PIK3CA c.47T>C, p.Met16Thr
NM_006218.4:c.47T>C
Variant of Uncertain Significance (VUS)
c.47T>C (p.Met16Thr) in PIK3CA is absent from population databases (PM2_Supporting) but lacks any supporting pathogenic or benign criteria. In silico and splicing predictions are not applicable for VCEP BP4, and there is no functional, segregation, de novo or case-level evidence. Therefore, the variant remains classified as a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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.47T>C
Protein Change
M16T
Location
Exon 2
(Exon 2 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 16 in gene PIK3CA
Variant interpretation based on transcript NM_006218.4
Genome Browser
Loading genome browser...
HGVS InputNM_006218:c.47T>C
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
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 16 in gene PIK3CA
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.55
0.55
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:
primateai: D
Benign:
CADD: 4.32metasvm: Tmetalr: 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, canonical +/−1 or 2 splice sites, initiation codon, single exon 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 (M16T), not a null variant. Therefore, this criterion is not applied because the variant does not lead to loss of function.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines (no modification to PS1), 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: there is no previously established pathogenic variant resulting in Met16Thr. Therefore, this criterion is not applied because the variant does not match any known pathogenic amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2_Strong is: "Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled. Criteria 1. The variant is present at a detectable allele fraction but is absent from parental samples with confirmed maternity and paternity. Criteria 2. The variant is present at a detectable allele fraction in an affected tissue sample but is absent from or detected at a lower allelic fraction in another tissue." The evidence for this variant shows: no de novo or tissue allele fraction data are available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3_Strong is: "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required." The evidence for this variant shows: no functional assays or validated experimental data are available. Therefore, this criterion is not applied because functional impact has not been experimentally assessed.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B)." The evidence for this variant shows: no published case reports or phenotype data. Therefore, this criterion is not applied due to absence of case-level evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1_Supporting is: "Residues affecting critical functional domains provided in Table 4 for each gene." The evidence for this variant shows: Met16 is not located in a VCEP-defined critical hotspot or functional domain for PIK3CA. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2_Supporting is: "Absent/rare from controls in an ethnically-matched cohort population sample ( ≥1)." The evidence for this variant shows: it is absent from gnomAD, ExAC, 1000 Genomes and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
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 evidence of trans configuration with another pathogenic PIK3CA variant. Therefore, this criterion is not applied because trans data are not available or not relevant for this dominant gene.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions." The evidence for this variant shows: Met16Thr is a missense substitution without change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines (no modification to PM5), the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows: no other pathogenic variants at codon 16 are reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Unconfirmed de novo variant in a patient with the disease and no family history." The evidence for this variant shows: no parental testing or de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation 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 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2_Supporting is: "Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09." The evidence for this variant shows: no missense constraint z-score ≥3.09 is provided. Therefore, this criterion is not applied.
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 on gene or gene product." The evidence for this variant shows: in silico predictions are mixed (CADD low, REVEL intermediate, SpliceAI no impact). Therefore, this criterion is not applied due to conflicting computational evidence.
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 phenotype or clinical context provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic." The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1_Stand Alone is: "Allele frequency (>0.0926%)." The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1_Strong is: "Allele frequency (>0.0185%)." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2_Strong is: "Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members." The evidence for this variant shows: no homozygotes or well‐phenotyped carriers reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3_Strong is: "Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required." The evidence for this variant shows: no functional studies demonstrating benign effect. 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 are known to cause disease." The evidence for this variant shows: PIK3CA disease mechanism is gain-of-function missense, not loss-of-function. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2_Supporting is: "Observed in cis or trans with a known pathogenic variant in the same gene." The evidence for this variant shows: no evidence of cis or trans occurrence with another pathogenic PIK3CA variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame insertions/deletions in a repetitive region without a known function." The evidence for this variant shows: M16T is a single amino acid substitution, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4_Supporting is: "Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function." The evidence for this variant shows: M16T is a missense coding change, not a synonymous or non-coding variant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5_Supporting is: "No change from standard." The evidence for this variant shows: no evidence it is observed in a case with an alternate genetic etiology. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign." The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7_Supporting is: "For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1)." The evidence for this variant shows: M16T is a missense change. Therefore, this criterion is not applied.