Variant classification summary

NM_006218.4:c.317G>C

PIK3CA · NP_006209.2:p.(Gly106Ala) · NM_006218.4

GRCh37: chr3:178916930 G>C · GRCh38: chr3:179199142 G>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.(Gly106Ala)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with no observed control carriers.

2

Overall classification: VUS — the single supporting PM2 criterion does not reach any pathogenic or benign combination threshold under ACMG/AMP 2015 rules.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion alone does not satisfy any pathogenic or likely pathogenic combination, so the classification is 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: PVS1 covers null variant classes (nonsense, frameshift, canonical splice); this missense substitution triggers no null mechanism.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no ClinVar record, literature PMID, or prior pathogenic report of the same amino acid change was available.	cspec clinvar
PS2	Not assessed	Not assessed: no proband genotype, parental testing, or confirmed de novo evidence was available.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay or animal-model evidence was available.	cspec
PS4	Not assessed	Not assessed: no affected-individual phenotype data or case-control enrichment evidence was available.	cspec gnomad_v2 gnomad_v4
PM1	Not met	Not met: Gly106 lies outside the VCEP kinase-domain intervals (residues 322-483 and 797-1068), and the Cancer Hotspots hit does not satisfy this domain rule.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with no observed control carriers.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: PIK3CA disease variants are heterozygous, while PM3 applies to recessive disorders.	cspec
PM4	N/A	Not applicable: missense substitution causes no protein length change, which PM4 requires.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at residue Gly106 previously determined pathogenic was identified.	cspec pm5_candidates
PM6	N/A	Not applicable: assumed de novo evidence is addressed through PS2 under the VCEP.	cspec
PP1	N/A	Not applicable: familial cosegregation is not evaluated because PIK3CA variants are generally de novo or mosaic.	cspec
PP2	Not assessed	Not assessed: no PIK3CA missense-constraint z-score was available to adjudicate the >3.09 threshold.	cspec
PP3	N/A	Not applicable: traditional mutation-prediction algorithms are excluded for this gain-of-function disorder.	cspec
PP4	N/A	Not applicable: phenotype evidence is accounted for under the PS4 framework.	cspec
PP5	N/A	Not applicable: ClinVar has no exact-variant record for this variant.	cspec clinvar
BA1	Not met	Not met: variant is absent from gnomAD, below the >0.0926% allele-frequency BA1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: variant is absent from gnomAD, below the >0.0185% allele-frequency BS1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: BS2 requires at least 3 homozygotes or 3 heterozygous family observations; none were present.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay evidence demonstrating no damaging effect on protein function was available.	cspec
BS4	N/A	Not applicable: lack of familial segregation is not used for de novo, mosaic, or post-zygotic mutations.	cspec
BP1	N/A	Not applicable: loss of function is not the disease mechanism; PIK3CA disease is gain of function.	cspec
BP2	Not assessed	Not assessed: no phase results or co-occurring known pathogenic PIK3CA variant were available.	cspec
BP3	N/A	Not applicable: missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: BP4 is restricted to synonymous or noncoding variants; this is an exonic missense variant.	cspec spliceai
BP5	Not assessed	Not assessed: no alternate molecular diagnosis explaining the phenotype was documented.	cspec
BP6	N/A	Not applicable: ClinVar has no exact-variant record for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; this missense change alters the protein sequence.	generic_acmg_combination_rules

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.