PIK3CA c.1747-11C>A, p.?
NM_006218.4:c.1747-11C>A
Variant of Uncertain Significance (VUS)
The variant NM_006218.4:c.1747-11C>A in PIK3CA is classified as a Variant of Uncertain Significance. It is absent from population databases (PM2_Supporting) and computational tools predict no splicing impact (BP4_Supporting). No additional pathogenic or benign evidence is available, leaving its clinical significance unresolved.
ACMG/AMP Criteria Applied
PM2
BP4
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.1747-11C>A
Protein Change
?
Location
Exon 11
(Exon 11 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.1747-11C>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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.59
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PVS1 rule applies to null variants (nonsense, frameshift, canonical ±1/2 splice site, initiation codon, single/multi-exon deletion) in a gene where loss-of-function is a known mechanism of disease. The variant NM_006218.4:c.1747-11C>A is an intronic change at position -11, outside of canonical splice sites, and does not create a null allele. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 requires the same amino acid change as a previously established pathogenic variant, regardless of nucleotide change. NM_006218.4:c.1747-11C>A is intronic and does not alter an amino acid. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence (with maternity and paternity confirmed). No parental or de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 requires well-established functional studies showing a damaging effect on the gene or gene product. No functional studies have been performed for NM_006218.4:c.1747-11C>A. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines for PS4, case counts with phenotype data and absence from controls are required to assign strength points. There are no reported cases or phenotype data for NM_006218.4:c.1747-11C>A. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants affecting critical functional domains or mutational hotspots. NM_006218.4:c.1747-11C>A is intronic and does not affect a defined functional domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 (Supporting) applies when a variant is absent or at extremely low frequency in population databases. NM_006218.4:c.1747-11C>A is absent from gnomAD and other control databases. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders with detected in trans with a pathogenic variant. PIK3CA-related disorders are typically dominant and no trans data exist. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels, stop-loss). NM_006218.4:c.1747-11C>A is intronic with no protein length impact. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 applies when a novel missense change occurs at an amino acid where a different pathogenic missense change has been observed. This variant is intronic and does not change an amino acid. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to presumed de novo cases without confirmation. No de novo or parental data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 requires co-segregation with disease in multiple affected family members. No segregation data are available for this variant. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, PP2 (Supporting) applies to missense variants in genes with a low rate of benign missense variation (z-score >3.09). NM_006218.4:c.1747-11C>A is intronic and not a missense change. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 applies when multiple computational tools predict a deleterious effect. In silico predictors (CADD 0.59, SpliceAI 0.02) indicate no deleterious impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires a specific phenotype highly specific for a single gene. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source classifies the variant as pathogenic. NM_006218.4:c.1747-11C>A is not found in ClinVar or other databases. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 (Stand Alone) applies to allele frequency >0.0926%. The variant is absent from population databases, below this threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 (Strong) applies to allele frequency >0.0185%. The variant is absent from population databases, below this threshold. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires observation in healthy adult individuals or homozygotes in gnomAD. No such observations exist for this variant. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires well-established functional studies showing no damaging effect. No functional data are available for this variant. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 requires non-segregation in affected family members. No family data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in a gene where only truncating variants cause disease. This variant is intronic. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when a variant is observed in cis or trans with a pathogenic variant. No such data exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This variant is a single nucleotide intronic change. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4 (Supporting) applies to intronic variants (except canonical splice sites) when two of three splicing tools predict no impact on splicing. SpliceAI (0.02), MaxEntScan and varSEAK predict no splicing effect. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a gene for which an alternate molecular basis explains the disease. Not applicable here. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a variant is reported as benign by a reputable source without available evidence. NM_006218.4:c.1747-11C>A is not reported in such sources. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 (Supporting) applies to synonymous or intronic (except canonical) variants with low conservation (PhyloP <0.1). Conservation data are not available. Therefore, BP7 is not applied.