PIK3CA c.1048G>T, p.Asp350Tyr
NM_006218.4:c.1048G>T
Likely Pathogenic
NM_006218.4:c.1048G>T (p.D350Y) in PIK3CA is classified as Likely Pathogenic based on one Moderate criterion (PM5) and three Supporting criteria (PM1, PM2, PP3), with no conflicting benign evidence.
ACMG/AMP Criteria Applied
PM1
PM2
PM5
PP3
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.1048G>T
Protein Change
D350Y
Location
Exon 5
(Exon 5 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 350: D350N, D350G
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.1048G>T
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
Hotspot
PM1
Mutation Count
36
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (36 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 350: D350N, D350G
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.773
0.773
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
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.59
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PVS1 rule is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence shows: this variant is a missense change not predicted to cause loss of function and PIK3CA-associated disease is due to gain of function. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 rule is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence shows: no other nucleotide change at codon D350 resulting in p.D350Y has been reported as pathogenic. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 rule is: 'De novo (both maternity and paternity confirmed).' The evidence shows: no de novo inheritance data are available. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 rule is: 'Functional assay meets acceptability criteria with quality metrics and minimum validation controls.' The evidence shows: no functional studies have been performed for p.D350Y. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 rule is: 'Prevalence in affected individuals is significantly increased compared with controls.' The evidence shows: no case-level phenotypic data or aggregation analyses are available. Therefore, PS4 is not applied.
PM1
PM1 (Supporting) Strength Modified
According to VCEP guidelines, PM1 rule is: 'Supporting: Residues affecting critical functional domains provided in Table 4 for each gene.' The evidence shows: p.D350Y lies within the C2 domain of PIK3CA, a well-established functional domain. Therefore, PM1 is applied at Supporting strength because the variant affects a critical functional domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 rule is: 'Supporting: Absent/rare from controls in an ethnically-matched cohort population sample (≥1).' The evidence shows: the variant is absent from gnomAD and other population databases. Therefore, PM2 is applied at Supporting strength because it is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 rule is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence shows: PIK3CA disorders are not recessive and no trans observations are reported. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 rule is: 'Protein length changes due to in-frame indels or stop-loss.' The evidence shows: this is a missense change without alteration of protein length. Therefore, PM4 is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, PM5 rule is: 'Moderate: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence shows: other missense changes at residue D350 have been reported as pathogenic. Therefore, PM5 is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 rule is: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence shows: no de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 rule is: 'Cosegregation with disease in multiple affected family members.' The evidence shows: no family segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, PP2 rule is: 'Supporting: Missense constraint computed in ExAC/gnomAD z-score > 3.09 for PIK3CA.' The evidence shows: no specific z-score was provided in the data. Therefore, PP2 is not applied due to lack of precise constraint evidence.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, PP3 rule is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product.' The evidence shows: REVEL score 0.77 exceeds the VCEP threshold of 0.75 and multiple in silico tools predict a damaging effect. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 rule is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' The evidence shows: no specific clinical phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 rule is: 'Reputable source recently reports variant as pathogenic, but evidence is not available for independent evaluation.' The evidence shows: no such external report exists. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 rule is: 'Stand Alone: Allele frequency >0.0926%.' The evidence shows: variant frequency is 0% in controls. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 rule is: 'Strong: Allele frequency >0.0185%.' The evidence shows: variant frequency is 0% in controls. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 rule is: 'Strong: Observed in ≥3 homozygotes or ≥3 well-phenotyped heterozygotes.' The evidence shows: no such observations exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 rule is: 'Strong: Well-validated functional studies show no damaging effect.' The evidence shows: no functional studies available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 rule is: 'Lack of segregation in affected members of a family.' The evidence shows: no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 rule is: 'Missense variant in gene for which primarily truncating variants cause disease.' The evidence shows: PIK3CA disease is driven by gain-of-function missense changes. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 rule is: 'Observed in trans or cis with a pathogenic variant.' The evidence shows: no such observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 rule is: 'In-frame deletions/insertions in a repetitive region without a known function.' The evidence shows: this is a missense change. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 rule is: 'Supporting for synonymous or non-coding variants when ≥2 splice tools predict no impact.' The evidence shows: this is a missense variant. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 rule is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence shows: no such alternate diagnosis. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 rule is: 'Reputable source reports variant as benign.' The evidence shows: no such report. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 rule is: 'Supporting for synonymous variants at non-conserved positions.' The evidence shows: this is a missense change. Therefore, BP7 is not applied.