PIK3CA c.2979G>T, p.Gln993His
NM_006218.4:c.2979G>T
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
0.579
Uncertain (High)
COSMIC Recurrence
0 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.2979G>T
Protein Change
Q993H
Location
Exon 21
(Exon 21 of 21)
5'
Exon Structure (21 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 993 in gene PIK3CA
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 993 in gene PIK3CA
Functional Studies
Summary
The PIK3CA Q993H variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.579
0.579
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
No
Additional Predictors
Pathogenic:
sift: D
mutationtaster: D
primateai: D
deogen2: D
Benign:
CADD: 4.29
fathmm: T
provean: N
metasvm: T
metalr: T
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
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: c.2979G>T is a missense change (Q993H), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Strong Strength: 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 993 changing Q to H. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Strong: Award PS2_Strong if both Criteria 1 (absent from parental samples with confirmed maternity and paternity) and Criteria 2 (present in affected tissue and absent/at lower fraction in another tissue) are fulfilled'. The evidence for this variant shows: no de novo or somatic mosaicism data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Strong: Functional assays meeting VCEP-specified quality metrics'; 'Moderate/Supporting: per detailed VCEP specifications'. The evidence for this variant shows: no functional characterization has been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Assign phenotype points ≥0.5 if variant is absent from controls (PM2) and reported in cases; strength determined by total points'. 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, the rule for PM1 is: 'Supporting: Residues affecting critical functional domains provided in Table 4 for each gene'. The evidence for this variant shows: Q993 is not located within a VCEP-defined critical functional domain of PIK3CA. 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: absent from gnomAD (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: 'Moderate: Detected in trans with a pathogenic variant in recessive disorders'. The evidence for this variant shows: gene/disease context is not recessive and no trans observations. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Moderate: Protein length changes due to in-frame indels or stop-loss'. The evidence for this variant shows: missense 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: Different missense change at same residue as known pathogenic variant'. The evidence for this variant shows: no other pathogenic variant reported at residue 993. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Moderate: Assumed de novo without confirmation'. The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Supporting: Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no segregation data 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 with z-score >3.09'. The evidence for this variant shows: PIK3CA missense z-score >3.09 indicating constraint. Therefore, this criterion is applied at Supporting strength.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Supporting: Multiple lines of computational evidence support a deleterious effect'. The evidence for this variant shows: in silico predictions are mixed with intermediate REVEL (0.58). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting: Patient’s phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotype or clinical presentation data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting: Reputable source reports variant as pathogenic'. The evidence for this variant shows: not found 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 population databases. 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: zero occurrences in gnomAD. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong/Supporting: Well-validated functional studies show no damaging effect'. The evidence for this variant shows: no functional study data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Strong: Lack of segregation in affected members of a family'. The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Supporting: 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 LOF. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Supporting: Observed in trans with a pathogenic variant in the same gene'. The evidence for this variant shows: no observations in trans with a pathogenic allele. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting: In-frame indels in repetitive regions without a known function'. The evidence for this variant shows: it is a missense change, not an in-frame 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 for synonymous, intronic (non-canonical) or UTR variants when ≥2 of 3 splicing tools predict no impact'. The evidence for this variant shows: it is missense, not a splicing or synonymous variant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Supporting: 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: 'Supporting: Reputable source reports variant as benign'. The evidence for this variant shows: no such reports in ClinVar or expert panels. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting: Synonymous/intronic (non-canonical) or UTR variants with non-conserved nucleotide (PhyloP <0.1)'. The evidence for this variant shows: it is missense, not synonymous or intronic. Therefore, this criterion is not applied.