Submissions for variant NM_000546.6(TP53):c.658T>C (p.Tyr220His)

dbSNP: rs530941076

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566866	SCV000664417	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-06	criteria provided, single submitter	clinical testing	The p.Y220H pathogenic mutation (also known as c.658T>C), located in coding exon 5 of the TP53 gene, results from a T to C substitution at nucleotide position 658. The tyrosine at codon 220 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 capacity 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 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). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215103	SCV001386826	pathogenic	Li-Fraumeni syndrome	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 220 of the TP53 protein (p.Tyr220His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 376687). 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). This variant disrupts the p.Tyr220 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8118819, 10432928, 15977174, 18307025, 19101993, 19556618). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003476013	SCV004204263	likely pathogenic	Adrenocortical carcinoma, hereditary	2023-01-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001215103	SCV004840278	likely pathogenic	Li-Fraumeni syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 220 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 missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (ClinVar: SCV001386826.4). Different missense variants occurring at the same codon (p.Tyr220Cys, p.Tyr220Ser) are known to be disease-causing (ClinVar Variation IDs: 12383, 127819). This variant has been identified in 1/251400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV004022253	SCV004932232	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: 7718482, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785254	SCV000923822	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research