Variant classification summary

NM_006218.4:c.3G>A

PIK3CA · NP_006209.2:p.(Met1?) · NM_006218.4

GRCh37: chr3:178916616 G>A · GRCh38: chr3:179198828 G>A

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Met1?)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting is met because the variant has 0 of 1,513,740 alleles and 0 homozygotes in gnomAD v4.1.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not meet any pathogenic, likely pathogenic, benign, or likely benign combination threshold, resulting in a 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: the governing VCEP identifies PIK3CA brain-malformation disease as gain of function, so PVS1 is not used for this initiation-codon variant.	cspec
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.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). 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 proband, parental testing, maternity/paternity confirmation, or tissue allele-fraction data are available to meet the VCEP PS2 criteria.	cspec
PS3	Not assessed	Not assessed: available functional papers do not test c.3G>A (p.M1?), so no variant-specific damaging assay result meets the VCEP PS3 requirements.	cspec PMID:29533785 PMID:31996845
PS4	Not assessed	Not assessed: the variant is absent from gnomAD, but no verified affected-individual phenotype observation was available to assign Table 2A PS4 points.	cspec gnomad_v2 gnomad_v4 gnomad_canada PMID:29533785 PMID:31996845
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.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). 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: the variant has 0/1,513,740 alleles and 0 homozygotes in gnomAD v4.1, within the VCEP one-person maximum.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the VCEP specifies PM3 is not applicable because disease-causing PIK3CA variants 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.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). 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	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.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). 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 routes assumed de novo evidence without parental confirmation to PS2 rather than allowing PM6.	cspec
PP1	N/A	Not applicable: the VCEP excludes PP1 for this disorder because its disease-causing variants are 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.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). 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: initiation-loss variant p.(Met1?) is outside the VCEP's PP3 scope, which excludes this gain-of-function consequence.	cspec
PP4	N/A	Not applicable: the Brain Malformations VCEP explicitly accounts for phenotype-specific evidence under PS4 rather than PP4.	cspec
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel pathogenic or likely pathogenic classification for NM_006218.4:c.3G>A.	clinvar cspec
BA1	Not met	Not met: gnomAD v4.1 allele frequency is 0/1,513,740 (0%), below the VCEP BA1 threshold of >0.0926%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 allele frequency is 0/1,513,740 (0%), below the VCEP BS1 threshold of >0.0185%.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports 0 homozygotes, below the VCEP requirement of at least 3 homozygotes or 3 qualifying family observations.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no fetched functional paper tests c.3G>A (p.M1?) and reports a validated normal-function result required for BS3.	cspec PMID:29533785 PMID:31996845
BS4	N/A	Not applicable: the VCEP excludes BS4 because this disorder is evaluated using de novo, germline-mosaic, or post-zygotic 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.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). 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 documented cis/trans PIK3CA pathogenic-variant pair or phase result is available for NM_006218.4:c.3G>A.	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.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). 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: initiation-loss variant p.(Met1?) is neither synonymous, intronic, nor UTR, the VCEP-defined BP4 scope.	cspec
BP5	Not assessed	Not assessed: no case was documented in which this exact variant co-occurred with a confirmed alternate molecular basis in another gene.	cspec
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign or likely benign classification for NM_006218.4:c.3G>A.	clinvar cspec
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.3G>A in PIK3CA is a variant affecting the translation-initiation codon (Met1) predicted to produce NP_006209.2:p.(Met1?). 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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