rs587780070
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.535C>T(p.His179Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H179Q) has been classified as Pathogenic.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.535C>T | p.His179Tyr | missense_variant | 5/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.535C>T | p.His179Tyr | missense_variant | 5/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461882Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727242
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74380
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 13, 2023 | This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16633321]. Functional studies indicate this variant impacts protein function [PMID: 12509279, 17530187]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 16, 2018 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 13, 2022 | The p.H179Y pathogenic mutation (also known as c.535C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 535. The histidine at codon 179 is replaced by tyrosine, an amino acid with similar properties. This mutation has been reported in the germline of multiple individuals with Li-Fraumeni syndrome (Lefrou L et al. Gastroenterol. Clin. Biol., 2006 Mar;30:484-6; Bougeard G et al. J. Clin. Oncol., 2015 Jul;33:2345-52; Zerdoumi Y et al. Hum. Mol. Genet., 2017 Jul;26:2591-2602). Numerous functional assays conducted in yeast and mammalian cells have shown the p.Y179H variant has decreased transactivation activity compared to wild type, and exerts a dominant negative effect (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9, Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98; Scian MJ et al. Oncogene, 2004 May;23:4430-43). Further functional studies indicate this mutation has oncogenic properties through upregulation of genes involved in cell cycle progression and proliferation (Ko JL et al. DNA Repair Amst; Yang D et al. Mol. Cell. Biochem., 2007 Oct;304:219-26; Scian MJ et al. Oncogene, 2004 May;23:4430-43). 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 alteration is located in the DNA binding domain, and is one of four residues necessary to bind the zinc molecule that stabilizes the beta sheet structure of the p53 protein (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). 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). In addition, another alteration at this same position, p.H179Q was identified as a de novo mutation in a patient with two Li-Fraumeni core cancers (Gonzalez KD et al. J. Med. Genet. 2009 Oct; 46(10):689-93). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Small cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Li-Fraumeni syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2023 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 179 of the TP53 protein (p.His179Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of Li-Fraumeni syndrome (PMID: 16633321, 18511570, 25433984). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 127815). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 11896595, 12509279, 12726864, 12826609, 17530187, 26497680). For these reasons, this variant has been classified as Pathogenic. - |
Glioblastoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
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
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2014 | This variant is denoted TP53 c.535C>T at the cDNA level, p.His179Tyr (H179Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT) in exon 5. This mutation has been observed as a somatic mutation in over 100 different cancers but has only been observed as a germline mutation in one patient with a history of six cancers, most being classic Li-Fraumeni tumors: fibrosarcoma, adrenal cortical carcinoma, osteosarcoma, ductal carcinoma in situ, infiltrating ductal carcinoma and adenocarcinoma of the pancreas (IARC TP53 Database, Lefrou 2006). Two in vitro functional assays have shown that this mutation has similar protein activity as cells null for the p53 protein (Ko 2002, Yang 2007). TP53 His179Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Variant Server, indicating it is not a common benign variant in these populations. This mutation is a non-conservative substitution in which a positive polar amino acid is replaced with a neutral polar one, altering a position that is well conserved throughout evolution and is located in within the DNA-binding domain and the region that interacts with HIPK1, ZNF385A, FBX042 and AXIN1. Based on the currently available information, we consider TP53 His179Tyr to be a pathogenic mutation This variant has been seen apparently mosaic. The variant is found in BR-OV-HEREDIC panel(s). - |
Ovarian serous cystadenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant melanoma of skin Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Ovarian neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Uterine carcinosarcoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Acute myeloid leukemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Adrenocortical carcinoma, hereditary Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 17, 2023 | - - |
Malignant neoplasm of body of uterus Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Pancreatic adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Gallbladder carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
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 | - - |
Neoplasm of the large intestine Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
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 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at