Submissions for variant NM_000546.6(TP53):c.577C>T (p.His193Tyr)

dbSNP: rs876658468

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221478	SCV000273726	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-16	criteria provided, single submitter	clinical testing	The p.H193Y pathogenic mutation (also known as c.577C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 577. The histidine at codon 193 is replaced by tyrosine, an amino acid with some similar properties. This variant is located in the highly-conserved DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Additional 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). It has been reported in the database as both a germline mutation in a family with classic Li-Fraumeni Syndrome (LFS), and a somatic mutation in numerous tumors (IARC TP53 database). This alteration has also been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Another variant at this same amino acid position, p.H193R, has been identified in a patient with LFS, and shown to be severely deficient in transcriptional activation in yeast based assays (Frebourg et al. Am. J. Hum. Genet. 1995 Mar;56(3):608-15; Monti et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV000412758	SCV000491082	pathogenic	not provided	2021-08-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression ability (Kato 2003, Kotler 2018); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31105275, 15510160, 31500291, 29936259, 27659017, 28599463, 26667234, 23028800, 25343854, 21290192, 21514416, 14559903, 12509970, 21197471, 25655233, 26467027, 26230955, 26068095, 8053493, 23384396, 29979965)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809571	SCV000949726	likely pathogenic	Li-Fraumeni syndrome	2024-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 193 of the TP53 protein (p.His193Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 27328919, 31105275, 32817165). ClinVar contains an entry for this variant (Variation ID: 230256). 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, 14559903, 21514416). This variant disrupts the p.His193 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7887414, 22265402, 25945745, 28724667; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Genome-Nilou Lab	RCV000221478	SCV002582376	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288851	SCV002583037	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288851	SCV004932201	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-15	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 14559903, 23028800, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28772286].
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332145	SCV004040491	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research