PIK3CA c.2118C>T, p.Val706=
NM_006218.4:c.2118C>T
COSMIC ID: COSM10258256
Likely Benign
This synonymous variant is extremely rare in population databases (PM2), predicted by multiple computational tools to have no effect on splicing (BP4), and reported as Likely Benign by reputable sources (BP6). No evidence supports pathogenicity; with three supporting benign criteria, the variant is classified as Likely Benign.
ACMG/AMP Criteria Applied
PM2
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.2118C>T
Protein Change
V706=
Location
Exon 14
(Exon 14 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM10258256
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.2118C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0012%
Rare
Highest in Population
South Asian
0.00654%
Rare
Global: 0.0012%
South Asian: 0.00654%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 249202Alt: 3Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0012%, 3/249202 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00654%, 2/30588 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: 0.55
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 for this variant shows: it is a synonymous change (p.V706=) with no predicted loss-of-function. Therefore, this criterion is not applied at Not Applied strength because the variant does not create a null allele.
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 for this variant shows: there is no amino acid change. Therefore, this criterion is not applied at Not Applied strength because the variant does not alter the protein sequence.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed)". The evidence for this variant shows: no data on de novo occurrence. Therefore, this criterion is not applied at Not Applied strength due to absence of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies show a deleterious effect." The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied at Not Applied strength because functional impact is unevaluated.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence of the variant in affected individuals is significantly increased compared to controls." The evidence for this variant shows: no case-control or case-level data demonstrating enrichment in affected individuals. Therefore, this criterion is not applied at Not Applied strength because no phenotype-based enrichment data are available.
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: it is outside of known critical functional domains of PIK3CA. Therefore, this criterion is not applied at Not Applied strength.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Supporting Absent/rare from controls in an ethnically-matched cohort population sample ( ≥1)." The evidence for this variant shows: MAF=0.0012% in gnomAD (3/249202 alleles) with no homozygotes, indicating extreme rarity. Therefore, this criterion is applied at Supporting strength because the variant is absent/rare in population controls.
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: PIK3CA disorders are not recessive and no trans observations. 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 deletions/insertions in non-repeat regions or stop-loss variants." The evidence for this variant shows: it is synonymous 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 is pathogenic." The evidence for this variant shows: it is synonymous, not missense. 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. 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." The evidence for this variant shows: no segregation data. 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 synonymous, not missense. 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: computational tools (CADD=0.55, SpliceAI=0.02) predict no deleterious impact. 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-specific data provided. 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 supporting evidence is not available." The evidence for this variant shows: reputable sources report it as benign, not 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 Strength: Allele frequency (>0.0926%)." The evidence for this variant shows: MAF=0.0012%, well below the BA1 threshold. 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 Strength: Allele frequency (>0.0185%)." The evidence for this variant shows: MAF=0.0012%, below the BS1 threshold. 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 Strength: ≥3 homozygotes in gnomAD or ≥3 heterozygotes in well-phenotyped family members." The evidence for this variant shows: zero homozygotes observed. 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 evidence from well-established functional studies showing no deleterious effect." The evidence for this variant shows: no functional studies available. 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 in affected members of a family." The evidence for this variant shows: no segregation data. 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 cause disease." The evidence for this variant shows: it is synonymous. 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/disease." The evidence for this variant shows: no such observations. 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 synonymous. Therefore, this criterion is not applied at Not Applied strength.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: 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 predicts no impact (score 0.02) and additional in silico tools predict no splicing change. Therefore, this criterion is applied at Supporting strength because multiple computational tools predict no impact on splicing.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no such co-occurrence data. 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 reports this variant as Likely Benign by two clinical laboratories. Therefore, this criterion is applied at Supporting strength because of reputable source classification.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Supporting For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved (PhyloP score <0.1) award this point." The evidence for this variant shows: conservation data (PhyloP) not available. Therefore, this criterion is not applied at Not Applied strength due to missing conservation data.