NM_006218.4:c.3189dup

PIK3CA · NP_006209.2:p.(Gln1064ThrfsTer9) · NM_006218.4

GRCh37: chr3:178952131 T>TA · GRCh38: chr3:179234343 T>TA

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Gln1064ThrfsTer9)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): the exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

Overall classification: VUS - PM2 at Supporting strength is the only met criterion and satisfies no ACMG/AMP 2015 Pathogenic or Likely Pathogenic combination.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion alone meets no pathogenic, likely pathogenic, benign, or likely benign combination and is classified as VUS.

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: the ClinGen Brain Malformations VCEP excludes PVS1 because PIK3CA brain malformations arise from gain-of-function, not loss of function.	cspec
PS1	N/A	Not applicable: PS1 requires the same amino acid change as a previously established pathogenic variant, but a frameshift produces no amino acid change to compare.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband phenotype, parental genotypes, or de novo testing results were available, so de novo occurrence cannot be evaluated.	cspec
PS3	Not assessed	Not assessed: no validated variant-specific functional assay or animal-model evidence was available.	cspec
PS4	Not assessed	Not assessed: no affected cerebral-malformation cases, case-control data, or phenotype-point evidence for this exact variant were available.	cspec gnomad_v2 gnomad_v4
PM1	N/A	Not applicable: PM1 requires a missense change in a mutational hotspot; this frameshift produces no altered residue to evaluate.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): the exact variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Flagged for human review: indel population calls may be unreliable and coverage/quality metrics were not available.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: PM3 is reserved for recessive disorders, whereas PIK3CA brain-malformation variants are heterozygous.	cspec
PM4	N/A	Not applicable: PM4 is defined for in-frame insertions/deletions and stop-loss extensions; this frameshift does not meet that structural premise.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense change at a residue where a different pathogenic missense is established; a frameshift produces no missense change.	generic_acmg_combination_rules
PM6	N/A	Not applicable: per the VCEP, de novo evidence is addressed through PS2, not PM6.	cspec
PP1	N/A	Not applicable: per the VCEP, co-segregation does not apply to variants that arise de novo or as germline or post-zygotic mosaics.	cspec
PP2	N/A	Not applicable: PP2 is defined for missense variants in genes with low benign missense variation; this frameshift has no missense change.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the VCEP excludes PP3 because prediction tools target loss-of-function, while PIK3CA brain malformations are gain-of-function.	cspec
PP4	N/A	Not applicable: the VCEP accounts for phenotype evidence under PS4.	cspec
PP5	N/A	Not applicable: the VCEP does not use PP5, and no ClinVar record for this exact variant exists.	cspec clinvar
BA1	Not met	Not met: the variant is absent (frequency 0) from all gnomAD sources, far below the VCEP BA1 threshold of >0.0926%.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from gnomAD, far below the VCEP BS1 threshold of >0.0185%.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: BS2 requires at least 3 gnomAD homozygotes or 3 heterozygous well-phenotyped relatives; the variant is absent from gnomAD with no such family observations.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay or animal-model evidence demonstrating absence of a damaging effect was available.	cspec
BS4	N/A	Not applicable: per the VCEP, lack of segregation (BS4) does not apply because these variants are de novo, germline mosaic, or post-zygotic.	cspec
BP1	N/A	Not applicable: BP1 is defined for missense variants in genes where truncating variants cause disease; this frameshift has no missense change.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no genotype data, second PIK3CA variant, or phase information was available to assess cis/trans status with a pathogenic allele.	cspec
BP3	N/A	Not applicable: BP3 is defined for in-frame indels in repetitive regions; this frameshift is outside its scope.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: BP4 is restricted to synonymous, intronic, or non-coding variants; this exonic frameshift is ineligible.	cspec
BP5	Not assessed	Not assessed: no individual carrying this variant with an alternate molecular diagnosis was reported.	cspec
BP6	N/A	Not applicable: the VCEP does not use BP6, and no ClinVar record for this exact variant exists.	cspec clinvar
BP7	N/A	Not applicable: BP7 is defined for synonymous variants with no predicted splice impact; this frameshift changes 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.