ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.701A>G (p.Tyr234Cys) (rs587780073)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492245 SCV000581157 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Structural Evidence,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position
Database of Curated Mutations (DoCM) RCV000433924 SCV000510285 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445147 SCV000510286 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422171 SCV000510287 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432406 SCV000510288 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444325 SCV000510289 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425854 SCV000510290 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435258 SCV000510291 likely pathogenic Adrenocortical carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444475 SCV000510292 likely pathogenic Small cell lung cancer 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425220 SCV000510293 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435287 SCV000510294 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420460 SCV000510295 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430670 SCV000510296 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438314 SCV000510297 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420651 SCV000510298 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
GeneDx RCV000115732 SCV000149641 pathogenic not provided 2014-03-10 criteria provided, single submitter clinical testing This variant is denoted TP53 c.701A>G at the cDNA level and p.Tyr234Cys (Y234C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC) in exon 7. This TP53 Tyr234Cys has previously been identified in over 100 tumors as a somatic mutation, most frequently in tumors of the lung, ovaries, brain, breast, and bladder (Petitjean 2007). In addition, this mutation has been observed as a germline mutation in at least one patient with Li Fraumeni syndrome (Pepper 2003). Functional studies have shown loss of transcriptional activation, loss of growth arrest, and loss of induction of apoptosis for this mutation as compared to wild type (Smith 1999, Monti 2007, Monti 2011). Smith et al. (1999) identified that this mutation failed to suppress oncogenic transformation and instead acts as a gain of function mutation, enhancing oncogenic transformation. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Variant Server, suggesting it is not a common benign variant in these populations. This variant is a non-conservative amino acid, altering a position that is well conserved throughout evolution, and is located in the DNA domain which interacts with HIPK1, ZNF385A, FOXO42, and AXIN1 (UniProt). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. We therefore consider this mutation to be pathogenic. This variant has been seen apparently mosaic. The variant is found in ENDOM-HEREDIC panel(s).
Genetic Services Laboratory, University of Chicago RCV000200601 SCV000597518 likely pathogenic Li-Fraumeni syndrome 2016-10-26 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785536 SCV000924108 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000200601 SCV000253701 likely pathogenic Li-Fraumeni syndrome 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 234 of the TP53 protein (p.Tyr234Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual affected with B-cell chronic lymphocytic leukemia with family history suggestive of Li Fraumeni syndrome (PMID: 12695689) and in an individual affected with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 127820). This variant has been classified as a severe deficiency allele due to reduced transactivation capability, apoptosis-inducing activity and cell proliferation suppression observed in yeast- and human cell line-based functional assays (PMID: 16861262, 17606709, 21343334, 10229196). Results of experiments in rat embryo fibroblasts indicated that this variant also conferred enhanced transformation properties to the cells, suggesting a gain-of-function mechanism (PMID: 10229196). This variant falls in a mutational 'hotspot', which is defined as a clustering of plausible observations within a localized region of the protein (PMID: 11358831). This indicates that this region of the protein may be critical for proper protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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