Submissions for variant NM_000546.6(TP53):c.613T>C (p.Tyr205His)

dbSNP: rs1057520008

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819983	SCV000960674	pathogenic	Li-Fraumeni syndrome	2023-05-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr205 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10922393, 21356188, 29324801). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 376685). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 205 of the TP53 protein (p.Tyr205His).
Ambry Genetics	RCV000775886	SCV001187031	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-09-09	criteria provided, single submitter	clinical testing	The p.Y205H variant (also known as c.613T>C), located in coding exon 5 of the TP53 gene, results from a T to C substitution at nucleotide position 613. The tyrosine at codon 205 is replaced by histidine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). 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). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000775886	SCV004359996	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 205 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 disrupted function in yeast transactivation assays (PMID: 12826609), human cell proliferation assays (PMID: 29979965), and human cell growth suppression assays (PMID: 30224644). This variant has been reported in families affected with Li-Fraumeni syndrome meeting Chompret criteria (PMID: 36219266; ClinVar SCV000960674.4, SCV002654466.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Tyr205Cys, is a well documented pathogenic mutation (ClinVar Variation ID: 376681), indicating that tyrosine at this position is important for TP53 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV004022252	SCV004932319	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: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].