Variant classification summary

NM_006218.4:c.1634A>T

PIK3CA · NP_006209.2:p.(Glu545Val) · NM_006218.4

GRCh37: chr3:178936092 A>T · GRCh38: chr3:179218304 A>T

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PS4 supporting PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Glu545Val)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS4 supporting: four reported COSMIC occurrences yield 1.00 VCEP points, within the supporting range.

2

PM2 supporting: the variant is absent from the reported gnomAD datasets.

Final determination: Under the generic ACMG/AMP 2015 fallback, two supporting criteria alone do not satisfy any pathogenic, likely pathogenic, likely benign, or benign combination, resulting in 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.1634A>T in PIK3CA is a missense substitution predicted to produce NP_006209.2:p.(Glu545Val). 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	Not assessed	Not assessed: no previously established pathogenic variant producing the same PIK3CA p.Glu545Val amino-acid change was identified in the reviewed sources.	cspec clinvar PMID:19349352 PMID:24504419
PS2	Not assessed	Not assessed: no documented proband allele fraction, parental absence with confirmed maternity and paternity, or affected-versus-other-tissue comparison is available.	cspec
PS3	Not assessed	Not assessed: no reviewed functional assay directly tested PIK3CA p.Glu545Val, so variant-specific PS3 cannot be assigned.	cspec PMID:19349352 PMID:24504419
PS4	Met	Met at Supporting: four reported COSMIC occurrences yield 4 × 0.25 = 1.00 points, within the VCEP PS4 Supporting range of 0.5–1.25 points.	cspec gnomad_v2 gnomad_v4
PM1	Not met	Not met: PIK3CA residue 545 lies outside all approved PM1 domains, whose highest relevant interval ends at amino acid 483.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2	Met	Met, supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, satisfying the VCEP one-person-maximum PM2 rule.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the PIK3CA VCEP excludes PM3 because disease-causing variants in this disorder are heterozygous.	cspec
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_006218.4:c.1634A>T in PIK3CA is a missense substitution predicted to produce NP_006209.2:p.(Glu545Val). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4'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
PM5	Not assessed	Not assessed: the collected PM5 search found 0 same-residue comparators, but candidate harvesting ended with an HTTP 429 retrieval failure.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1 pm5_candidates clinvar PMID:19349352 PMID:24504419
PM6	N/A	Not applicable: the VCEP directs all unconfirmed de novo evidence to PS2 and prohibits use of PM6.	cspec
PP1	N/A	Not applicable: the VCEP excludes familial cosegregation evidence because these PIK3CA disease-causing variants are typically de novo or mosaic.	cspec
PP2	Not assessed	Not assessed: the VCEP requires a PIK3CA missense-constraint z-score >3.09, but no applicable z-score is provided.	cspec
PP3	N/A	Not applicable: the governing PIK3CA VCEP excludes PP3 for gain-of-function variants, so predictor scores are not used.	cspec
PP4	N/A	Not applicable: the governing VCEP accounts for phenotype-specific evidence under PS4 rather than PP4.	cspec
PP5	N/A	Not applicable: the VCEP prohibits PP5, and no exact-variant ClinVar expert-panel classification is present.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, below the VCEP BA1 threshold of >0.0926%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from all reported gnomAD datasets, below the VCEP BS1 allele-frequency threshold of >0.0185%.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: no homozygous gnomAD observations or qualifying healthy-family observations are reported, versus the VCEP requirement of at least 3.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no reviewed assay directly showed preserved function for PIK3CA p.Glu545Val, so BS3 cannot be assigned.	cspec PMID:19349352 PMID:24504419
BS4	N/A	Not applicable: the VCEP excludes lack of familial segregation because these mutations are de novo, germline mosaic, or post-zygotic.	cspec
BP1	N/A	Not applicable: the VCEP excludes BP1 because PIK3CA brain-malformation disease is caused by gain of function, not loss of function.	cspec vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2	Not assessed	Not assessed: no documented cis or trans observation with a known pathogenic PIK3CA variant is available for NM_006218.4:c.1634A>T.	cspec
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_006218.4:c.1634A>T in PIK3CA is a missense substitution predicted to produce NP_006209.2:p.(Glu545Val). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3'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
BP4	N/A	Not applicable: the governing PIK3CA VCEP limits BP4 to non-missense splicing or non-coding variants, not this missense change.	cspec
BP5	Not assessed	Not assessed: no documented case shows this exact variant with an alternate molecular diagnosis in a different gene.	cspec
BP6	N/A	Not applicable: the VCEP prohibits BP6, and no exact-variant ClinVar expert-panel benign classification is present.	cspec clinvar
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.1634A>T in PIK3CA is a missense substitution predicted to produce NP_006209.2:p.(Glu545Val). 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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