NM_006218.4:c.412G>T

PIK3CA · NP_006209.2:p.(Asp138Tyr) · NM_006218.4

GRCh37: chr3:178917537 G>T · GRCh38: chr3:179199749 G>T

Gene: PIK3CA Transcript: NM_006218.4

Final call

VUS

PM2_supporting PP2_supporting

Variant details

Gene

PIK3CA

Transcript

NM_006218.4

Protein

NP_006209.2:p.(Asp138Tyr)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_006218.4:c.412G>T (p.Asp138Tyr; p.D138Y) is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at supporting strength under the Brain Malformations specification.

PIK3CA is missense constrained, and the gnomAD missense z-score is 8.75, which is greater than the PP2 threshold of 3.09 defined in the specification.

Asp138 is outside the PIK3CA adaptor-binding domain (amino acids 31-108), Ras-binding domain (173-292), and kinase domains (322-483 and 797-1068) listed in Table 4, so PM1 is not supported.

ClinVar does not contain this variant, and no case-level, segregation, or functional evidence sufficient for PS1, PS2, PS3, PS4, PM5, BS3, PP1, BP2, or BP5 was available.

With PM2_supporting and PP2_supporting alone, the variant is classified as a variant of uncertain significance.

Final determination:

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 assessed	No established pathogenic variant producing the same amino acid change was documented in the case materials, so PS1 was not applied.	clinvar
BS4	N/A	BS4 is designated not applicable by the Brain Malformations VCEP for this gene-disease framework.	cspec
BS2	Not met	The variant is absent from gnomAD v2.1 and gnomAD v4.1, so there are not at least 3 homozygotes to support BS2, and no well-phenotyped unaffected family data were provided.	gnomad_v2 gnomad_v4 cspec
PS2	Not assessed	No de novo or mosaic tissue-distribution data were provided to evaluate PS2 under the Brain Malformations specification.	cspec
PP4	N/A	PP4 is designated not applicable by the Brain Malformations VCEP because phenotype specificity is incorporated into PS4.	cspec
PP3	N/A	PP3 is not applicable in this gain-of-function framework for PIK3CA.	cspec
PM1	Not met	Asp138 lies outside the PIK3CA critical regions listed in Table 4 of the Brain Malformations specification: adaptor-binding domain amino acids 31-108, Ras-binding domain amino acids 173-292, and kinase domains amino acids 322-483 and 797-1068; therefore PM1 is not met.	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	No qualifying affected case evidence or literature-based point total was available, so PS4 was not met.	cspec clinvar
PVS1	N/A	PVS1 is not applicable in this Brain Malformations VCEP framework because loss of function is not the established disease mechanism for these genes.	cspec
PP5	N/A	PP5 is not used by this VCEP framework.	cspec
BP7	N/A	BP7 is limited to synonymous, certain intronic, and non-coding variants and is not applicable to this missense substitution.	cspec
BP5	Not assessed	No alternate molecular diagnosis was provided to support BP5.	cspec
BP4	N/A	BP4 is restricted by this specification to synonymous, selected intronic, and non-coding variants, so it is not applicable to this missense variant despite a low SpliceAI score.	cspec spliceai
BP3	N/A	BP3 is designated not applicable by the Brain Malformations VCEP for these genes.	cspec
BP2	Not assessed	No cis/trans phasing data with another known pathogenic PIK3CA variant were provided, so BP2 was not assessed.	cspec
BP1	N/A	BP1 is not applicable because loss of function is not the relevant disease mechanism in this VCEP framework.	cspec
BS3	Not assessed	No well-validated functional studies showing no damaging effect were provided, so BS3 was not applied.	cspec
BA1	Not met	The variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0 and does not exceed the BA1 threshold of greater than 0.0926%.	gnomad_v2 gnomad_v4 cspec
PP2	Met	PP2 is met at supporting strength because PIK3CA has a gnomAD missense constraint z-score of 8.75, which is greater than the Brain Malformations specification threshold of 3.09.	cspec
PP1	N/A	PP1 is designated not applicable by the Brain Malformations VCEP for this disorder framework.	cspec
PM5	Not assessed	No established pathogenic missense variant at codon 138 was documented in the supplied materials, so PM5 was not applied.	clinvar
PM4	N/A	PM4 is not applicable in this VCEP framework.	cspec
PM3	N/A	PM3 is not applicable because the disorder mechanism in this framework is heterozygous rather than recessive.	cspec
PM2	Met	PM2 is met at supporting strength because the variant is absent from both gnomAD v2.1 and gnomAD v4.1; the Brain Malformations specification defines PM2 for variants absent or rare in controls and does not provide a more granular quantitative cutoff beyond that statement.	gnomad_v2 gnomad_v4 cspec
PS3	Not assessed	No validated functional assay data meeting Brain Malformations VCEP requirements were provided, so PS3 was not applied.	cspec
BP6	N/A	BP6 is not used by this VCEP framework.	cspec
BS1	Not met	The variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0 and does not exceed the BS1 threshold of greater than 0.0185%.	gnomad_v2 gnomad_v4 cspec
PM6	N/A	PM6 is not used in this framework because de novo evidence is handled under PS2.	cspec

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