PIK3CA c.1417_1419dup, p.Leu473dup
NM_006218.4:c.1417_1419dup
Variant of Uncertain Significance (VUS)
The PIK3CA c.1417_1419dup (L473dup) variant is absent from population databases (PM2 Supporting) but lacks functional, segregation, and phenotypic evidence for pathogenicity. Only PM2 is met; thus it remains 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.1417_1419dup
Protein Change
L473dup
Location
Exon 9
(Exon 9 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.1417_1419dup
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
Unknown
PP3 Applied
No
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: an in-frame duplication (L473dup) that does not introduce a premature stop codon or disrupt splicing at a canonical site. 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 prior reports of a pathogenic L473dup or equivalent amino acid change at this residue. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 (Strong) is: de novo occurrence with confirmed maternity and paternity and detectable allele fraction absent in parents plus tissue comparison (Criteria 1 and 2) or (Moderate) if only Criteria 1 or 2 is met. The evidence for this variant shows: no data on parental testing or tissue allele fraction. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: functional assay meeting VCEP/BMVCEP quality metrics demonstrating a damaging effect. The evidence for this variant shows: no functional studies of L473dup have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: absent from controls (PM2) plus phenotype points ≥0.5 for Supporting up to ≥16 for Very Strong. The evidence for this variant shows: no case-level phenotype or literature reports. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 (Supporting) is: residue affecting a critical functional domain per gene‐specific Table 4. The evidence for this variant shows: L473 is not listed as a critical hotspot or functional domain in PIK3CA. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Absent/rare from controls in an ethnically-matched cohort population sample (≥1)". The evidence for this variant shows: not found in gnomAD or other population databases (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: detected in trans with a pathogenic variant for a recessive disorder. The evidence for this variant shows: no data on trans configuration with another pathogenic allele. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: in-frame indels or stop-loss variants in non-repeat regions that change protein length. The evidence for this variant shows: an in-frame single amino acid duplication but without evidence of pathogenic impact or localization to a repetitive region. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: novel missense change at a residue with a known pathogenic missense. The evidence for this variant shows: this is an in-frame duplication rather than a missense substitution at L473. 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 without confirmation of paternity or maternity. The evidence for this variant shows: no parental or 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 segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2 is: missense constraint (z-score >3.09) applied to missense variants. The evidence for this variant shows: it is an in-frame duplication, not a 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. The evidence for this variant shows: SpliceAI predicts no splicing impact, but this criterion applies only to missense or splicing predictions for non-synonymous SNVs. 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 highly specific for gene. The evidence for this variant shows: no phenotype data 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 reports variant as pathogenic. The evidence for this variant shows: not found 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 is: allele frequency >0.0926% in population. The evidence for this variant shows: MAF=0% in available databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: allele frequency >0.0185%. The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: ≥3 homozygotes or heterozygotes in healthy individuals. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 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 multiple affected family members. 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 in a gene where only truncating variants cause disease. The evidence for this variant shows: PIK3CA disease mechanism is predominantly activating missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: observed in cis/trans with a known pathogenic variant. The evidence for this variant shows: no such observations. 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 repetitive regions. The evidence for this variant shows: L473dup is not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: two of three splicing tools predict no impact for synonymous or non-coding variants. The evidence for this variant shows: it is an in-frame coding duplication, not applicable under BP4. Therefore, this criterion is not applied.
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 context. 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. The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: synonymous/intronic non-conserved with no splicing impact. The evidence for this variant shows: it is a coding duplication. Therefore, this criterion is not applied.