PIK3CA c.2237A>T, p.Asp746Val
NM_006218.4:c.2237A>T
COSMIC ID: COSM5346973
Variant of Uncertain Significance (VUS)
This missense variant D746V in PIK3CA is absent from population databases (PM2_Supporting), occurs in a missense‐constrained gene (PP2_Supporting), and computational predictions favor benign impact (BP4_Supporting). No other evidence for pathogenicity or benign impact is available. The total evidence is insufficient to classify as pathogenic or benign; therefore, it remains a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
PP2
BP4
Genetic Information
Gene & Transcript Details
Gene
PIK3CA
Transcript
NM_006218.4
MANE Select
Total Exons
21
Strand
Forward (+)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_006218.2 | Alternative | 21 exons | Forward |
| NM_006218.3 | Alternative | 21 exons | Forward |
Variant Details
HGVS Notation
NM_006218.4:c.2237A>T
Protein Change
D746V
Location
Exon 15
(Exon 15 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 746 in gene PIK3CA
Alternate Identifiers
COSM5346973
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.2237A>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 746 in gene PIK3CA
Functional Summary
The PIK3CA D746V variant has not been functionally characterized, and its effect on protein function is currently unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.697
0.697
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
mutationtaster: D
Benign:
CADD: 4.57polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null Variant (nonsense, frameshift, start codon, canonical ±1 or 2 splice sites, single or multi-exon deletion) in a gene where loss-of-function is a known mechanism of disease." The evidence for this variant shows: it is a missense change (D746V), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no previous reports of D746V as pathogenic and no other nucleotide change at codon 746 known to be pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Award PS2_Strong if Criteria 1 AND Criteria 2 are fulfilled for high-confidence somatic de novo mutations with confirmed maternity/paternity and tissue heterogeneity." The evidence for this variant shows: no de novo or parental data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Functional assays meeting SVI/BMVCEP quality metrics demonstrating a damaging effect on protein function." The evidence for this variant shows: no functional studies have been performed for D746V. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Points assigned for phenotype in cases absent from controls (PM2), with strength based on total points from case reports." The evidence for this variant shows: no published case reports or patient data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Supporting evidence for residues affecting critical functional domains provided in Table 4 for each gene." The evidence for this variant shows: D746V lies outside the established helical and kinase hotspot domains in PIK3CA. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent/rare from controls in an ethnically-matched cohort population sample." The evidence for this variant shows: it is absent from gnomAD and other population databases (MAF 0%). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no recessive inheritance or trans data available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: it is a missense change, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate: Different missense change at the same residue previously established as pathogenic." The evidence for this variant shows: no other missense change at codon 746 reported as pathogenic. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "De novo occurrence without confirmation of maternity and paternity." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: "Supporting: Missense constraint computed in ExAC/gnomAD score > 3.09 (applicable to PIK3CA)." The evidence for this variant shows: PIK3CA has a missense Z-score > 3.09, indicating constraint. Therefore, this criterion is applied at Supporting strength.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows: mixed in silico predictions with both benign and pathogenic outputs (REVEL 0.70, SpliceAI 0.02), thus conflicting. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no disease-specific phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source classifies variant as pathogenic without primary evidence." The evidence for this variant shows: not present in ClinVar or other reputable sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Allele frequency > 0.0926%." The evidence for this variant shows: allele frequency = 0% in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: Allele frequency > 0.0185%." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong: ≥3 homozygotes in gnomAD or ≥3 heterozygotes in well-phenotyped family members." The evidence for this variant shows: zero occurrences in gnomAD. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong: Well-validated functional studies show no damaging effect." The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants cause disease." The evidence for this variant shows: PIK3CA disease mechanism is gain-of-function, not solely truncating. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant disorder." The evidence for this variant shows: no data on cis/trans with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function." The evidence for this variant shows: this is a missense single-nucleotide change. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: majority of in silico tools (CADD, PolyPhen-2, MetaSVM, MetaLR, PrimateAI) predict benign and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without primary evidence." The evidence for this variant shows: not reported. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted splice impact and low conservation." The evidence for this variant shows: it is nonsynonymous. Therefore, this criterion is not applied.