TP53 c.776A>T, p.Asp259Val
NM_000546.6:c.776A>T
COSMIC ID: COSM43724
Likely Pathogenic
The TP53 D259V variant has strong functional evidence of loss of function (PS3_Strong) and is absent from population databases (PM2_Supporting), but lacks additional moderate or supporting criteria. Therefore, it is classified as a Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PS3
PM2
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.776A>T
Protein Change
D259V
Location
Exon 7
(Exon 7 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 259 in gene TP53
Alternate Identifiers
COSM43724
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.776A>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
4 publications
Likely Pathogenic
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
2 Path
4 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
The p.D259V pathogenic mutation (also known as c.776A>T), located in coding exon 6 of the TP53 gene, results from an A to T substitution at nucleotide position 776. The aspartic acid at codon 259 is replaced by valine, an amino acid with highly dissimilar properties. Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). This variant was detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Well-established functional studies have demonstrated this variant to have a damaging effect on protein function or splicing (ACMG/AMP: PS3; PMIDs:12826609, 30224644). This variant is located in a mutational hot spot and/or critical and well-established functional domain (ACMG/AMP: PM1_Supporting). This variant is absent from or present at an exceedingly low frequency in gnomAD, a large-scale control population database (ACMG/AMP: PM2_Supporting).
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 259 of the TP53 protein (p.Asp259Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 485034). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Pathogenic (2 clinical laboratories) and as Likely Pathogenic (1 clinical laboratories).
COSMIC ID
COSM43724
Recurrence
29 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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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 259 in gene TP53
Functional Summary
The TP53 D259V variant, located in the DNA-binding domain, has been functionally characterized as inactivating. In vivo studies using yeast models demonstrated a loss of transactivational activity, and in vitro studies with human cancer cell lines showed reduced growth suppression activity compared to the wildtype. These findings support a damaging effect on TP53 function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: D
Benign:
CADD: 4.61primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines for PVS1: "Very Strong Strength: Very Strong Please utilize the PVS1 decision tree for application of PVS1 code. The decision tree details the specific strengths each type of null variant may be applied at." The evidence for this variant shows it is a missense substitution, not predicted to result in a null allele. Therefore, this criterion is not applied because the variant is not a predicted loss‐of‐function.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PS1: "Strong Strength: Strong Can be applied to variants asserted as Pathogenic following the TP53 VCEP’s specifications." The evidence shows no other pathogenic variant results in the same D259V amino acid change via a different nucleotide. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines for PS2: "Very Strong Strength: Very Strong ≥ 8 points" (de novo occurrences scoring). No confirmed de novo observations are available. Therefore, PS2 is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines for PS3: "Strong Strength: Strong Non-functional on Kato et al. data AND loss of function (LOF) on another assay (e.g., Giacomelli et al., Kotler et al., or another assay showing low function)" The evidence shows D259V is non-functional in yeast transactivation assays (Kato) and exhibits LOF in human cell‐based growth suppression assays. Therefore, PS3 is applied at Strong strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines for PS4: "Very Strong Strength: Very Strong ≥ 8 points" (case‐control/proband data). No proband point data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PM1: "Moderate Strength: Moderate Missense variants within the following codons using transcript NM_00546.4: 175, 245, 248, 249, 273, 282. This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥ 10 somatic occurrences for the same amino acid change." D259 is not among these codons. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PM2: "Supporting Strength: Supporting This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population." The D259V variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM3: applies to recessive disorders with variants observed in trans. No data demonstrate this variant in trans with a pathogenic allele in a recessive context. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM4: applies to protein length changes (in‐frame indels or stop‐loss variants). This is a missense change with no protein length alteration. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PM5: "Moderate Strength: Moderate Missense variant at an amino acid residue where 1 different missense variant previously determined to be pathogenic according to the TP53 VCEP’s specifications has been seen before." No other pathogenic missense variant at codon 259 has been reported. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines for PM6: applies to assumed de novo occurrences without confirmation of paternity/maternity. No such information is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for PP1: "Supporting Strength: Supporting Cosegregation must be observed in 3-4 meioses in/across 1 or more families." No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP2: applies when a missense variant occurs in a gene with few benign missense variants and where missense is a known mechanism. No gene‐level tolerance data or evidence specific to TP53 benign variation have been provided. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines for PP3: "Moderate Strength: Moderate Missense variants (See flowchart for application of PP3 and BP4 rules for missense variants) aGVGD Class C65 and BayesDel score ≥ 0.16"; and "Supporting Strength: Supporting Missense variants ... BayesDel score ≥ 0.16 ... SpliceAI ≥ 0.2 predicts splicing impact." BayesDel score is not provided and in silico predictions are conflicting. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines for PP4: applies when patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 (reputable source reports as pathogenic) is no longer recommended as standalone evidence. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1: "Stand Alone Strength: Stand Alone Filtering allele frequency (FAF) of ≥ 0.001 ... in gnomAD ..." The variant is absent from gnomAD. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1: "Strong Strength: Strong Filtering allele frequency (FAF) of ≥ 0.0003 but < 0.001 ..." The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for BS2: "Strong Strength: Strong ≥ 8 unrelated females ... without cancer." No data on unaffected older individuals exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BS3: "Strong Strength: Strong Functional on Kato et al. data AND no loss of function (LOF) on another assay ..." The variant shows LOF. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines for BS4: "Strong Strength: Strong Lack of segregation in affected family members ..." No data demonstrating lack of segregation. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP1: applies when a missense variant occurs in a gene for which only truncating variants are known to cause disease. TP53 disease mechanism is frequently missense. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP2: applies when observed in trans with a pathogenic variant for a dominant disorder. No such data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP3: applies to in‐frame insertions/deletions in repetitive regions. This is a non‐repetitive missense change. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines for BP4: "Moderate Strength: Moderate Missense variants ... BayesDel ≤ -0.008 irrespective of aGVGD score ... SpliceAI < 0.2" and "Supporting Strength: Supporting ... BayesDel < 0.16 and > -0.008 ... SpliceAI < 0.2." BayesDel score is not provided and computational predictions are conflicting. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines for BP5: applies when variant found in a case with an alternate molecular basis for disease. No such evidence. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 (reputable source reports as benign) is no longer recommended. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines for BP7: applies to synonymous or intronic variants with no splicing impact. This is a missense variant. Therefore, BP7 is not applied.