Submissions for variant NM_000546.6(TP53):c.404G>A (p.Cys135Tyr)

dbSNP: rs587781991

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130396	SCV000185255	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-05	criteria provided, single submitter	clinical testing	The p.C135Y pathogenic mutation (also known as c.404G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 404. The cysteine at codon 135 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in one Chinese patient diagnosed with sporadic triple negative breast cancer. This individual also carried a likely pathogenic variant in the MSH6 gene (Yi D et al. Hum. Genomics. 2019 01;13:4). 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). The p.C135Y variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and dominant negative activity in yeast based assays (Dearth LR et al. Carcinogenesis. 2007 Feb; 28(2):289-98; Jordan JJ et al. Mol. Cancer Res. 2010 May;8(5):701-16; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition, internal structural analysis suggests this variant, which is a buried residue in the secondary shell of the DNA binding surface, is structurally destabilizing (Cho Y et al. Science. 1994 Jul 15;265(5170):346-55; Ambry internal data). 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 alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000130396	SCV000686738	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 135 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). Experimental studies have shown that this variant yields protein that is non-functional in yeast transactivation assays (PMID: 12826609, 15017592, 16861262, 20407015), human cell proliferation assays (PMID: 29979965), and human cell growth suppression assays (PMID: 16247456, 30224644). This variant has been reported in a Chinese individual affected with gastric cancer (PMID: 21080251) and in a Chinese individual with sporadic triple-negative breast cancer carrying a second variant in MSH6 (PMID: 30630526). 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.
Invitae	RCV001069143	SCV001234291	uncertain significance	Li-Fraumeni syndrome	2023-05-27	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 141762). This missense change has been observed in individual(s) with breast cancer at an allele fraction of 0.16 (PMID: 30630526). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 135 of the TP53 protein (p.Cys135Tyr).
CeGaT Center for Human Genetics Tuebingen	RCV000581322	SCV001335063	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004019738	SCV004933960	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-13	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7651740, 16247456, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Database of Curated Mutations (DoCM)	RCV000419337	SCV000507444	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430048	SCV000507445	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437052	SCV000507446	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419825	SCV000507447	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428748	SCV000507448	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439440	SCV000507449	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422242	SCV000507450	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429447	SCV000507451	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438381	SCV000507452	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421166	SCV000507453	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431855	SCV000507454	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444676	SCV000507455	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423651	SCV000507456	likely pathogenic	Adrenal cortex carcinoma	2016-05-31	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000581322	SCV000692089	likely pathogenic	not provided		no assertion criteria provided	clinical testing