Submissions for variant NM_000546.6(TP53):c.614A>G (p.Tyr205Cys)

dbSNP: rs1057520007

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704312	SCV000833256	pathogenic	Li-Fraumeni syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 205 of the TP53 protein (p.Tyr205Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 10922393, 21356188, 29324801). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 376681). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 17724467, 20505364, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002356520	SCV002654466	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-22	criteria provided, single submitter	clinical testing	The p.Y205C pathogenic mutation (also known as c.614A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 614. The tyrosine at codon 205 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in families meeting classic Li Fraumeni syndome (LFS) criteria and LFS-like criteria (Portwine C et al. J Med Genet, 2000 Aug;37:E13; Plon SE et al. Cancer Genet, 2011 Jan;204:19-25; Stoltze U et al. PLoS One, 2018 Jan;13:e0190050). Another alteration at the same codon, p.Y205H (c.613T>C), has been detected in a patient meeting Chompret criteria (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-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 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). 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). 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.
Myriad Genetics, Inc.	RCV004022251	SCV004933435	pathogenic	Li-Fraumeni syndrome 1	2024-02-15	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 7718482, 7761089, 15037740]. 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: 29324801, 21356188].
GeneDx	RCV004721353	SCV005327535	pathogenic	not provided	2023-11-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 29979965, 17724467, 15037740, 30224644, 15161705, 16861262, 7718482, 7761089, 15510160, 15541116, 10753186, 20505364, 23117049, 30840781, 30720243, 32817165, 34240179, 10922393, 21356188, 29324801)
Database of Curated Mutations (DoCM)	RCV000430410	SCV000510113	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440667	SCV000510114	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422980	SCV000510115	likely pathogenic	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433236	SCV000510116	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439980	SCV000510117	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422077	SCV000510118	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432320	SCV000510119	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443687	SCV000510120	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424901	SCV000510121	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431652	SCV000510122	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443828	SCV000510123	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427749	SCV000510124	likely pathogenic	Non-Hodgkin lymphoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437968	SCV000510125	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442863	SCV000510126	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427034	SCV000510127	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437254	SCV000510128	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004745373	SCV005344111	likely pathogenic	TP53-related disorder	2024-04-05	no assertion criteria provided	clinical testing	The TP53 c.614A>G variant is predicted to result in the amino acid substitution p.Tyr205Cys. This variant has been reported in multiple individuals with Li-Fraumeni syndrome (Portwine et al. 2000. PubMed ID: 10922393; Plon et al. 2011. PubMed ID: 21356188; Stoltze et al. 2018. PubMed ID: 29324801; Gao et al. 2020. PubMed ID: 32817165; Ceyhan-Birsoy et al. 2021. PubMed ID: 34240179). In vitro functional studies have demonstrated that this variant results in a loss of function with a dominant-negative effect on wild type p53 (Kato et al. 2003. PubMed ID: 12826609; Dearth et al. 2007. PubMed ID: 16861262; Kotler et al. 2018. PubMed ID: 29979965). This variant has not been reported in a large population database, indicating this variant is rare. This variant is listed in ClinVar as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/376681/). Of note, other missense variants at the same amino acid position (p.Tyr205Asp, p.Tyr205His) have also been reported as disease-causing in patients with Li-Fraumeni syndrome (Renaux-Petel et al. 2018. PubMed ID: 29070607; Kai et al. 2022. PubMed ID: 36219266). Taken together, this variant is interpreted as likely pathogenic.