PIK3CA c.184C>A, p.Leu62Ile
NM_006218.4:c.184C>A
COSMIC ID: COSM6444823
Variant of Uncertain Significance (VUS)
PIK3CA L62I is a missense variant absent from population databases with only two supporting criteria (PM2, PP2) and no evidence for pathogenicity or benignity, resulting in a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
PP2
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.184C>A
Protein Change
L62I
Location
Exon 2
(Exon 2 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 62 in gene PIK3CA
Alternate Identifiers
COSM6444823
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.184C>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
No evidence of other pathogenic variants at position 62 in gene PIK3CA
Functional Summary
The PIK3CA L62I variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.575
0.575
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.44
Neutral: Show all
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: it is a missense change (L62I), not a null variant. Therefore, this criterion is not applied.
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: there is no previously established pathogenic variant causing L62I. Therefore, this criterion is not applied.
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". The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional characterization studies have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Phenotype criteria can only be used if the variant is absent/rare from controls according to PM2; strength of evidence is determined by points according to case reports". The evidence for this variant shows: no case or phenotype data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Supporting: Residues affecting critical functional domains provided in Table 4 for each gene". The evidence for this variant shows: residue L62 is not within a critical functional domain or known hotspot. Therefore, this criterion is not applied.
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 large 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: "For recessive disorders, detected in trans with a pathogenic variant in affected individuals". The evidence for this variant shows: no data on trans occurrence with another variant. 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 as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants". The evidence for this variant shows: it is a single amino acid change without length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate: novel missense change at an amino acid residue where a different missense change is pathogenic". The evidence for this variant shows: no pathogenic variants have been reported at residue L62. 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". The evidence for this variant shows: no de novo information. 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 are available. Therefore, this criterion is not applied.
PP2
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: "Supporting: Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09". The evidence for this variant shows: PIK3CA has a missense z-score > 3.09 and this is a missense change. Therefore, this criterion is applied at Supporting strength.
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 predictions are mixed and inconclusive. 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". The evidence for this variant shows: no specific 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 evidence for this variant shows: not reported in ClinVar or other expert-reviewed databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Allele frequency (>0.0926%)". The evidence for this variant shows: 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: "Strong: Allele frequency (>0.0185%)". The evidence for this variant shows: absent from controls. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong: ≥3 homozygotes in gnomAD or ≥3 heterozygotes in well-phenotyped family members". 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: "Strong: Well-established 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 affected members of a family". 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 variant in a gene for which primarily truncating variants cause disease". The evidence for this variant shows: PIK3CA disease mechanism is gain-of-function missense, not truncating. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene". 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 deletions/insertions in a repetitive region without a known function". The evidence for this variant shows: not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting: applicable only to synonymous, intronic (non-canonical) or UTR variants when two of three splicing tools predict no impact". The evidence for this variant shows: it is a missense change, not eligible for 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 case data. 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: "Supporting: applicable only to synonymous, intronic (non-canonical) or UTR variants with low conservation". The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.