Variant classification summary

NM_006218.4:c.1255_1264delinsA

PIK3CA · NP_006209.2:p.(His419_Leu422delinsMet) · NM_006218.4

GRCh37: chr3:178927977 CACTGTCCAT>A · GRCh38: chr3:179210189 CACTGTCCAT>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.(His419_Leu422delinsMet)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PIK3CA c.1255_1264delinsA (p.His419_Leu422delinsMet; p.H419_L422delinsM) variant has not been reported in ClinVar, while OncoKB classifies it as Likely Oncogenic.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting that it is absent or extremely rare in population controls.

3

The altered residues fall within the PIK3CA kinase domain spanning amino acids 322 to 483, which is an approved Brain Malformations VCEP critical functional domain and supports PM1 at Supporting strength.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01.

Final determination: Using the Brain Malformations Tavtigian point framework, PM1_Supporting and PM2_Supporting total 2 points, supporting 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
PS1	Not met	No previously established pathogenic variant producing the same protein change was identified. This variant is absent from ClinVar, and no published case reports were identified to support PS1.	clinvar
BS4	N/A	BS4 is not applicable under the Brain Malformations VCEP because these disorders are typically caused by de novo, germline mosaic, or post-zygotic variants, so lack of segregation is not used.	cspec
BS2	Not met	This variant has not been observed in gnomAD, so it does not meet the BS2 requirement of at least 3 homozygotes in population data. No evidence of at least 3 well-phenotyped unaffected heterozygous family members was identified.	gnomad_v2 gnomad_v4 cspec
PS2	Not assessed	No parental testing results or multi-tissue allele-fraction data were identified. Available evidence therefore does not establish the de novo or tissue-restricted mosaic findings required for PS2 under the Brain Malformations VCEP.	cspec
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 this VCEP because these disorders are driven by gain-of-function mechanisms, and conventional pathogenicity prediction tools are not considered reliable for this purpose.	cspec
PM1	Met	This protein-altering variant affects residues 419 to 422, which fall within the PIK3CA kinase domain spanning amino acids 322 to 483. The Brain Malformations VCEP lists this interval as an approved 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
PS4	Not met	This variant is absent from population databases and therefore satisfies the PM2 prerequisite for PS4 consideration, but no qualifying affected case reports or phenotype points were identified. Available evidence does not support any PS4 point total above the Supporting threshold of 0.5 points.	gnomad_v2 gnomad_v4 cspec clinvar
PVS1	N/A	PVS1 is not applicable for PIK3CA in the Brain Malformations VCEP because the disease mechanism is gain of function rather than loss of function. The variant-specific PVS1 scaffold also does not place this delins variant into a generic null-variant category.	cspec pvs1_gene_context pvs1_variant_assessment
PP5	N/A	PP5 is not used under current ClinGen SVI recommendations and is explicitly marked not applicable in this VCEP.	cspec
BP7	N/A	BP7 is restricted to synonymous, intronic, or UTR variants. This is a protein-altering in-frame delins variant, so BP7 does not apply.	cspec
BP5	Not assessed	No alternate molecular diagnosis or other established molecular basis for the reported phenotype was identified. BP5 cannot be assessed from the available evidence.
BP4	N/A	BP4 is restricted by this VCEP to synonymous, intronic, or UTR variants evaluated with splice-prediction tools. Although SpliceAI predicts a low splice effect for this variant (max delta score 0.01), BP4 is not applicable to this protein-altering delins variant.	cspec spliceai
BP3	N/A	BP3 is not applicable under this VCEP because these genes are not interpreted using a repetitive-region benign framework for in-frame indels.	cspec
BP2	Not assessed	No data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant. BP2 cannot be assessed from the available evidence.
BP1	N/A	BP1 is not applicable because the Brain Malformations VCEP does not use loss-of-function-based benign reasoning for PIK3CA gain-of-function disease.	cspec
BS3	Not assessed	No well-established functional studies showing no damaging effect were identified. BS3 therefore cannot be assessed.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BA1 threshold of greater than 0.0926%. BA1 is therefore not met.	gnomad_v2 gnomad_v4 cspec
PP2	N/A	PP2 in this VCEP is a missense-constraint criterion for missense variants. This variant is an in-frame deletion-insertion rather than a missense change, so PP2 does not apply.	cspec
PP1	N/A	PP1 is not applicable under this VCEP because disease-causing variants are typically de novo or mosaic rather than segregating through families.	cspec
PM5	N/A	PM5 is a novel missense criterion for a different missense change at the same residue. This variant is an in-frame deletion-insertion rather than a missense substitution, so PM5 does not apply.	cspec
PM4	N/A	Although this is an in-frame deletion-insertion, the Brain Malformations VCEP specifically does not use PM4 for these gain-of-function genes.	cspec
PM3	N/A	PM3 is not applicable because the relevant PIK3CA brain malformation disorders are not interpreted as recessive conditions in this VCEP.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting that it is absent or extremely rare in population controls. Under the Brain Malformations VCEP, this meets PM2 at Supporting strength.	gnomad_v2 gnomad_v4 cspec
PS3	Not assessed	No validated functional assay data specific to this variant were identified. PS3 therefore cannot be assessed from the available evidence.	cspec
BP6	N/A	BP6 is not used under current ClinGen SVI recommendations and is explicitly marked not applicable in this VCEP.	cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 threshold of greater than 0.0185%. BS1 is therefore not met.	gnomad_v2 gnomad_v4 cspec
PM6	N/A	PM6 is not applied in this VCEP because de novo evidence is addressed through PS2.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.