rs1057519986
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000546.6(TP53):c.809T>G(p.Phe270Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F270I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.809T>G | p.Phe270Cys | missense_variant | 8/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.809T>G | p.Phe270Cys | missense_variant | 8/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Carcinoma of esophagus Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell carcinoma of the skin Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Gastric adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Breast neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2022 | Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression ability, and dominant negative effect (Kato et al., 2003; Dearth et al., 2007; Giacomelli et al., 2018; Kotler et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in the literature in families with Li-Fraumeni syndrome (Gao et al., 2020); This variant is associated with the following publications: (PMID: 15510160, 26619011, 32817165, 32358561, 29979965, 28160562, 30808373, 27662657, 16861262, 15308588, 30224644, 12826609) - |
Ovarian serous cystadenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Li-Fraumeni syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 20, 2024 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7651740, 10713666, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Adrenocortical carcinoma, hereditary Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 22, 2023 | - - |
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of brain Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 21, 2023 | This missense variant replaces phenylalanine with cysteine at codon 270 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant is defective in transcriptional transactivation of TP53 target genes, displays loss of function and dominant negative activity in human cell growth suppression assays, and is non-functional in human cell proliferation assays (PMID: 12826609, 29979965, 30224644). This variant has been observed germline in two individuals suspected of having Li-Fraumeni syndrome (PMID: 32817165). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Squamous cell carcinoma of the head and neck Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Li-Fraumeni syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 26, 2022 | This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 270 of the TP53 protein (p.Phe270Cys). 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 (PMID: 32817165). ClinVar contains an entry for this variant (Variation ID: 376597). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at