Total submissions: 27
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000235220 | SCV000211756 | likely pathogenic | not provided | 2021-11-24 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (Epstein 1998, Kato 2003, Dearth 2007, Monti 2011, Kotler 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16861262, 26425688, 23297687, 11051239, 21343334, 26619011, 29979965, 30322717, 17606709, 9572492, 16322298, 16818505, 1915267, 19367287, 14673037, 17764544, 28861920, 29177603, 28335073, 30720243, 30840781, 12406399, 11793474, 30352134, 31134617, 30715630, 30554333, 32152322, 32164171, 12826609, 34332791, 34548910, 32547059, 33309985, 31105275, 32622356, 34234554, 32971811) |
Ambry Genetics | RCV000161034 | SCV000216065 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-04-08 | criteria provided, single submitter | clinical testing | The p.C238Y pathogenic mutation (also known as c.713G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 713. The cysteine at codon 238 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was identified as de novo in a patient under 20 with osteosarcoma (Spector et al. Cancer Res 2016;76(5 Suppl):Abstract nr A37). This alteration has been reported in a 15 year-old individual with a personal history of pleomorphic myxoid liposarcoma and the patient's mother, who had a personal history of pre-menopausal breast cancer; there was also a strong family history of malignancy (Sinclair TJ et al. Pediatr Surg Int, 2017 May;33:631-635). This variant was also identified in a cohort of 4439 women with ovarian cancer undergoing multigene panel testing at one laboratory (Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488). This variant is in the DNA binding domain and is one of four amino acid residues required for zinc binding and protein stabilization (Martin et al Hum. Mutat. 2002 Feb;19(2):149-64). This variant is reported to have loss of transactivation capacity, and a dominant negative effect in yeast-based functional assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). 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). In addition, this alteration is predicted to be deleterious by in silico analysis. Several other alterations at this amino acid position (p.C238R, p.C238G and p.C238S) have been reported in patients with Li-Fraumeni or Li-Fraumeni-Like syndrome (Kurtilkova et al Eur J Cancer. 2005 Jul;41(11):1597-603; Balmaña J et al. Med Clin (Barc) 2002 Oct;119(13):497-9; internal Ambry data). Based on the available evidence, p.C238Y is classified as a pathogenic mutation. |
Invitae | RCV000167907 | SCV000218555 | pathogenic | Li-Fraumeni syndrome | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 238 of the TP53 protein (p.Cys238Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with breast cancer, Hodgkins disease, liposarcoma, and/or osteosarcoma (PMID: 11051239, 14673037; Invitae). ClinVar contains an entry for this variant (Variation ID: 182935). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 21343334, 29979965, 30224644). This variant disrupts the p.Cys238 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12506399, 15925506, 21343334). 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. |
Color Diagnostics, |
RCV000161034 | SCV000908788 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-06-08 | criteria provided, single submitter | clinical testing | This missense variant replaces cysteine with tyrosine at codon 238 of the TP53 protein. The cysteine residue at codon 238 is one of the cysteine ligands required for the tetrahedrally coordinated zinc atom important for the structure and DNA binding activity of the TP53 DNA binding domain (PMID: 8276238, 8023157, 11793474). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have shown that the mutant protein is non-functional in growth suppression and transactivation assays (PMID: 12826609, 17606709, 21343334, 30224644) and has a dominant-negative effect on growth suppression (PMID: 30224644). However, one study had previously reported contradictory findings in limited transactivation and DNA damage response assays (PMID: 16818505). This variant has been reported in individuals affected with breast cancer (PMID: 11051239, 31105275, 33471991), sarcoma (PMID: 31105275), osteosarcoma (DOI: 10.1158/1538-7445.PEDCA15-A37), pleomorphic myxoid liposarcoma (PMID: 28160093), ovarian cancer (PMID: 30322717), Hodgkin's disease (PMID: 14673037), and two individuals affected with malignant peripheral nerve sheath tumor, one of whom also had childhood onset non-Hodgkin's lymphoma (PMID: 16818505). This variant has been identified in 2/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple variants affecting the same position, p.Cys238Trp, p.Cys238Phe, p.Cys238Arg and p.Cys238Ser, are considered to be disease-causing (ClinVar variation ID: 161515, 376574, 376576, 485039). Based on the available evidence, this variant is classified as Pathogenic. |
Genome- |
RCV000161034 | SCV002582368 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV002288693 | SCV002583029 | likely pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV003462109 | SCV004206249 | pathogenic | Adrenocortical carcinoma, hereditary | 2023-08-08 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV002288693 | SCV004931630 | pathogenic | Li-Fraumeni syndrome 1 | 2024-02-16 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 7478555, 21343334, 7791795]. 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: 28160093]. |
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 | Neoplasm of uterine cervix | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426546 | SCV000507688 | likely pathogenic | Breast neoplasm | 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 | Gastric adenocarcinoma | 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 | B-cell chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785261 | SCV000923829 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research | |
Institute of Medical Sciences, |
RCV001374444 | SCV001571407 | pathogenic | Gallbladder cancer | 2020-10-30 | no assertion criteria provided | research |