TP53 c.206C>T, p.Ala69Val
NM_000546.6:c.206C>T
COSMIC ID: COSM44680
Variant of Uncertain Significance (VUS)
p.A69V is absent from population databases and has a predicted splicing impact (SpliceAI 0.61), satisfying PM2_Supporting and PP3_Supporting only. No other evidence supports pathogenicity or benignity, thus the variant remains a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
PP3
Genetic Information
Gene & Transcript Details
Gene
TP53
Transcript
NM_000546.6
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.6:c.206C>T
Protein Change
A69V
Location
Exon 4
(Exon 4 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 69 in gene TP53
Alternate Identifiers
COSM44680
Variant interpretation based on transcript NM_000546.6
Genome Browser
Loading genome browser...
HGVS InputNM_000546:c.206C>T
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
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
1 publications
Uncertain Significance (VUS)
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
3 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
In 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.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (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 69 in gene TP53
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.314
0.314
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
Pathogenic:
metasvm: Dmetalr: D
Benign:
CADD: 1.52polyphen_prediction: benignprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
PS3 (Not Applied) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
PM5 (Not Applied) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
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
PP2 (Not Applied) Strength Modified
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
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, "BA1: FAF ≥0.001 in gnomAD". The variant is absent from gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
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
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, "BS2: ≥8 unrelated females ≥60 years without cancer". No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, "BS3: Functional assays showing no loss of function". No functional data are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, "BS4: Lack of segregation in affected family members". No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
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
BP4 (Not Applied) Strength Modified
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.