Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000546.3 | Alternative | 2640 nt | 252–1433 |
| NM_000546.5 | RefSeq Select | 2591 nt | 203–1384 |
| 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
OpenThis variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15077194, 21561095, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
The p.V157F variant (also known as c.469G>T), located in coding exon 4 of the TP53 gene, results from a G to T substitution at nucleotide position 469. The valine at codon 157 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with adrenocortical carcinoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This variant has also been reported as confirmed de novo in a 5 year-old patient who was diagnosed with medulloblastoma (Azzollini J et al. Cancers (Basel), 2020 Sep;12:). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, a dominant negative effect, and is predicted to affect several p53 isoforms in yeast based assays (IARC TP53 databse; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98; Baroni TE et al. Proc. Natl. Acad. Sci. U.S.A., 2004 Apr;101:4930-5; Gorgoulis VG et al. Br. J. Cancer, 1998;77:374-84; Ishii N et al. Oncogene, 1999 Oct;18:5870-8; Obata A et al. Int. J. Cancer, 2000 Mar;89:187-93; Concin N et al. Breast Cancer Res. Treat., 2003 May;79:37-46; Millon R et al. Oral Oncol., 2001 Dec;37:620-31; Fouquet C et al. Clin. Cancer Res., 2004 May;10:3479-89; Schlichtholz B et al. Carcinogenesis, 2004 Dec;25:2319-23; Scian MJ et al. Oncogene, 2004 May;23:4430-43; Mizuarai S et al. Cancer Res., 2006 Jun;66:6319-26; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability of the DNA-binding domain (Kitayner et al. Nat. Struct. Mol. Biol., 2010 Apr;17(4):423-9; Calhoun S et al. Biochemistry, 2011 Jun;50:5345-53). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 157 of the TP53 protein (p.Val157Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with adrenocortical carcinoma, medulloblastoma and/or breast cancer (PMID: 15564800, 26580448, 29785153, 32899294). ClinVar contains an entry for this variant (Variation ID: 12353). 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: 9472631, 10713666, 16861262). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
"This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Pathogenic (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The TP53 V157F variant has been functionally characterized and is likely damaging. It is located in the DNA-binding domain of the TP53 protein. In vitro and structural studies have shown that this mutation results in a rearranged DNA-binding surface, reduced DNA-binding activity, and impaired transcriptional activity. Additionally, it leads to decreased expression of pro-apoptotic proteins and a reduced apoptotic response. The variant also confers a gain of function, resulting in aberrant gene regulation, including suppression of uPA in cell culture.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -143 bp |
| Donor Loss (DL) | 0.0 | -44 bp |
| Acceptor Gain (AG) | 0.0 | -189 bp |
| Donor Gain (DG) | 0.0 | 35 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "PVS1 applies to null variants (nonsense, frameshift, canonical ±1,2 splice) predicted to undergo NMD (or in‐frame but targeting critical domains)." The evidence for this variant shows: it is a missense change (p.V157F). Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "PS1 applies to variants asserting the same amino acid change as another pathogenic variant (following TP53 VCEP specifications)." The evidence for this variant shows: no other pathogenic variant at codon 157 yielding p.V157F has been reported. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "PS2 applies when de novo occurrence is confirmed per TP53 VCEP specifications (≥2 points for moderate, ≥4 for strong)." The evidence for this variant shows: no data on de novo occurrence. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 (Strong) is: "Non‐functional on Kato et al. data AND loss of function on another assay (e.g., Giacomelli et al.)." The evidence for this variant shows: in vitro studies demonstrate reduced DNA binding and impaired transcriptional activity, but no specific Kato et al. or Giacomelli assay results are provided. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Proband points ≥2 for Moderate, ≥4 for Strong following the TP53 proband points table." The evidence for this variant shows: no case‐control or proband data reported. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 (Moderate) is: "Missense variants within codons 175, 245, 248, 249, 273, 282 are hotspots for TP53." The evidence for this variant shows: p.V157F lies outside these hotspot codons. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Allele frequency <0.00003 in gnomAD or other large databases." The evidence for this variant shows: absent from gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant in recessive disorders." The evidence for this variant shows: TP53 is autosomal dominant and no such trans observations exist. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes (in‐frame indels or stop‐loss) not affecting functionally critical region." The evidence for this variant shows: it is a missense variant, not a length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 (Moderate) is: "Missense variant at a residue where ≥1 other pathogenic missense variant is reported." The evidence for this variant shows: no other TP53 pathogenic missense variants at codon 157 have been established under VCEP specifications. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo without confirmation of parental relationships." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 requires: "Cosegregation in ≥3 meioses across ≥1 families for Supporting, 5–6 for Moderate, ≥7 for Strong." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation." The evidence for this variant shows: TP53 has numerous reported missense variants. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 (Moderate) is: "BayesDel ≥0.16 and no splicing impact (SpliceAI <0.2)." The evidence for this variant shows: BayesDel score not provided. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 requires: "Clinical phenotype highly specific to TP53-associated syndromes." The evidence for this variant shows: no clinical phenotype data provided. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only truncating variants cause disease." The evidence for this variant shows: TP53 disease is caused by missense variants as well. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant condition." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame indels in repetitive regions without a known function." The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 (Moderate) is: "BayesDel ≤ -0.008 and no splicing impact (SpliceAI <0.2)." The evidence for this variant shows: BayesDel score not provided. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternative molecular basis for disease." The evidence for this variant shows: no such case. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence unavailable." The evidence for this variant shows: no benign assertions. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant outside core splice sites with no predicted splicing impact." The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 (Stand Alone) is: "MAF ≥0.001 in gnomAD subpopulations." The evidence for this variant shows: absent in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 (Strong) is: "Filtering allele frequency ≥0.0003 but <0.001 in gnomAD." The evidence for this variant shows: absent in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 (Strong) is: "≥8 unrelated unaffected females ≥60 years without cancer." The evidence for this variant shows: no such data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 (Strong) is: "Functional data showing normal function on Kato et al. AND no loss of function on another assay." The evidence for this variant shows: studies demonstrate damaging effect, not normal function. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected family members." The evidence for this variant shows: no segregation analysis. Therefore, this criterion is not applied.