TP53 c.776A>T, p.Asp259Val
NM_000546.6:c.776A>T
COSMIC ID: COSM43724
Likely Pathogenic
The TP53 D259V variant shows well-established loss-of-function in assays (PS3 Strong) and is absent from population databases (PM2 Supporting). No additional criteria are met, resulting in an overall classification of Variant of Uncertain Significance.
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This submission and the accompanying classification are no longer maintained by the submitter.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 has been functionally characterized as damaging. In vivo studies using yeast models have shown that this mutation results in the loss of transactivational activity compared to the wildtype. Additionally, in vitro studies with human cancer cell lines have demonstrated reduced growth suppression activity, indicating an inactivating effect of the mutation.
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, PVS1 applies to null variants (e.g., nonsense or frameshift leading to NMD). NM_000546.6:c.776A>T is a missense variant (D259V) and does not create a null allele. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant leads to the same amino acid change as a previously established pathogenic variant via a different nucleotide change. There are no known pathogenic missense changes at codon 259. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 applies to confirmed de novo occurrences with parental confirmation. There is no de novo or segregation data available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 Strong strength is: "Non-functional on Kato et al. data AND loss of function (LOF) on another assay." The evidence for this variant shows: in vivo yeast models (Kato-like transactivation assay) demonstrate complete loss of TP53 transactivation activity, and in vitro human cancer cell line assays demonstrate reduced growth suppression (LOF). Therefore, this criterion is applied at Strong strength because the variant meets VCEP criteria for non-functionality on Kato and LOF on another assay.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 applies when proband case counts reach specified point thresholds. No case or segregation counts are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 Moderate applies to missense changes at established TP53 hotspot codons (175, 245, 248, 249, 273, 282). Codon 259 is not listed as a hotspot. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 Supporting strength is: "Variant allele frequency less than 0.00003 in gnomAD." The evidence for this variant shows: 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 applies to recessive disorders when the variant is detected in trans with a pathogenic variant. TP53 disease is autosomal dominant and no trans data are relevant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels or stop loss). This is a missense substitution with no change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies when ≥1 different pathogenic missense variant has been seen at the same residue. There are no previously classified pathogenic variants at codon 259. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo occurrences without parental confirmation. No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies when cosegregation is observed in affected family members (Supporting: 3–4 meioses). No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies for missense variants in genes with low rates of benign missense variation. TP53 does not meet these conditions under VCEP specification and evidence is lacking. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 Moderate requires BayesDel ≥ 0.16 and no conflicting data. In silico predictors are mixed and BayesDel was not provided. SpliceAI < 0.2 but computational evidence is conflicting. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies to variant observations in tumor sequence data at specified VAFs. No tumor VAF data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source reports pathogenicity without available evidence. ClinVar submissions are conflicting (4 VUS, 2 Pathogenic, 1 Likely Pathogenic), so no consensus. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies at FAF ≥ 0.001 in gnomAD subpopulations. This variant is absent. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies at FAF ≥ 0.0003 but < 0.001. This variant is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies when ≥ 8 unaffected older females are observed. No such data exist. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 Strong requires functional assays showing no loss of function. Available functional data show loss of function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies for 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 applies to missense changes in a gene where only truncating variants cause disease. TP53 disease mechanism includes dominant-negative and missense effects. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when observed in cis with a pathogenic variant. No cis data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 Moderate requires BayesDel ≤ –0.008 and SpliceAI < 0.2. BayesDel was not provided and computational predictions are mixed. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a patient with an alternate molecular basis for disease. No alternate cause is documented. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies for reputable source reporting benignity without evidence. No such benign consensus exists. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants with no splicing impact. This is a missense change. Therefore, this criterion is not applied.