NM_006218.4:c.1265del

PIK3CA · NP_006209.2:p.(Leu422TrpfsTer6) · NM_006218.4

GRCh37: chr3:178927985 AT>A · GRCh38: chr3:179210197 AT>A

Gene: PIK3CA Transcript: NM_006218.4

Final call

PM1_Supporting PM2_Supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Leu422TrpfsTer6)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PIK3CA c.1265del (p.(Leu422TrpfsTer6)) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at Supporting strength, and its observed population frequency of 0% is below the VCEP BS1 threshold of >0.0185% and BA1 threshold of >0.0926%.

The altered residue lies within the approved PIK3CA kinase-domain interval spanning amino acids 322-483, which is a Brain Malformations VCEP critical functional domain and supports PM1_Supporting.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.07, although computational pathogenicity criteria are not applied for PIK3CA gain-of-function interpretation in this VCEP framework.

Final determination: Two pathogenic supporting criteria yield 2 Tavtigian points, which falls in the 0 to 5 range and supports a classification 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	This frameshift variant would ordinarily trigger generic loss-of-function review, but the Brain Malformations VCEP specifies that PVS1 is not applicable for PIK3CA because the relevant disease mechanism is gain of function.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 is defined for a variant that creates the same amino acid substitution as a previously established pathogenic variant. This variant is a frameshift, not an amino acid substitution, so PS1 is not applicable.	cspec
PS2	Not assessed	No confirmed de novo or tissue-mosaic data were identified. Available evidence does not show absence from both parents with confirmed maternity and paternity, or a higher allele fraction in affected tissue than in another tissue, so PS2 cannot be assessed from the current evidence.	cspec
PS3	Not assessed	No validated functional studies demonstrating an abnormal effect of this specific variant were identified, so PS3 is not assessed.	cspec
PS4	Not met	This variant meets the PM2 population prerequisite because it is absent from gnomAD v2.1 and v4.1, but the available case-level observation data do not reach the VCEP PS4 threshold. Only a single somatic cancer observation was identified and no phenotype-pointed germline case series were identified, so the evidence does not reach the minimum PS4_Supporting threshold of 0.5 points.	cspec gnomad_v2 gnomad_v4
PM1	Met	The altered residue Leu422 lies within the approved PIK3CA kinase-domain interval spanning amino acids 322-483 in the Brain Malformations VCEP specification. This location is a listed critical functional domain, which supports PM1 at Supporting strength.	cspec vcep_c_l_i_n_g_e_n___b_r_a_i_n_m_a_l_f_o_r_m___a_c_m_g___s_p_e_c_i_f_i_c_a_t_i_o_n_s___v_1___1
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the Brain Malformations VCEP PM2 threshold requiring absence or rarity in controls with no more than one person observed. These data support PM2 at Supporting strength.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this VCEP framework.	cspec
PM4	N/A	PM4 is not applicable in this VCEP framework.	cspec
PM5	N/A	PM5 applies to a novel missense change at an amino acid residue where a different missense pathogenic variant has been established. This variant is a frameshift, so PM5 is not applicable.	cspec
PM6	N/A	PM6 is not applicable in this VCEP framework.	cspec
PP1	N/A	PP1 is not applicable in this VCEP framework.	cspec
PP2	N/A	PP2 applies to missense variants. This variant is a frameshift, so PP2 is not applicable.	cspec
PP3	N/A	PP3 is not applicable in the Brain Malformations VCEP framework for PIK3CA gain-of-function interpretation, so computational pathogenicity prediction is not used to support pathogenicity here.	cspec spliceai
PP4	N/A	PP4 is not applicable in this VCEP framework because phenotype specificity is incorporated into the PS4 point-based system.	cspec
PP5	N/A	PP5 is not applicable in this VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, so the observed population 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
BS1	Not met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, so the observed population 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
BS2	Not met	BS2 requires at least 3 homozygotes in gnomAD or at least 3 heterozygous occurrences in well-phenotyped family members. This variant is absent from gnomAD and no such family observations were identified, so BS2 is not met.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	No well-validated functional studies demonstrating a normal effect for this specific variant were identified, so BS3 is not assessed.	cspec
BS4	N/A	BS4 is not applicable in this VCEP framework because these disorders are interpreted in the context of de novo, germline mosaic, or post-zygotic variation rather than conventional lack-of-segregation evidence.	cspec
BP1	N/A	BP1 is not applicable in this VCEP framework.	cspec
BP2	Not assessed	No evidence was identified showing this variant in cis or trans with a known pathogenic variant in PIK3CA, so BP2 is not assessed.	cspec
BP3	N/A	BP3 is not applicable in this VCEP framework.	cspec
BP4	N/A	BP4 in this VCEP framework is limited to synonymous, non-canonical intronic, and UTR variants with no predicted splice effect. This variant is a frameshift, so BP4 is not applicable, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.07.	cspec spliceai
BP5	Not assessed	No evidence was identified showing an alternate molecular explanation that would account for the phenotype independently of this variant, so BP5 is not assessed.	cspec
BP6	N/A	BP6 is not applicable in this VCEP framework.	cspec
BP7	N/A	BP7 applies to synonymous, non-canonical intronic, and UTR variants with low conservation and no predicted splice impact. This variant is a frameshift, so BP7 is not applicable.	cspec spliceai

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