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.
PIK3CA
Final classification
VUS
PIK3CA c.412G>T · p.Asp138Tyr
PIK3CA
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
Gene diagram
· NM_006218.4 · variants mapped to exon structure
PIK3CA
NM_006218.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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