The PIK3CA c.1132T>C (p.Cys378Arg) variant has been reported in ClinVar with an overall Pathogenic classification, and curated somatic oncology resources also list this variant in cancer-associated context.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, including 0/1519490 alleles and 0 homozygotes in gnomAD v4.1, which supports rarity in population controls.2 Curated functional literature links and a published PIK3CA study support a gain-of-function disease mechanism for mutant PIK3CA, but variant-specific assay evidence meeting Brain Malformations VCEP PS3 requirements was not established for p.Cys378Arg.3 The variant lies in a Brain Malformations VCEP-approved PIK3CA functional domain, a different missense change at the same residue has been reported as pathogenic, and SpliceAI predicts no splice effect; REVEL and BayesDel scores are also elevated, although PP3 is not applied by this VCEP for gain-of-function missense variants.4
Final classification
VUS
PM1PM2PM5
PIK3CA
c.1132T>C
p.Cys378Arg
This variant
The PIK3CA c.1132T>C (p.Cys378Arg) variant has been reported in ClinVar with an overall Pathogenic classification, and curated somatic oncology resources also list this variant in cancer-associated context.
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PM1 supporting (+1) + PM2 supporting (+1) + PM5 moderate (+2) = 4 points, which maps to VUS.
Classification rationale
PM1PM2PM5
VUS
PIK3CA c.1132T>C
PM1 + PM2 + PM5
→
VUS
4
cspec ↗clinvar ↗spliceai ↗revelbayesdelvcep_clingen_brainmalform_acmg_specifications_v1_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 · 3 applied · 11 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PM1
supporting
Pathogenic
Residue Cys378 lies within the PIK3CA amino acid 322-483 interval listed by the Brain Malformations VCEP as an approved critical functional domain for PM1_Supporting, so PM1 is met at supporting strength.
PIK3CA Table 4 approved domain AA 322-483Variant protein consequence p.Cys378Arg
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0/1519490 alleles and 0 homozygotes in gnomAD v4.1; this is below the VCEP PM2 requirement for absent or rare variation in controls and supports PM2 at supporting strength.
gnomAD v2.1 absentgnomAD v4.1 total AC 0 of 1519490 alleles
PM5
moderate
review
Pathogenic
A different missense change at the same residue, PIK3CA p.Cys378Tyr, is reported in ClinVar as Pathogenic with multiple submitters and no conflicts. Because this variant is also a missense change at codon 378 and SpliceAI predicts no splice impact (max delta score 0.00), classic same-residue PM5 is supported at moderate strength.
ClinVar same-residue comparator p.Cys378Tyr classified PathogenicSpliceAI max delta score 0.00 for p.Cys378Arg
Assessed · not applied
· 4 not met · 7 not assessed
Pathogenic
PS1
No alternate nucleotide change producing the same p.Cys378Arg amino acid substitution was identified in the reviewed ClinVar evidence, and SpliceAI predicts no splice effect that would complicate a protein-based comparison.
PS2
No confirmed de novo or tissue-comparison data were identified to show this variant was absent from parental samples and enriched in affected tissue, so PS2 cannot be applied from the reviewed evidence.
PS3
Curated literature links and a published PIK3CA functional study support a gain-of-function disease mechanism for PIK3CA variants, but variant-specific assay details meeting the Brain Malformations VCEP validation requirements were not established for p.Cys378Arg from the reviewed evidence.
PS4
This variant is rare enough to satisfy the PM2 prerequisite, but the reviewed evidence did not provide a consolidated phenotype-based point total under the Brain Malformations VCEP PS4 scoring system, so PS4 was not applied.
PP2
The Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the gene-specific missense constraint threshold is exceeded, but a registered case-source record documenting that threshold assessment for this case was not included in the reviewed evidence, so PP2 was left unscored.
Benign
BA1
This variant does not meet BA1 because it is absent from gnomAD, with 0/1519490 alleles in gnomAD v4.1, which is below the VCEP BA1 threshold of greater than 0.0926%.
BS1
This variant does not meet BS1 because it is absent from gnomAD, with 0/1519490 alleles in gnomAD v4.1, which is below the VCEP BS1 threshold of greater than 0.0185%.
BS2
This variant does not meet BS2 because no homozygotes were observed in gnomAD v4.1, whereas the Brain Malformations VCEP requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected family observations.
BS3
No well-established study demonstrating normal or non-damaging function for p.Cys378Arg was identified, so BS3 was not applied.
BP2
No phase information was identified showing this variant in cis or trans with another known pathogenic PIK3CA variant, so BP2 was not applied.
BP5
No alternate molecular diagnosis was identified that would explain the phenotype independently of this variant, so BP5 was not applied.
N/A · 14
PVS1 · PM3 · PM4 · PM6 · PP1 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1519490 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73306 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,519,490
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 917489)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.817. BayesDel score = 0.273988.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55882697, n = 16 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links
Triaged references · 14 PMIDs not cited in assessment
17363507 ↗
Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis.
ONCOKB
23652378 ↗
A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.
CLINVAR
25626707 ↗
Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
CLINVAR
25730230 ↗
Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
31585106 ↗
Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism: A Five-Year Cumulative Cohort.
CLINVAR
33105631 ↗
Somatic Variant Analysis Identifies Targets for Tailored Therapies in Patients with Vascular Malformations.
CLINVAR
22947299 ↗
Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.
CLINVAR
23037933 ↗
Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.
CLINVAR
23881473 ↗
Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.
CLINVAR
24022298 ↗
Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].
CLINVAR
24394680 ↗
Parental permission for pilot newborn screening research: guidelines from the NBSTRN.
CLINVAR
31022120 ↗
ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.
CLINVAR