PIK3CA c.814-15C>G, p.?
NM_006218.4:c.814-15C>G
Likely Benign
This intronic variant (c.814-15C>G) is classified as Likely Benign based on strong population frequency evidence (BS1), supporting computational/splicing evidence (BP4), and reputable benign classification (BP6). Although rare (PM2), no pathogenic moderate or strong criteria are met, and benign evidence outweighs any supporting pathogenic evidence.
ACMG/AMP Criteria Applied
PM2
BS1
BP4
BP6
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.814-15C>G
Protein Change
?
Location
Exon 4
(Exon 4 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.814-15C>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00558%
Rare
Highest in Population
African/African American
0.0585%
Common
Global: 0.00558%
African/African American: 0.0585%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 268592Alt: 15Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00558%, 15/268592 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.0585%, 14/23914 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).
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
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.28
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, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence shows: this is an intronic variant at c.814-15, not at a canonical splice site and does not create a null allele. Therefore, this criterion is not applied because the variant does not meet the null variant definition.
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 shows: this is an intronic variant with no amino acid change. Therefore, this criterion is not applied because there is no amino acid alteration.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Award PS2_Strong if de novo in patient with confirmed maternity and paternity or PS2_Moderate if partial evidence.' The evidence shows: no parental or de novo data are available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Functional assay meeting VCEP quality metrics demonstrating a damaging effect.' The evidence shows: no functional studies have been performed for this variant. Therefore, this criterion is not applied due to absence of functional data.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Case-level data scored per phenotype guidelines, requiring absence/rarity in controls (PM2).' The evidence shows: no case or phenotype data are available. Therefore, this criterion is not applied due to lack of case reports.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Residues affecting critical functional domains (Supporting).' The evidence shows: this intronic variant does not lie within a defined protein domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Absent/rare from controls in an ethnically-matched cohort population sample (Supporting).' The evidence shows: observed at MAF=0.00558% overall, extremely rare and absent or very rare in matched populations. Therefore, this criterion is applied at Supporting strength because the variant is rare in population databases.
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 shows: no evidence of trans configuration with a pathogenic allele. 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 due to in‐frame indels or stop-loss.' The evidence shows: this variant is intronic and does not alter protein length. Therefore, this criterion is not applied.
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 is pathogenic.' The evidence shows: this is not a missense variant. 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 and maternity.' The evidence shows: no de novo data are 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.' The evidence shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2 is: 'Missense constraint (z-score >3.09) supporting missense variants.' The evidence shows: this is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Computational evidence supporting a deleterious effect.' The evidence shows: in silico predictors are mixed and SpliceAI predicts minimal splicing impact. Therefore, this criterion is not applied because computational evidence for pathogenicity is lacking.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype highly specific for a disease with a single genetic etiology.' The evidence shows: no phenotype 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.' The evidence shows: reputable sources report this variant as benign. 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% (Stand Alone).' The evidence shows: highest observed MAF is 0.0585%, below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Strong)
According to VCEP guidelines, the rule for BS1 is: 'Allele frequency >0.0185% (Strong).' The evidence shows: highest subpopulation MAF in African/African American is 0.0585%, exceeding threshold. Therefore, this criterion is applied at Strong strength because allele frequency is too high for disease causation.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: '≥3 homozygotes or well‐phenotyped heterozygotes (Strong).' The evidence shows: zero homozygotes and no phenotyped individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Well‐validated functional studies show no damaging effect.' The evidence shows: no functional benign studies. 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 (non‐segregation).' The evidence 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 gene where only loss‐of‐function causes disease.' The evidence shows: this is intronic. 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.' The evidence shows: no data on trans configuration. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In‐frame indel in repetitive region without known function.' The evidence shows: this is a single‐nucleotide intronic change. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Intronic (non‐canonical) variant if two of three splicing tools predict no impact (Supporting).' The evidence shows: SpliceAI predicts minimal impact and other tools align with no splicing change. Therefore, this criterion is applied at Supporting strength because computational splicing models do not predict an effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in case with an alternate molecular basis for disease.' The evidence shows: no alternate etiology data. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, without available evidence for independent evaluation (Supporting).' The evidence shows: ClinVar lists this variant as Likely Benign from two clinical laboratories. Therefore, this criterion is applied at Supporting strength because a reputable database reports it as benign.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Intronic (non‐canonical) or synonymous variant with PhyloP <0.1 (Supporting).' The evidence shows: no conservation score (PhyloP) is provided. Therefore, this criterion is not applied due to missing conservation data.