PIK3CA c.1171A>G, p.Ile391Val
NM_006218.4:c.1171A>G
Variant of Uncertain Significance (VUS)
This missense variant (I391V) in PIK3CA is absent from population databases (PM2) and occurs in a gene with high missense constraint (PP2). No other pathogenic or benign evidence is available. The net evidence is insufficient to classify beyond uncertain significance, thus the variant remains a VUS.
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.1171A>G
Protein Change
I391V
Location
Exon 7
(Exon 7 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 391 in gene PIK3CA
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.1171A>G
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
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 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
No evidence of other pathogenic variants at position 391 in gene PIK3CA
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.312
0.312
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
Benign:
CADD: 3.30polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
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, frameshift, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: NM_006218.4:c.1171A>G is a missense variant (I391V), 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: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: I391V has not been reported as a pathogenic change at this residue. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Award the PS2 point if the variant is de novo with confirmed maternity and paternity and meets tissue fraction criteria for somatic mutations." The evidence for this variant shows: no de novo or parental testing data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Functional assays meeting the BMVCEP quality metrics and validation controls demonstrating a damaging effect on the gene or gene product." The evidence for this variant shows: no functional studies are available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Case-control or case series data assigning points for phenotypic match in affected individuals absent from controls (PM2 required)." The evidence for this variant shows: no reported cases in the literature or series. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Residues affecting critical functional domains provided in Table 4 for each gene (Supporting)." The evidence for this variant shows: I391 is not located within a known PIK3CA critical hotspot 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 for this variant shows: it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders (Moderate)." The evidence for this variant shows: PIK3CA-associated disease is dominantly acting and no trans data are available. 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 deletions/insertions or stop-loss variants (Moderate)." The evidence for this variant shows: it is a missense change with no length alteration. 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 (Moderate)." The evidence for this variant shows: no other pathogenic missense changes at residue I391 have been reported. 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 (Supporting)." The evidence for this variant 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: "Cosegregation with disease in multiple affected family members (Supporting)." 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: "Missense constraint computed in ExAC/gnomAD >3.09 for PIK3CA (Supporting)." The evidence for this variant shows: PIK3CA has a missense constraint z-score >3.09 in gnomAD. 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 computational tools predict a deleterious effect (Supporting)." The evidence for this variant shows: in silico tools (CADD, PolyPhen, REVEL, SpliceAI) predict a benign impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient phenotype is highly specific for a disease with a single genetic etiology (Supporting)." The evidence for this variant shows: no specific clinical phenotype information is 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 the variant as pathogenic (Supporting)." The evidence for this variant shows: ClinVar lists it as VUS, not pathogenic. 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% in population databases (Stand Alone)." The evidence for this variant shows: it is 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: "Allele frequency >0.0185% in population databases (Strong)." The evidence for this variant shows: it is 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: "Observed in ≥3 homozygotes in gnomAD or well-phenotyped family members (Strong)." 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: "Well-validated functional assays demonstrating no damaging effect (Strong)." The evidence for this variant shows: no benign functional data. 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 family members (Strong)." 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 where only loss-of-function causes disease (Supporting)." The evidence for this variant shows: PIK3CA pathogenic mechanism is gain-of-function. 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 in a dominant disorder or in cis with a pathogenic variant (Supporting)." 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 repetitive regions without a known function (Supporting)." The evidence for this variant shows: it is a missense variant, 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: "Applicable only to synonymous, intronic (non-canonical) or non-coding UTR variants when ≥2 splice tools predict no impact (Supporting)." The evidence for this variant shows: it is a missense change, not eligible. 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 gene with an alternative molecular basis for disease in the same individual (Supporting)." The evidence for this variant shows: no evidence of alternative etiology. 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 the variant as benign (Supporting)." 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: "Synonymous or intronic (non-canonical) variants with low conservation (PhyloP <0.1) (Supporting)." The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied.