PIK3CA c.969T>A, p.Ser323=
NM_006218.4:c.969T>A
Variant of Uncertain Significance (VUS)
This synonymous PIK3CA variant (c.969T>A, p.Ser323=) is absent from population databases (PM2_Supporting) and predicted by in silico tools to have no impact on splicing (BP4_Supporting). No functional, segregation, de novo, or case-level evidence is available to support pathogenicity or benign impact. The net evidence remains insufficient, resulting in a classification of Variant of Uncertain Significance.
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.969T>A
Protein Change
S323=
Location
Exon 5
(Exon 5 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.969T>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: 0.63
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, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease." The evidence for this variant shows that it is a synonymous change (S323=) with no predicted loss of function. Therefore, this criterion is not applied because the variant does not meet the definition of a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG 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 that it is synonymous and does not change the amino acid. Therefore, this criterion is not applied because there is no amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There are no data on de novo occurrence for this variant. Therefore, this criterion is not applied due to absence of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines for PS3, the rule is: "Award PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP." The evidence for this variant shows that no functional assays have been performed. Therefore, this criterion is not applied due to lack of functional data.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines for PS4, the rule is: "Points are assigned for phenotype according to Table 2A, only if the variant is absent from controls (PM2), with strength based on total points." There are no reported case‐level phenotypes for this variant. Therefore, this criterion is not applied due to absence of case‐level evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PM1, the rule is: "Residues affecting critical functional domains provided in Table 4 for each gene." The evidence for this variant shows it is synonymous and does not alter any critical functional residue. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PM2, the rule 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 (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from 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." There is no evidence of this variant being observed in trans in a recessive context. 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 synonymous without protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PM5, the rule is: "Moderate: No change from standard ACMG." Standard ACMG PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." The evidence for this variant shows it is synonymous. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." There are 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." There are no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines for PP2, the rule is: "Supporting: Missense constraint computed in ExAC/gnomAD (z-score > 3.09) applies to missense variants." The evidence for this variant shows it is synonymous, not missense. 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 the gene or gene product." The evidence for this variant shows mixed in silico results and SpliceAI predicts no splicing impact. 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." There are no 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 reports variant as pathogenic." The variant is not in ClinVar or other curated databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1, the rule is: "Stand Alone: Allele frequency > 0.0926%." The evidence for this variant shows it is absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1, the rule is: "Strong: Allele frequency > 0.0185%." The evidence for this variant shows it is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for BS2, the rule is: "Strong: ≥3 homozygotes in gnomAD or ≥3 heterozygotes in well‐phenotyped family members." The evidence for this variant shows no homozygotes. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BS3, the rule is: "Strong/Supporting: Well-established functional studies show no damaging effect." There are no functional studies. 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." There are 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 variant is synonymous. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Variant observed in trans with a pathogenic variant for a dominant gene or in cis with a pathogenic variant." There is no such evidence. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in a repetitive region without a known function." The variant is not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines for BP4, the rule is: "Supporting: Award BP4 for synonymous, intronic (except canonical splice sites) or UTR variants if two of three splicing prediction tools predict no impact on splicing function (tools: varSEAK, SpliceAI, MaxEntScan)." The evidence for this variant shows SpliceAI predicts no impact on splicing and other in silico tools support benign effect. 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." There is no evidence of an alternate molecular basis. 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." There are no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines for BP7, the rule is: "Supporting: For synonymous, intronic (except canonical splice sites) or UTR variants, if the nucleotide is non-conserved (PhyloP < 0.1)." Conservation data (PhyloP) are unavailable. Therefore, this criterion is not applied due to missing conservation data.