PIK3CA c.10_57del, p.Arg4_Arg19del
NM_006218.4:c.10_57del
Variant of Uncertain Significance (VUS)
This in-frame deletion (R4_R19del) in PIK3CA is absent from population databases (PM2_Supporting) and results in a protein length change (PM4_Moderate) but lacks any functional, segregation, or case-level data. No benign criteria apply. The available moderate+supporting evidence is insufficient for a pathogenic or likely benign classification, resulting in a final designation of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
PM4
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.10_57del
Protein Change
R4_R19del
Location
Exon 2
(Exon 2 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.10_57del
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 deletion of amino acids R4_R19, which does not introduce a premature stop codon or disrupt canonical splice sites. 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 a multi‐amino acid deletion, not the same single amino acid substitution as any known pathogenic PIK3CA variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2_Strong is: "The variant is present at a detectable allele fraction but is absent from parental samples with confirmed maternity and paternity, and present in affected tissue sample absent or lower in another tissue"; for PS2_Moderate: "Award if only one of those criteria is fulfilled." There are no parental or tissue‐fraction data for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Follow recommendations set forth by the SVI... (functional assay quality metrics required)." No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4_VeryStrong/Strong/Moderate/Supporting is: "Points are assigned for phenotype according to Table 2A; criterion applies only if variant is absent from controls (PM2)." There are no case‐level or segregation reports in the literature. Therefore, this criterion is not applied.
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 deleted region R4_R19 is not annotated as a critical functional domain in PIK3CA by the VCEP. 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 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: "Detected in trans with a pathogenic variant for a recessive disorder." PIK3CA disorders are not recessive, and no trans data exist. Therefore, this criterion is not applied.
PM4
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region." The evidence shows an in-frame deletion of 16 amino acids (R4_R19del) in a non-repeat region of PIK3CA. Therefore, this criterion is applied at Moderate strength.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Moderate strength for a novel missense change at a residue where a different pathogenic missense change has been seen before." This variant is an in-frame deletion, not a missense substitution. 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/maternity." No de novo information is available. 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." No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2_Supporting is: "Missense constraint z-score >3.09 in ExAC for PIK3CA." This variant is an in-frame deletion, not a missense change. 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." Computational tools are not designed for multi-amino-acid in-frame deletions here, and SpliceAI predicts no splicing impact. There is insufficient evidence of deleterious effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient phenotype highly specific for a disease with a single genetic etiology." No phenotype or clinical correlation data are 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." This variant is not found in ClinVar or other variant 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% is stand-alone benign." The variant is absent from population 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% is strong benign." The variant is absent from gnomAD (MAF = 0%). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2_Strong is: "Observed in ≥3 healthy adults or homozygotes in gnomAD." No such observations exist. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect." No benign functional data exist. 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 family members." No segregation data are available. 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 gene where only LOF causes disease." Not applicable to an in-frame deletion in PIK3CA. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in cis or trans with a pathogenic variant." No such data exist. 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." R4_R19 is not a repetitive sequence. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4_Supporting is: "Applicable only to synonymous, intronic (non-canonical) or UTR variants if ≥2/3 splicing tools predict no impact." This is an in-frame deletion, not eligible. 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 cause." No such reports exist. 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 as benign." Not reported in any database. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous or intronic variant with no splicing impact and low conservation." Not applicable to an in-frame deletion. Therefore, this criterion is not applied.