PIK3CA c.1379G>A, p.Gly460Asp
NM_006218.4:c.1379G>A
COSM9101292
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
0.853
Likely Pathogenic
COSMIC Recurrence
1 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.1379G>A
Protein Change
G460D
Location
Exon 8
(Exon 8 of 21)
5'
Exon Structure (21 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 460 in gene PIK3CA
Alternate Identifiers
COSM9101292
Variant interpretation based on transcript NM_006218.4
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
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 460 in gene PIK3CA
Functional Studies
Summary
The PIK3CA L452_G460del variant, which results in the deletion of nine amino acids in the C2 PI3K-type domain, has not been functionally characterized. Its effect on Pik3ca protein function remains unknown.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.853
0.853
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damaging
mutationtaster: D
metasvm: D
metalr: D
primateai: D
Benign:
CADD: 5.21
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to VCEP guidelines, PVS1 refers to null variants in a gene where loss-of-function is a known mechanism of disease. 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 NM_006218.4:c.1379G>A is a missense change, not a null variant. Therefore, this criterion is not applied because the variant type does not meet the null variant requirement.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines, PS1 is: "Strong - Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no previously established pathogenic variant at amino acid position G460. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, PS2 is: "Strong - Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled (de novo with confirmed maternity/paternity in affected tissue)." The evidence for this variant shows no de novo or parental data. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to VCEP guidelines, PS3 is: "Strong - Follow SVI and BMVCEP specifications for functional assay quality metrics and validation controls." The evidence for this variant shows no functional studies for G460D. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, PS4 is: "Very Strong - Points assigned for phenotype in cases if variant is absent/rare from controls (PM2)." The evidence for this variant shows no case reports or phenotype data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, PM1 is: "Supporting - Residues affecting critical functional domains provided in Table 4 for each gene." The evidence for this variant shows that G460 is not within a defined critical hotspot domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines, 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 absent from controls.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM3 is: "Moderate - Detected in trans with a pathogenic variant in recessive disorders." The evidence for this variant shows no trans data and PIK3CA disorders are dominant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM4 is: "Moderate - Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows a missense change without length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM5 is: "Moderate - Novel missense change at an amino acid residue where a different missense variant is established as pathogenic." The evidence for this variant shows no other pathogenic missense at G460. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PM6 is: "Moderate - Unconfirmed de novo occurrence." The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP1 is: "Supporting - 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, PP2 is: "Supporting - Missense constraint computed in ExAC/gnomAD (z-score > 3.09)." The evidence for this variant shows no available gene constraint z-score. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, PP3 is: "Supporting - Multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows a REVEL score of 0.85 (>0.75) and consistent damaging predictions from multiple tools. Therefore, this criterion is applied at Supporting strength because in silico tools strongly predict deleterious effect.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP4 is: "Supporting - 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 family history. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, PP5 is: "Supporting - Reputable source reports variant as pathogenic." The evidence for this variant shows it is not found in ClinVar or other expert-reviewed sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, BA1 is: "Stand Alone - Allele frequency > 0.0926%." The evidence for this variant shows an allele frequency of 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, BS1 is: "Strong - Allele frequency > 0.0185%." The evidence for this variant shows an allele frequency of 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, BS2 is: "Strong - ≥3 homozygotes or heterozygotes in well-phenotyped individuals." The evidence for this variant shows no such occurrences. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, BS3 is: "Strong - Well-validated functional studies show no damaging effect." The evidence for this variant shows no functional studies. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BS4 is: "Strong - Lack of segregation in 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, BP1 is: "Supporting - Missense variant in a gene where only truncating variants cause disease." The evidence for this variant shows PIK3CA disease is due to gain-of-function missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP2 is: "Supporting - Observed in trans or cis with a 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, BP3 is: "Supporting - In-frame indels in a repetitive region without a known function." The evidence for this variant shows a missense change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP4 is: "Supporting - Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows damaging computational predictions. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP5 is: "Supporting - 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, BP6 is: "Supporting - Reputable source reports variant as benign." The evidence for this variant shows no reputable source classification. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, BP7 is: "Supporting - Synonymous variant with no predicted splice impact and low conservation." The evidence for this variant shows a missense change. Therefore, this criterion is not applied.