PIK3CA c.1902G>A, p.Gln634=
NM_006218.4:c.1902G>A
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Likely Benign
0 publications
REVEL Score
N/A
Not Available
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.1902G>A
Protein Change
Q634=
Location
Exon 12
(Exon 12 of 21)
5'
Exon Structure (21 total)
3'
Functional Consequence
Loss of Function
Related Variants
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
Likely Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 clinical laboratories).
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
Functional Studies
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.54
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, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion) in a gene where loss-of-function is a known mechanism of disease.' The evidence for this variant shows: it is a synonymous change (c.1902G>A, p.Q634=) and does not introduce a stop codon or affect canonical splice sites. Therefore, this criterion is not applied at Not Applied strength because it does not result in a null effect on the gene product.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as an established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: it is a synonymous variant with no amino acid change. Therefore, this criterion is not applied at Not Applied strength because there is no amino acid alteration.
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 or parental testing data are available. Therefore, this criterion is not applied at Not Applied strength due to lack of de novo evidence.
PS3
PS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required. Award PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348).' The evidence for this variant shows: no functional assays or in vivo/in vitro studies have been reported. Therefore, this criterion is not applied at Not Applied strength because there are no functional data.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Points are assigned for phenotype according to (Table 2A). Strength of evidence is determined by points according to (Table 2B).' The evidence for this variant shows: no affected cases or phenotype data have been reported. Therefore, this criterion is not applied at Not Applied strength due to absence of case-level phenotype data.
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: codon Q634 is not located within a critical functional domain of PIK3CA. Therefore, this criterion is not applied at Not Applied strength because the residue is outside known functional hotspots.
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 not present in gnomAD, ExAC, 1000 Genomes, or other population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from large control cohorts.
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.' The evidence for this variant shows: no evidence of occurrence in trans with a pathogenic PIK3CA variant. Therefore, this criterion is not applied at Not Applied strength.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame indels or stop-loss variants.' The evidence for this variant shows: it is a synonymous nucleotide substitution with no change in protein length. Therefore, this criterion is not applied at Not Applied strength.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.' The evidence for this variant shows: it is synonymous and not a missense change. Therefore, this criterion is not applied at Not Applied strength.
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 data are available. Therefore, this criterion is not applied at Not Applied strength.
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 in a gene definitively known to cause the disease.' The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied at Not Applied strength.
PP2
PP2 (Not Applied)
Strength Modified
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: it is a synonymous change, not a missense variant. Therefore, this criterion is not applied at Not Applied 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 predictors (CADD=0.54, SpliceAI=0.02, varSEAK and MaxEntScan) predict no impact on splicing or function. Therefore, this criterion is not applied at Not Applied strength.
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 phenotype or family history data linked to this variant. Therefore, this criterion is not applied at Not Applied strength.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows: no reputable source reports it as pathogenic. Therefore, this criterion is not applied at Not Applied strength.
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: allele frequency is 0% in population databases. Therefore, this criterion is not applied at Not Applied strength.
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: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied at Not Applied strength.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members.' The evidence for this variant shows: no homozygotes or heterozygotes observed in gnomAD. Therefore, this criterion is not applied at Not Applied strength.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.' The evidence for this variant shows: no functional assay demonstrating lack of damaging effect. Therefore, this criterion is not applied at Not Applied strength.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation of variant with disease in affected members of a family.' The evidence for this variant shows: no segregation or family data available. Therefore, this criterion is not applied at Not Applied strength.
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 are known to cause disease.' The evidence for this variant shows: it is a synonymous substitution, not a missense variant. Therefore, this criterion is not applied at Not Applied strength.
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/disorder or in cis with a pathogenic variant in recessive gene/disorder.' The evidence for this variant shows: no data on cis/trans observation with other variants. Therefore, this criterion is not applied at Not Applied strength.
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: it is a single nucleotide substitution, not an indel. Therefore, this criterion is not applied at Not Applied strength.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function.' The evidence for this variant shows: SpliceAI max score=0.02, varSEAK and MaxEntScan predict no splicing impact. Therefore, this criterion is applied at Supporting strength because two out of three tools predict no effect on splicing.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant located in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular basis data in affected cases. Therefore, this criterion is not applied at Not Applied strength.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows: ClinVar lists this variant as Likely benign (one clinical laboratory). Therefore, this criterion is applied at Supporting strength because a reputable source reports benign status without primary data.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1).' The evidence for this variant shows: conservation metric (PhyloP score) is not available. Therefore, this criterion is not applied at Not Applied strength due to missing conservation data.