NM_006218.4:c.335T>C

PIK3CA · NP_006209.2:p.(Ile112Thr) · NM_006218.4

GRCh37: chr3:178916948 T>C · GRCh38: chr3:179199160 T>C

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Ile112Thr)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The PIK3CA c.335T>C (p.Ile112Thr, p.I112T) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2_Supporting under the Brain Malformations VCEP rule for variants observed in no more than 1 person.

The p.Ile112Thr change affects residue 112, which is outside the PIK3CA Table 4 approved kinase-domain intervals of amino acids 322-483 and 797-1068, so PM1 is not met.

Computational data show no predicted splice impact by SpliceAI (max delta score 0.00), with REVEL 0.39 and BayesDel 0.238394, but under this VCEP PP3 is not applicable and BP4 is restricted to synonymous, intronic, or UTR variants.

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 previously established pathogenic variant producing the same amino acid change was identified in the available sources, so PS1 could not be assessed.	clinvar
BS4	N/A	BS4 is not applicable under the Brain Malformations VCEP framework for this gene-disease context.	cspec
BS2	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so there are 0 observed homozygotes, which is below the VCEP BS2 threshold of at least 3 homozygotes or at least 3 well-phenotyped unaffected heterozygous family members.	cspec gnomad_v2 gnomad_v4
PS2	Not assessed	No confirmed de novo result, parental testing, or tissue mosaicism data were identified for this variant, so PS2 could not be assessed.	cspec clinvar
PP4	N/A	PP4 is not applicable under the Brain Malformations VCEP framework for this gene-disease context.	cspec
PP3	N/A	PP3 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Available computational results include SpliceAI max delta score 0.00, REVEL 0.39, and BayesDel 0.238394, but these do not create a PP3 call when the VCEP has marked PP3 not applicable.	cspec spliceai revel bayesdel
PM1	Not met	The p.Ile112Thr change affects residue 112, which is outside the PIK3CA Table 4 approved kinase-domain intervals of amino acids 322-483 and 797-1068, so PM1 is not met. Available hotspot evidence was marked uncertain and does not establish a validated hotspot at codon 112.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 hotspots
PS4	Not met	This variant meets PM2_Supporting because it is absent from gnomAD, but no affected-case phenotype point data were identified to reach the VCEP PS4 thresholds of at least 0.5 points for supporting evidence.	cspec gnomad_v2 gnomad_v4 clinvar
PVS1	N/A	PVS1 is not applicable under the Brain Malformations VCEP framework for PIK3CA because the disease mechanism is gain of function, and this variant is also a missense change rather than a canonical null variant.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 pvs1_variant_assessment
PP5	N/A	PP5 is not applicable under the Brain Malformations VCEP framework for this gene-disease context.	cspec
BP7	N/A	BP7 is not applicable because this is a missense variant, whereas the VCEP limits BP7 to synonymous, non-canonical intronic, or UTR variants.	cspec spliceai
BP5	Not assessed	No evidence was identified showing an alternate molecular explanation for the reported phenotype in a person carrying this variant, so BP5 could not be assessed.	cspec clinvar
BP4	N/A	BP4 is not applicable because this is a missense variant, whereas the VCEP restricts BP4 to synonymous, non-canonical intronic, or UTR variants assessed for lack of splice impact. SpliceAI predicts no splice effect with a max delta score of 0.00, but that does not create a BP4 call for this missense change.	cspec spliceai
BP3	N/A	BP3 is not applicable under the Brain Malformations VCEP framework for this gene-disease context.	cspec
BP2	Not assessed	No phase data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 could not be assessed.	cspec clinvar
BP1	N/A	BP1 is not applicable under the Brain Malformations VCEP framework for PIK3CA.	cspec
BS3	Not assessed	No validated functional study was identified showing normal or non-damaging function for p.Ile112Thr, so BS3 could not be assessed.	cspec oncokb
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0%, which is below the VCEP BA1 threshold of greater than 0.0926%.	cspec gnomad_v2 gnomad_v4
PP2	Not assessed	PP2 may be applicable for PIK3CA missense variants when the missense constraint z-score is greater than 3.09, but the required gene-level constraint value was not identified in the available evidence, so PP2 could not be assessed.	cspec
PP1	N/A	PP1 is not applicable under the Brain Malformations VCEP framework for this gene-disease context.	cspec
PM5	Not assessed	No validated same-residue pathogenic comparator variant was identified for codon 112, so PM5 could not be assessed from the available evidence.	cspec pm5_candidates
PM4	N/A	PM4 is not applicable under the Brain Malformations VCEP framework for this gene-disease context.	cspec
PM3	N/A	PM3 is not applicable under the Brain Malformations VCEP framework for this gene-disease context.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0 observed individuals across both datasets, which satisfies the Brain Malformations VCEP PM2 threshold of absent or rare in controls with no more than 1 person observed.	cspec gnomad_v2 gnomad_v4
PS3	Not assessed	No validated functional study was identified showing an abnormal effect of p.Ile112Thr in an assay meeting the Brain Malformations VCEP PS3 requirements, so PS3 could not be assessed.	cspec oncokb
BP6	N/A	BP6 is not applicable under the Brain Malformations VCEP framework for this gene-disease context.	cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0%, which is below the VCEP BS1 threshold of greater than 0.0185%.	cspec gnomad_v2 gnomad_v4
PM6	N/A	PM6 is not applicable under the Brain Malformations VCEP framework for this gene-disease context.	cspec

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