NM_006218.4:c.2782C>T

PIK3CA · NP_006209.2:p.(Gln928Ter) · NM_006218.4

GRCh37: chr3:178947907 C>T · GRCh38: chr3:179230119 C>T

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM1_Supporting PM2_Supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Gln928Ter)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PIK3CA c.2782C>T (p.Gln928Ter; p.Q928*) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is within the Brain Malformations VCEP PM2_Supporting threshold of at most 1 occurrence in population data and below the BS1 (>0.0185%) and BA1 (>0.0926%) thresholds.

The variant lies within the PIK3CA kinase domain approved for PM1_Supporting by the Brain Malformations VCEP (amino acids 797-1068), supporting location in a critical functional region.

SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.10, although PP3 and BP4 are not applicable to this nonsense variant under the Brain Malformations VCEP specifications.

Final determination: With only PM1_Supporting and PM2_Supporting met, the criteria combination does not reach Likely Pathogenic or Likely Benign thresholds and is therefore classified as 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
PS1	Not met	This nonsense variant results in p.(Gln928Ter), but no previously established pathogenic variant with the same amino acid change was identified. ClinVar contains no entry for this variant and no literature reports were identified, so PS1 is not met.	cspec clinvar literature_pass
BS4	N/A	BS4 is not applicable under the Brain Malformations VCEP because these disorders are interpreted in the context of de novo, germline mosaic, or post-zygotic variants rather than lack of segregation in affected relatives.	cspec
BS2	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the VCEP BS2 threshold of at least 3 homozygotes in population data. No well-phenotyped unaffected family members carrying the variant were identified.	cspec gnomad_v2 gnomad_v4
PS2	Not assessed	No case-specific parental testing or multi-tissue allele fraction data were identified. Available evidence therefore does not allow assessment of the Brain Malformations VCEP PS2 de novo/mosaic criteria.	cspec literature_pass
PP4	N/A	PP4 is not applicable under the Brain Malformations VCEP because phenotype specificity is incorporated into the PS4 point-based framework.	cspec
PP3	N/A	PP3 is not applicable under the Brain Malformations VCEP because these disorders are primarily interpreted as gain-of-function conditions, and the specification states that traditional pathogenicity prediction algorithms are not used for this criterion.	cspec spliceai
PM1	Met	This variant truncates PIK3CA at p.(Gln928Ter), which lies within the PIK3CA kinase domain approved by the Brain Malformations VCEP for PM1_Supporting (amino acids 797-1068). This location is within a critical functional domain, so PM1 is met at supporting strength.	cspec
PS4	Not met	This variant is absent from gnomAD and therefore satisfies the population prerequisite for PS4 consideration, but no phenotype-based case evidence was identified to contribute PS4 points. The variant was not found in COSMIC, is absent from ClinVar, and no literature reports were identified, so PS4 is not met.	cspec gnomad_v2 gnomad_v4 cosmic clinvar literature_pass
PVS1	N/A	Although this is a nonsense variant, PVS1 is not applicable under the Brain Malformations VCEP because the specification states that loss of function is not the established disease mechanism for these genes and that the relevant disease mechanism is gain of function. The generic PVS1 scaffold was not used because official VCEP rules take precedence.	cspec pvs1_gene_context pvs1_variant_assessment
PP5	N/A	PP5 is not applicable because the ClinGen SVI VCEP Review Committee does not recommend use of this criterion.	cspec
BP7	N/A	BP7 is limited to synonymous, intronic non-canonical splice, or UTR variants with low conservation. This variant is a nonsense coding change, so BP7 is not applicable.	cspec
BP5	Not assessed	No evidence was identified showing that this variant was observed in an individual with an alternate molecular basis for disease in a different gene. BP5 therefore could not be assessed from the available evidence.	cspec literature_pass
BP4	N/A	BP4 under this VCEP is restricted to synonymous, intronic non-canonical splice, or UTR variants when at least 2 of 3 splicing tools predict no splicing impact. Although SpliceAI predicts no significant splice effect with a maximum delta score of 0.10, this variant is a nonsense coding change, so BP4 is not applicable.	cspec spliceai
BP3	N/A	BP3 is not applicable under the Brain Malformations VCEP because these genes do not have approved repetitive regions without known function for use of this criterion.	cspec
BP2	Not assessed	No evidence was identified showing that this variant was observed in cis or trans with a known pathogenic variant in PIK3CA. BP2 therefore could not be assessed from the available evidence.	cspec literature_pass
BP1	N/A	BP1 is not applicable under the Brain Malformations VCEP because loss of function is not the disease mechanism for these genes.	cspec
BS3	Not assessed	No well-established functional studies showing no damaging effect for this specific variant were identified. BS3 could not be assessed from the available evidence.	cspec literature_pass
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%. BA1 is not met.	cspec gnomad_v2 gnomad_v4
PP2	N/A	PP2 applies to missense variants in genes with missense constraint. This variant is a nonsense change rather than a missense variant, so PP2 is not applicable.	cspec
PP1	N/A	PP1 is not applicable under the Brain Malformations VCEP because disease-causing variants in this framework are typically germline mosaic, de novo, or mosaic rather than segregating through multiple affected relatives.	cspec
PM5	N/A	PM5 is restricted to a novel missense change at a residue where a different pathogenic missense change has been observed. This variant is a nonsense change, so PM5 is not applicable.	cspec
PM4	N/A	PM4 is not applicable under the Brain Malformations VCEP for these genes. This criterion is reserved for in-frame insertions/deletions or stop-loss variants and is not used in this framework.	cspec
PM3	N/A	PM3 is not applicable under the Brain Malformations VCEP because the relevant disease-causing variants are interpreted as heterozygous rather than recessive biallelic variants.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele count is 0, which is within the Brain Malformations VCEP PM2_Supporting threshold of at most 1 occurrence in population data. PM2 is met at supporting strength.	cspec gnomad_v2 gnomad_v4
PS3	Not assessed	No well-established functional studies supporting a damaging effect for this specific variant were identified. PS3 could not be assessed from the available evidence.	cspec literature_pass
BP6	N/A	BP6 is not applicable because the ClinGen SVI VCEP Review Committee does not recommend use of this criterion.	cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%. BS1 is not met.	cspec gnomad_v2 gnomad_v4
PM6	N/A	PM6 is not applicable under the Brain Malformations VCEP because de novo evidence is addressed through PS2 rather than PM6.	cspec

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