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.1 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.2 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.3 With PM2_supporting and PP2_supporting alone, the variant is classified as a variant of uncertain significance.
Final classification
VUS
PP2PM2
PIK3CA
c.412G>T
p.Asp138Tyr
This variant
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.
Brain Malformations VCEP qualitative combination
Classification rationale
PP2PM2
VUS
PIK3CA c.412G>T
PP2 + PM2
→
VUS
2
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_006218.4 · variants mapped to exon structure
PIK3CA
NM_006218.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PP2
Supporting
review
Pathogenic
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.
PIK3CA gnomAD missense z-score = 8.751433431539786.PP2 threshold in the specification is z-score > 3.09.
PM2
Supporting
review
Pathogenic
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.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.PM2 is specified at supporting strength for variants absent/rare in controls.
Assessed · not applied
· 5 not met · 7 not assessed
Pathogenic
PS1
No established pathogenic variant producing the same amino acid change was documented in the case materials, so PS1 was not applied.
PS2
No de novo or mosaic tissue-distribution data were provided to evaluate PS2 under the Brain Malformations specification.
PM1
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.
PS4
No qualifying affected case evidence or literature-based point total was available, so PS4 was not met.
PM5
No established pathogenic missense variant at codon 138 was documented in the supplied materials, so PM5 was not applied.
PS3
No validated functional assay data meeting Brain Malformations VCEP requirements were provided, so PS3 was not applied.
Benign
BS2
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.
BP5
No alternate molecular diagnosis was provided to support BP5.
BP2
No cis/trans phasing data with another known pathogenic PIK3CA variant were provided, so BP2 was not assessed.
BS3
No well-validated functional studies showing no damaging effect were provided, so BS3 was not applied.
BA1
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%.
BS1
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%.
N/A · 14
BS4 · PP4 · PP3 · PVS1 · PP5 · BP7 · BP4 · BP3 · BP1 · PP1 · PM4 · PM3 · BP6 · PM6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers.
COSMIC
Cancer hotspots
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV56030538, n = 2 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links