Variant classification summary

NM_006218.3:c.946C>T

PIK3CA · NP_006209.2:p.(Pro316Ser) · NM_006218.3

GRCh37: chr3:178921464 C>T · GRCh38: chr3:179203676 C>T

Gene: PIK3CA Transcript: NM_006218.3

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.3

Protein

NP_006209.2:p.(Pro316Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles, within the <=1 occurrence ceiling).

2

Overall classification: Variant of Uncertain Significance, because the single supporting PM2 criterion satisfies no benign or pathogenic combination threshold.

Final determination: Generic ACMG/AMP 2015 fallback: the only applied criterion is PM2 supporting (1 supporting); this satisfies none of the pathogenic, likely pathogenic, benign, or likely benign combination thresholds, so the variant is classified as 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: this missense variant does not trigger a null-variant mechanism such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic p.Pro316Ser change arising from a different nucleotide is on record.	clinvar pm5_candidates cspec
PS2	Not assessed	Not assessed: no parental or multi-tissue testing data were available to evaluate de novo occurrence.	cspec
PS3	Not assessed	Not assessed: insufficient functional-study evidence was available.
PS4	Not assessed	Not assessed: no affected individuals carrying this variant are reported, so no case phenotype points could be scored.	cspec clinvar gnomad_v2 gnomad_v4 gnomad_canada
PM1	Not met	Not met: p.Pro316 lies outside the VCEP-approved kinase domains (amino acids 322-483 and 797-1068).	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 final_classification_framework
PM2	Met	Met (Supporting): 0 alleles across gnomAD v2.1, v4.1, and gnomAD-Canada, within the <=1 occurrence ceiling.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM3	N/A	Not applicable: PIK3CA-related brain malformations are heterozygous, so trans-phase recessive evidence does not apply.	cspec
PM4	N/A	Not applicable: this missense substitution causes no change in protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no alternate missense change at Pro316 with a pathogenic classification was identified.	pm5_candidates clinvar cspec
PM6	N/A	Not applicable: de novo evidence is captured under PS2 per the VCEP.	cspec
PP1	N/A	Not applicable: disease variants are de novo or mosaic, so family segregation evidence does not apply.	cspec
PP2	Not assessed	Not assessed: the PIK3CA missense constraint z-score was unavailable, so the >3.09 rule could not be evaluated.	cspec final_classification_framework
PP3	N/A	Not applicable: the VCEP excludes computational prediction tools for gain-of-function variants.	cspec revel bayesdel spliceai
PP4	N/A	Not applicable: phenotype specificity is accounted for under PS4 per the VCEP.	cspec
PP5	N/A	Not applicable: the variant is absent from ClinVar, so no expert-panel pathogenic classification exists to trigger this criterion.	cspec clinvar
BA1	Not met	Not met: observed allele frequency 0, far below the 0.0926% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	Not met: observed allele frequency 0, below the 0.0185% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not met	Not met: zero homozygotes in gnomAD (threshold >=3) and no family-member observations.	gnomad_v2 gnomad_v4 gnomad_canada clinvar cspec
BS3	Not assessed	Not assessed: no functional study evidence was available to evaluate.
BS4	N/A	Not applicable: with a de novo/mosaic disease mechanism, non-segregation in relatives does not indicate benignity.	cspec
BP1	N/A	Not applicable: the disease mechanism is gain of function, not loss-of-function by truncation.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not met	Not met: no documented co-occurrence in cis or trans with a known pathogenic PIK3CA variant.	cspec clinvar gnomad_v2 gnomad_v4 gnomad_canada
BP3	N/A	Not applicable: this missense variant does not alter protein length within a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the VCEP restricts BP4 to synonymous, intronic, and noncoding variants; this is missense.	cspec spliceai
BP5	Not assessed	Not assessed: no case-level data were available on an alternate molecular basis of disease.	cspec clinvar
BP6	N/A	Not applicable: the variant is absent from ClinVar, so no expert-panel benign classification exists to trigger this criterion.	cspec clinvar
BP7	N/A	Not applicable: this missense variant alters the protein sequence, so the silent-variant premise does not hold.	generic_acmg_combination_rules

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