ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.659A>G (p.Tyr220Cys) (rs121912666)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 28
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213055 SCV000149640 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing This variant is denoted TP53 c.659A>G at the cDNA level, p.Tyr220Cys (Y220C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). TP53 Tyr220Cys has been identified in several Li-Fraumeni kindreds, with at least two de novo occurrences reported (Birch 1994, Huusko 1999, Capponcelli 2005, Izawa 2008, Lin 2009, Debelenko 2010, Wilson 2010, Melhem-Bertrandt 2012, Fostira 2015, Andrade 2016, Zerdoumi 2017). On functional interrogation, TP53 Tyr220Cys has been found to impact binding to typical p53-responsive elements and cause decreased transcriptional activation (Malcikova 2010, Monti 2011). Consistent with these findings, this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Tyr220Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000115731 SCV000183774 pathogenic Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other strong data supporting pathogenic classification
Invitae RCV000232050 SCV000285206 pathogenic Li-Fraumeni syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 220 of the TP53 protein (p.Tyr220Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs121912666, ExAC 0.005%). This variant has been reported as de novo in an individual with Li-Fraumeni syndrome (LFS) (PMID: 18307025), as well as in individuals with breast cancer and adrenal carcinoma (PMID: 21761402, 20805372). This variant has also been reported to segregate with LFS in several families (PMID: 8118819, 10432928, 19101993). ClinVar contains an entry for this variant (Variation ID: 127819). Experimental studies have shown that this missense change destabilizes the TP53 protein, and disrupts its DNA binding and transactivation activity (PMID: 20128691, 21343334, 22923379, 17015838). Many of these properties are reversed in cell culture by treatment with a small molecule (PMID: 23630318). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000232050 SCV000697444 pathogenic Li-Fraumeni syndrome 2017-04-27 criteria provided, single submitter clinical testing Variant summary: The TP53 c.659A>G (p.Tyr220Cys) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the p53 DNA-binding domain (InterPro). 5/5 in silico tools predict damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.000025 (3/119860 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398). This variant has been reported as a germline variant in several patients/families with Li-Fraumeni syndrome. This germline variant has also been reported in early-onset breast cancer patients (Wilson_2010; Melhem-Bertrandt_2012). In three LFS families, the variant co-segregated with disease in affected members genotyped over two-generations (Birch_1994/Varley_1997; Huusko_1999; Lin_2009). Functional studies show that the variant severely compromises the p53 binding and transactivation (Jordan_2010; Zachos_1998; TP53 database). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Another missense change at this residue Y220S is also classified as pathogenic in ClinVar by multiple submitters. This variant is located in a mutational hot spot and a small molecule capable of targeting the p.Y220C mutant has been identified (Reviewed by Soussi_2015). Taken together, this variant is classified as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000213055 SCV000700520 pathogenic not provided 2017-03-02 criteria provided, single submitter clinical testing
Mendelics RCV000232050 SCV000839116 pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213055 SCV000888669 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000417417 SCV000504719 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428097 SCV000504720 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439645 SCV000504721 likely pathogenic Acute myeloid leukemia 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418951 SCV000504722 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428791 SCV000504723 likely pathogenic Papillary renal cell carcinoma, sporadic 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439456 SCV000504724 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423111 SCV000504725 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433936 SCV000504726 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440244 SCV000504727 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423029 SCV000504728 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434614 SCV000504729 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442230 SCV000504730 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423624 SCV000504731 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434300 SCV000504732 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444717 SCV000504733 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425193 SCV000504734 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435063 SCV000504735 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444814 SCV000504736 likely pathogenic Small cell lung cancer 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425869 SCV000504737 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436553 SCV000504738 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785544 SCV000924116 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.