Total submissions: 19
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000128975 | SCV000172861 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-08-28 | criteria provided, single submitter | clinical testing | The p.C141Y pathogenic mutation (also known as c.422G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 422. The cysteine at codon 141 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported several times in families either meeting diagnostic criteria for Li-Fraumeni syndrome (LFS) or in families with features suggestive of LFS (Zhou XP et al. Ann Neurol. 1999 Dec;46(6):913-6; Monti P et al. Clin Cancer Res. 2007 Jul 1;13(13):3789-95; Bougeard G et al. J Med Genet. 2008 Aug;45(8):535-8; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8). This mutation is located in the DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity and reduced DNA-binding in yeast-based assays compared to wildtype p53 protein (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; Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Invitae | RCV000472876 | SCV000545264 | pathogenic | Li-Fraumeni syndrome | 2024-01-17 | 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 141 of the TP53 protein (p.Cys141Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with breast cancer, Li-Fraumeni syndrome (LFS)-related cancers (liposarcoma, astrocytoma, Hodgkin lymphoma), and in families with a strong history of LFS-related cancers (PMID: 10589545, 11370630, 20522432, 21232794; Invitae). ClinVar contains an entry for this variant (Variation ID: 140801). 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, 16861262, 20128691, 21343334, 24256616). For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV001582600 | SCV001812334 | pathogenic | not provided | 2020-09-18 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: loss of transactivation and cell growth suppression abilities (Kato 2003, Dearth 2007, Monti 2011, Malcikova 2010, Kotler 2018); Not observed in large population cohorts (Lek 2016); 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: 33138793, 31105275, 10589545, 31206626, 18511570, 26619011, 24256616, 21232794, 20522432, 11370630, 30840781, 30720243, 28975465, 28152038, 29979965, 17606709, 20128691, 16861262, 12826609, 21343334) |
Genome- |
RCV000128975 | SCV002582604 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV002288619 | SCV002583165 | pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV002288619 | SCV004930458 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-13 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8816796, 9418900]. 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: 11370630, 20522432]. |
Database of Curated Mutations |
RCV000427674 | SCV000507522 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437920 | SCV000507523 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444430 | SCV000507524 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427068 | SCV000507525 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435449 | SCV000507526 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417795 | SCV000507527 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428004 | SCV000507528 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436530 | SCV000507529 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418811 | SCV000507530 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429076 | SCV000507531 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439333 | SCV000507532 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423419 | SCV000507533 | likely pathogenic | Papillary renal cell carcinoma type 1 | 2016-05-31 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785510 | SCV000924082 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |