disease context.	cspec
PP2	Not assessed	The Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the missense constraint z-score is greater than 3.09, but no z-score evidence was provided in the reviewed materials.	cspec
PP3	N/A	The Brain Malformations VCEP states that PP3 is not applicable for these gain-of-function PIK3CA variants. Computational results were reviewed but not used for PP3; REVEL was 0.269, BayesDel was -0.264459, and SpliceAI max delta score was 0.12.	cspec revel bayesdel spliceai
PP4	N/A	The Brain Malformations VCEP states that PP4 is not applicable because phenotype specificity is incorporated into PS4.	cspec
PP5	N/A	PP5 is not for use under the ClinGen Sequence Variant Interpretation framework adopted by this VCEP.	cspec
BA1	Met	This variant exceeds the Brain Malformations VCEP BA1 threshold of 0.0926%. The highest observed population frequency is East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1, both above the BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Met	This variant exceeds the Brain Malformations VCEP BS1 threshold of 0.0185%. The highest observed population frequency is East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1, both above the BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not met	BS2 was not met because the Brain Malformations VCEP requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped family members. This variant has 2 homozygotes in gnomAD v2.1 and 2 homozygotes in gnomAD v4.1, which does not reach the threshold.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	No validated functional study was identified showing that p.Lys733Arg has a normal or benign effect under the Brain Malformations VCEP/SVI functional evidence framework.	cspec oncokb
BS4	N/A	The Brain Malformations VCEP states that BS4 is not applicable in this disease setting.	cspec
BP1	N/A	BP1 is not applicable because the Brain Malformations VCEP interprets PIK3CA-related disease through a gain-of-function mechanism rather than a mechanism in which missense change is generally less informative than truncating change.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	No evidence was identified showing that this variant has been observed in cis or trans with a known pathogenic PIK3CA variant.	cspec
BP3	N/A	The Brain Malformations VCEP states that BP3 is not applicable in this framework.	cspec
BP4	N/A	BP4 is limited by this VCEP to synonymous, intronic non-canonical splice, and UTR variants with no predicted splice effect. This is a missense variant, so BP4 is not applicable, although SpliceAI predicted no significant splice impact with a max delta score of 0.12.	cspec spliceai
BP5	Not assessed	No evidence was identified showing an alternate molecular explanation for the reported phenotype in a person carrying this variant.	cspec
BP6	Met	Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Benign.	cspec clinvar
BP7	N/A	BP7 is intended for synonymous, intronic non-canonical splice, or UTR variants with low conservation. This is a missense variant, so BP7 is not applicable.	cspec
PVS1	N/A	PVS1 is not applicable under the Brain Malformations VCEP because PIK3CA-related disease is interpreted through a gain-of-function mechanism, and this variant is a missense substitution rather than a null variant. The generic PVS1 scaffold also does not place this variant in a nonsense, frameshift, or canonical splice category.	cspec pvs1_variant_assessment vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1	N/A	The Brain Malformations VCEP states that PP1 is not applicable in this disease setting.	cspec
PM3	N/A	The Brain Malformations VCEP states that PM3 is not applicable in this framework.	cspec
PM4	N/A	The Brain Malformations VCEP states that PM4 is not applicable in this framework.	cspec
PM6	N/A	The Brain Malformations VCEP states that PM6 is not applicable in this framework.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.