Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 2591 nt | 203–1384 |
| NM_000546.3 | Alternative | 2640 nt | 252–1433 |
| NM_000546.6 | MANE Select | 2512 nt | 143–1324 |
| NM_000546.4 | Alternative | 2586 nt | 198–1379 |
| NM_000546.2 | Alternative | 2629 nt | 252–1433 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenIn summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies using site-directed mutagenesis in yeast have shown that this missense change does not alter TP53 function (PMID: 12826609 ). This variant has not been reported in the literature in individuals with TP53-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 69 of the TP53 protein (p.Ala69Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine.
"This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 90 bp |
| Donor Loss (DL) | 0.0 | -169 bp |
| Acceptor Gain (AG) | 0.04 | -95 bp |
| Donor Gain (DG) | 0.61 | 2 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, "PVS1 applies to null variants (nonsense, frameshift predicted to undergo NMD, canonical ±1,2 splice variants, initiation codon)". The variant p.A69V is a missense change. Therefore, this criterion is not applied because the variant is not a null variant.
PS1 (Not Applied)
According to VCEP guidelines, "PS1: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". There is no known pathogenic variant resulting in p.A69V. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, "PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, "PS3: Non-functional on Kato et al. data AND loss of function on another assay". No functional assay data are available for p.A69V. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, "PS4: Proband points ≥4 from case data". No case or proband data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, "PM1: Missense variants within codons 175, 245, 248, 249, 273, 282 (hotspots)". p.A69V is at codon 69, outside hotspot codons. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, "PM2: Supporting strength for allele frequency <0.00003 in gnomAD or other large population database". The variant is absent from gnomAD (MAF=0). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, "PM3: Detected in trans with a pathogenic variant for a recessive disorder". TP53 disease mechanism is autosomal dominant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, "PM4: Protein length changes due to in-frame indels or stop-loss variants". p.A69V is a missense change without length alteration. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, "PM5: Missense variant at a residue where ≥2 different pathogenic missense variants have been seen". No pathogenic variants are reported at residue 69. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, "PM6: Assumed de novo without confirmation". No de novo or familial data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, "PP1: Cosegregation observed in 3–4 meioses (Supporting), 5–6 meioses (Moderate), ≥7 meioses (Strong)". No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, "PP2: Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism". TP53 has numerous benign and pathogenic missense variants; no evidence supports PP2. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, "PP3: Exonic variants (including missense) or intronic splice variants with SpliceAI ≥0.2". SpliceAI predicts a donor gain score of 0.61. Therefore, this criterion is applied at Supporting strength.
PP4 (Not Applied)
According to standard ACMG guidelines, "PP4: Patient’s phenotype or family history is highly specific for a disease with a single genetic cause". No phenotype/family history data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, "PP5: Reputable source reports variant as pathogenic without supporting evidence". ClinVar entries are conflicting (VUS, Likely Benign). Moreover, VCEP discourages PP5. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, "BA1: FAF ≥0.001 in gnomAD". The variant is absent from gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, "BS1: FAF ≥0.0003 but <0.001 in gnomAD". The variant is absent from gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, "BS2: ≥8 unrelated females ≥60 years without cancer". No such data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, "BS3: Functional assays showing no loss of function". No functional data are available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, "BS4: Lack of segregation in affected family members". No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, "BP1: Missense in a gene where only truncating variants cause disease". TP53 pathogenicity is often driven by missense variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, "BP2: Observed in trans with a pathogenic variant for a dominant disorder". No such data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, "BP3: In-frame indel in repetitive region without known function". p.A69V is a missense variant. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, "BP4: BayesDel < -0.008 and SpliceAI <0.2". SpliceAI=0.61, and BayesDel not available; criteria for BP4 are not met. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, "BP5: Variant found in cis with a pathogenic variant". No such data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, "BP6: Reputable source reports variant as benign without evidence". ClinVar entries are conflicting; VCEP discourages BP6. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, "BP7: Synonymous or intronic variant outside core splice motifs with SpliceAI ≤0.1". p.A69V is missense. Therefore, this criterion is not applied.