Total submissions: 22
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000235220 | SCV000211756 | likely pathogenic | not provided | 2018-05-21 | criteria provided, single submitter | clinical testing | This variant is denoted TP53 c.713G>A at the cDNA level, p.Cys238Tyr (C238Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). This variant has been observed in either the homozygous or hemizygous state in blood cells from an individual with a history of Hodgkin's disease and other personal/family history not consistent with Li-Fraumeni syndrome (Nichols 2003). Although reported as a germline finding, testing of a second tissue was not performed, leaving open the possibility that this variant was present due to a somatic event in this individual's blood cells. Functional studies have demonstrated TP53 Cys238Tyr to impact transactivation (Epstein 1998, Dearth 2007, Monti 2011), consistent with it being 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 Cys238Tyr was not observed in large population cohorts (Lek 2016). This variant is located within 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 TP53 Cys238Tyr to be a likely pathogenic variant. |
| Ambry Genetics | RCV000161034 | SCV000216065 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-11-22 | criteria provided, single submitter | clinical testing | Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Deficient protein function in appropriate functional assay(s),Structural Evidence,Well-characterized mutation at same position |
| Invitae | RCV000167907 | SCV000218555 | likely pathogenic | Li-Fraumeni syndrome | 2018-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine with tyrosine at codon 238 of the TP53 protein (p.Cys238Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs730882005, ExAC 0.003%). This variant has been reported in an individual affected with Hodgkins disease (PMID: 14673037) and an individual affected with breast cancer (PMID: 11051239). ClinVar contains an entry for this variant (Variation ID: 182935). Experimental studies have shown that this missense change is a severe deficiency allele, resulting in significantly decreased transactivation activity of TP53, and that it may act in a dominant negative fashion, reducing the transactivation activity of the wild-type allele (PMID: 21343334). However, there is also experimental evidence that this variant has no effect on the protein compared to the wild-type and molecular modeling shows that the structure of the protein is similar (PMID: 16818505). The cysteine residue at codon 238 is involved in coordinating a zinc ion in the DNA-binding domain of the TP53 protein. Furthermore, other amino acid substitutions at this codon have been reported in affected patients, namely Cys238Gly and Cys238Ser. These sequence changes have also been described as severe deficiency alleles (PMID: 21343334). This indicates that the cysteine 238 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. |
| Color | RCV000161034 | SCV000908788 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-07-16 | criteria provided, single submitter | clinical testing | |
| Database of Curated Mutations |
RCV000442204 | SCV000507684 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000421991 | SCV000507685 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000433120 | SCV000507686 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000442285 | SCV000507687 | likely pathogenic | Uterine cervical neoplasms | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000426546 | SCV000507688 | likely pathogenic | Neoplasm of the breast | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000436794 | SCV000507689 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000444562 | SCV000507690 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000426733 | SCV000507691 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000437851 | SCV000507692 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000420202 | SCV000507693 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000431283 | SCV000507694 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000438032 | SCV000507695 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000417749 | SCV000507696 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000427976 | SCV000507697 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000439129 | SCV000507698 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000418002 | SCV000507699 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000429110 | SCV000507700 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
| German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne, |
RCV000785261 | SCV000923829 | likely pathogenic | Ovarian Neoplasms | 2018-12-01 | no assertion criteria provided | research |