Submissions for variant NM_000546.6(TP53):c.686G>A (p.Cys229Tyr)

dbSNP: rs1064793603

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482575	SCV000566570	uncertain significance	not provided	2015-05-12	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.686G>A at the cDNA level, p.Cys229Tyr (C229Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, this variant has been reported as a somatic variant in a pulmonary carcinoid and a breast tumor (Lohmann 1993, Shiao 1995). Functional studies in yeast and human tumor cell lines suggest TP53 Cys229Tyr is able to retain partial transcriptional activity compared to wildtype and null cells (Kato 2003, Kakudo 2005). TP53 Cys229Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Cys229Tyr occurs at a position that is not conserved and is located in the DNA binding domain and the region required for interaction with HIPK1, ZNF385A, FBX042, and AXIN1 (Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether TP53 Cys229Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000775944	SCV000910445	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215783	SCV001387545	uncertain significance	Li-Fraumeni syndrome	2022-11-23	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 does not substantially affect 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 not expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 419040). This variant has not been reported in the literature in individuals affected with TP53-related conditions. 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 229 of the TP53 protein (p.Cys229Tyr).
Genome-Nilou Lab	RCV000775944	SCV002582020	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289624	SCV002582157	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775944	SCV002666091	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-24	criteria provided, single submitter	clinical testing	The p.C229Y variant (also known as c.686G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 686. The cysteine at codon 229 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no 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 amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV004568157	SCV005054348	uncertain significance	Adrenocortical carcinoma, hereditary	2023-12-11	criteria provided, single submitter	clinical testing