PIK3CA c.2547G>A, p.Glu849=
NM_006218.4:c.2547G>A
Variant of Uncertain Significance (VUS)
c.2547G>A (p.Glu849=) in PIK3CA is a synonymous variant absent from controls (PM2_Supporting) with no predicted splicing impact (BP4_Supporting). No additional pathogenic or benign evidence is available; the net evidence remains conflicting and insufficient, resulting in a Variant of Uncertain Significance classification.
ACMG/AMP Criteria Applied
PM2
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.2547G>A
Protein Change
E849=
Location
Exon 18
(Exon 18 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.2547G>A
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.57
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 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 synonymous change (E849=) that does not introduce a null effect. Therefore, this criterion is not applied at Not Applied strength because the variant does not produce a loss-of-function.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Strong No change. Modification Type: None." The evidence for this variant shows: it does not result in an amino acid change matching a previously established pathogenic variant. Therefore, this criterion is not applied at Not Applied strength because there is no identical amino acid change to a known pathogenic variant.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Strong Strength: Strong Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled..." The evidence for this variant shows: no de novo or somatic tissue/family data are available. Therefore, this criterion is not applied at Not Applied strength because de novo confirmation criteria are unmet.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Strong Strength: Strong Follow recommendations set forth by the SVI..." The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional evidence is lacking.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Very Strong Strength: Points are assigned for phenotype according to (Table 2A)..." The evidence for this variant shows: no case or phenotype data have been reported. Therefore, this criterion is not applied at Not Applied strength because case/control evidence is absent.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Supporting Strength: Supporting Residues affecting critical functional domains provided in Table 4 for each gene." The evidence for this variant shows: it is synonymous and not located in a known functional domain. Therefore, this criterion is not applied at Not Applied strength because the variant does not alter a critical domain.
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 ( ≥1)." The evidence for this variant shows: it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is not observed in 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 information on trans configuration or recessive inheritance. Therefore, this criterion is not applied at Not Applied strength because recessive evidence is unavailable.
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 synonymous without any protein length change. Therefore, this criterion is not applied at Not Applied strength because there is no alteration of protein length.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate Strength: Moderate No change. Modification Type: None." The evidence for this variant shows: it does not result in a missense change and there is no known different amino acid substitution at this position. Therefore, this criterion is not applied at Not Applied strength because PM5 applies only to novel missense changes at the same residue.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied at Not Applied strength because de novo status is unconfirmed.
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 segregation data. Therefore, this criterion is not applied at Not Applied strength because family segregation information is lacking.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2 is: "Supporting Strength: Supporting Missense constraint computed in ExAC/gnomAD was utilized..." The evidence for this variant shows: it is a synonymous change, not a missense. Therefore, this criterion is not applied at Not Applied strength because PP2 applies only to missense variants.
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 the gene or gene product." The evidence for this variant shows: in silico predictors are benign and predict no splicing impact. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support pathogenicity.
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 data linked to PIK3CA-related disease. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity is unavailable.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: no entries in ClinVar or other databases. Therefore, this criterion is not applied at Not Applied strength because no external pathogenic assertion exists.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Stand Alone Allele frequency (>0.0926%)." The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied at Not Applied strength because the variant is not common.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Strong Allele frequency (>0.0185%)." The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied at Not Applied strength because frequency is not above the threshold.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Strong Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied at Not Applied strength because homozygote or family data are lacking.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Strong Follow recommendations set forth by the SVI..." The evidence for this variant shows: no functional assays demonstrating benign effect. Therefore, this criterion is not applied at Not Applied strength because functional benign evidence is lacking.
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 studies. Therefore, this criterion is not applied at Not Applied strength because segregation data are absent.
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: it is synonymous, not missense. Therefore, this criterion is not applied at Not Applied strength because BP1 applies only to missense changes.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in cis with a pathogenic variant in the same gene." The evidence for this variant shows: no data on cis/trans configuration with another variant. Therefore, this criterion is not applied at Not Applied strength because no cis/trans evidence is available.
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 a known function." The evidence for this variant shows: it is a synonymous SNV, not an indel. Therefore, this criterion is not applied at Not Applied strength because BP3 is not relevant.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Supporting 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 splicing prediction tools used are: varSEAK, spliceAI and MaxEntScan." The evidence for this variant shows: SpliceAI predicts no splicing impact and other in silico tools are concordant. Therefore, this criterion is applied at Supporting strength because multiple computational tools predict no splicing effect for this synonymous change.
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 such case reports. Therefore, this criterion is not applied at Not Applied strength because no alternate molecular cause has been identified.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without available evidence." The evidence for this variant shows: no entries in ClinVar or other databases reporting benign status. Therefore, this criterion is not applied at Not Applied strength because no benign assertion from a reputable source exists.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Supporting For synonymous... if the nucleotide is non-conserved award this point (PhyloP score <0.1)." The evidence for this variant shows: no conservation score data were provided. Therefore, this criterion is not applied at Not Applied strength because necessary conservation information is missing.