LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-14
Case ID: NM_006218.4_c.331_336del_20261014_132307
Framework: ACMG/AMP 2015
Variant classification summary

NM_006218.4:c.331_336del

PIK3CA  · NP_006209.2:p.(Lys111_Ile112del)  · NM_006218.4
GRCh37: chr3:178916943 AAAGATC>A  ·  GRCh38: chr3:179199155 AAAGATC>A
Gene: PIK3CA Transcript: NM_006218.4
Final call
VUS
PS4 supporting PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PIK3CA
Transcript
NM_006218.4
Protein
NP_006209.2:p.(Lys111_Ile112del)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
VUS: PS4 supporting reflects two COSMIC occurrences totaling 0.5 VCEP points.
2
VUS: PM2 supporting reflects complete absence from the available gnomAD datasets.
Final determination: Under the generic ACMG/AMP 2015 fallback, two supporting criteria do not satisfy any pathogenic, likely pathogenic, benign, or likely benign combination, so the final call is 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 PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_006218.4:c.331_336del in PIK3CA is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_006209.2:p.(Lys111_Ile112del). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
PS1 N/A PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_006218.4:c.331_336del in PIK3CA is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_006209.2:p.(Lys111_Ile112del). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
generic_acmg_combination_rules
PS2 Not assessed Not assessed: no documented proband allele fraction, parental maternity/paternity testing, or affected-versus-other-tissue comparison satisfies the VCEP PS2 criteria.
cspec
PS3 Not assessed Not assessed: no validated assay result for the exact p.K111_I112del variant was identified, and the available paper tested only the distinct nearby K111delK variant.
cspec
PS4 Met Met at supporting: two COSMIC occurrences contribute 0.5 points, which falls within the VCEP PS4 supporting range of 0.5–1.25 points after PM2 is satisfied.
cspec gnomad_v2 gnomad_v4
PM1 N/A PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_006218.4:c.331_336del in PIK3CA is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_006209.2:p.(Lys111_Ile112del). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
generic_acmg_combination_rules
PM2 Met Met at supporting strength: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, with 0 observed people versus the VCEP maximum of 1.
cspec gnomad_v2 gnomad_v4
PM3 N/A Not applicable: the VCEP excludes PM3 because PIK3CA brain-malformation disease-causing variants are heterozygous, not recessive in-trans observations.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM4 N/A Not applicable: the PIK3CA VCEP excludes PM4 despite this 6-nucleotide in-frame deletion producing p.(Lys111_Ile112del).
cspec
PM5 N/A PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_006218.4:c.331_336del in PIK3CA is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_006209.2:p.(Lys111_Ile112del). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
generic_acmg_combination_rules
PM6 N/A Not applicable: the VCEP explicitly directs that PM6 is addressed through PS2 and will not be used independently.
cspec
PP1 N/A Not applicable: the VCEP excludes PP1 because these PIK3CA disease-causing variants are typically germline mosaic, de novo, or mosaic.
cspec
PP2 N/A PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_006218.4:c.331_336del in PIK3CA is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_006209.2:p.(Lys111_Ile112del). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
generic_acmg_combination_rules
PP3 N/A Not applicable: the in-frame p.(Lys111_Ile112del) deletion is a protein-length-changing variant outside the VCEP's PP3 scope.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4 N/A Not applicable: the VCEP states that phenotype specificity is accounted for under PS4 rather than assigned separately as PP4.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5 N/A Not applicable: the VCEP prohibits PP5, and ClinVar has no exact-variant expert-panel pathogenic or likely-pathogenic classification.
cspec clinvar vcep_clingen_brainmalform_acmg_specifications_v1_1
BA1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, giving observed allele frequency 0 versus the VCEP BA1 threshold of >0.0926%.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, giving observed allele frequency 0 versus the VCEP BS1 threshold of >0.0185%.
cspec gnomad_v2 gnomad_v4
BS2 Not met Not met: gnomAD v2.1 and v4.1 report 0 variant observations, below the VCEP requirement of at least 3 homozygotes or qualifying family heterozygotes.
cspec gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: no validated benign functional result for the exact p.K111_I112del variant was identified; PMID:29533785 tested a different nearby variant.
cspec
BS4 N/A Not applicable: the VCEP excludes BS4 for these de novo, germline-mosaic, or post-zygotic PIK3CA disease mechanisms.
cspec
BP1 N/A BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_006218.4:c.331_336del in PIK3CA is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_006209.2:p.(Lys111_Ile112del). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
generic_acmg_combination_rules
BP2 Not assessed Not assessed: no cis/trans observation with a known pathogenic PIK3CA variant or phase result is available for this variant.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3 N/A Not applicable: the PIK3CA VCEP states its exon regions lack repetitive regions without known function, excluding BP3 for this in-frame deletion.
cspec
BP4 N/A Not applicable: the in-frame p.(Lys111_Ile112del) deletion is outside BP4's specified synonymous, intronic, splice-region, and UTR scope.
cspec spliceai vcep_clingen_brainmalform_acmg_specifications_v1_1
BP5 Not assessed Not assessed: two COSMIC cancer occurrences are reported, but no alternate molecular basis in a different gene is documented for those cases.
cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP6 N/A Not applicable: the VCEP prohibits BP6, and ClinVar has no exact-variant expert-panel benign or likely-benign classification.
cspec clinvar vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7 N/A BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006218.4:c.331_336del in PIK3CA is an in-frame insertion/deletion of undetermined repeat-region status predicted to produce NP_006209.2:p.(Lys111_Ile112del). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
generic_acmg_combination_rules
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