PIK3CA c.2953T>A, p.Tyr985Asn
NM_006218.4:c.2953T>A
Variant of Uncertain Significance (VUS)
The variant NM_006218.4:c.2953T>A (Y985N) in PIK3CA remains a VUS, supported only by PM2 (absent from population databases) and no other ACMG or VCEP criteria due to lack of functional, segregation, phenotypic, or domain information.
ACMG/AMP Criteria Applied
PM2
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.2953T>A
Protein Change
Y985N
Location
Exon 21
(Exon 21 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 985 in gene PIK3CA
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.2953T>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
No evidence of other pathogenic variants at position 985 in gene PIK3CA
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.448
0.448
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Benign
PP3 Applied
No
Additional Predictors
Pathogenic:
mutationtaster: Dprimateai: D
Benign:
CADD: 4.13sift: Tpolyphen_prediction: benignmutationassessor: Lprovean: Nmetasvm: Tmetalr: Tdeogen2: 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, canonical ±1 or 2 splice sites, initiation codon, 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.2953T>A results in a missense change (Y985N) and variant consequence/type is unknown. Therefore, this criterion is not applied because the variant is not a null variant or loss-of-function type.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: there is no previously established pathogenic variant resulting in Y985N. Therefore, this criterion is not applied because the variant does not match a known pathogenic amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Strong: Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled (confirmed de novo in patient with disease and confirmed in tissue heterogeneity context)." The evidence for this variant shows: no data on de novo occurrence or somatic tissue fraction. Therefore, this criterion is not applied due to lack of de novo or tissue evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Strong: Functional assay meets the acceptability criteria delimited in (PMID: 31892348) with VCEP specifications." The evidence for this variant shows: no functional characterization studies have been performed. Therefore, this criterion is not applied because functional data are absent.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Very Strong: ≥16 phenotype points for cases absent from controls; Strong: 3.5–15.75 points; Moderate: 1.5–3.25 points; Supporting: 0.5–1.25 points." The evidence for this variant shows: no case reports or phenotype data. Therefore, this criterion is not applied due to absence of case-level phenotype evidence.
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: the position Y985 has not been annotated as within a defined critical functional domain. Therefore, this criterion is not applied because domain mapping information is unavailable.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent/rare from controls in an ethnically-matched cohort population sample (≥1)." The evidence for this variant shows: NM_006218.4:c.2953T>A is not present in gnomAD or other population databases (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from 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: no data on cis/trans configuration with other PIK3CA variants. Therefore, this criterion is not applied due to absence of trans evidence.
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 variants." The evidence for this variant shows: NM_006218.4:c.2953T>A is a missense substitution without protein length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate: Novel missense change at an amino acid residue where a different missense change has been established as pathogenic." The evidence for this variant shows: no other pathogenic missense variant at residue Y985 has been reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Presumed de novo, without confirmation of paternity and maternity." 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: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2 is: "Supporting: Missense constraint computed in ExAC/gnomAD with z-score >3.09." The evidence for this variant shows: no ExAC/gnomAD z-score has been provided. Therefore, this criterion is not applied due to missing missense constraint data.
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." The evidence for this variant shows: the majority of in silico tools predict benign impact (SIFT, PolyPhen, MetaSVM benign; REVEL 0.45; low CADD; SpliceAI 0.01). Therefore, this criterion is not applied because computational evidence does not support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient phenotype or family history is highly specific for gene." The evidence for this variant shows: no phenotype or clinical presentation 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 recently reports variant as pathogenic." The evidence for this variant shows: not present in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Allele frequency >0.0926%." The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: Allele frequency >0.0185%." The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong: ≥3 homozygotes in gnomAD or ≥3 heterozygotes in well-phenotyped individuals." The evidence for this variant shows: no homozygotes or heterozygotes reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong: Well-validated functional studies show no damaging effect; Supporting: less robust functional evidence." The evidence for this variant shows: no functional studies are available. 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 of a family." 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 for which primarily loss-of-function causes disease." The evidence for this variant shows: PIK3CA disease mechanism is often gain-of-function, and this is a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting: Observed in cis or trans with a known pathogenic variant in the same gene." The evidence for this variant shows: no information on cis/trans status with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame insertions/deletions in repetitive regions without known function." The evidence for this variant shows: this is a single nucleotide substitution. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting: Applicable only to synonymous, intronic (except canonical splice sites), or UTR variants when two of three splice tools predict no impact." The evidence for this variant shows: Y985N is a missense change. Therefore, this criterion is not applied under VCEP specifications.
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 information on alternative molecular findings. 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 variant as benign." The evidence for this variant shows: not present in ClinVar or similar sources. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting: For synonymous or intronic positions (non-canonical) with PhyloP <0.1." The evidence for this variant shows: Y985N is a missense substitution. Therefore, this criterion is not applied.