ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.847C>T (p.Arg283Cys) (rs149633775)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000200641 SCV001142525 uncertain significance Li-Fraumeni syndrome 2019-09-16 reviewed by expert panel curation This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). However, transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.847C>T; p.Arg283Cys is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PP3 and BS3.
GeneDx RCV000585912 SCV000149648 uncertain significance not provided 2018-07-05 criteria provided, single submitter clinical testing This variant is denoted TP53 c.847C>T at the cDNA level, p.Arg283Cys (R283C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been reported in individuals with various cancers, none of whom met Li-Fraumeni syndrome criteria, as well as at least two healthy controls (Keller 2004, Pekova 2011, Schulz 2012, Melhem-Bertrandt 2012, Mitchell 2013, Bodian 2014, Yurgelun 2015, Goidescu 2018, Qian 2018). TP53 Arg283Cys was also observed in a woman with a personal history of breast cancer and leiomyosarcoma who met Chompret criteria; however, she was also found to harbor a truncating BRCA2 variant (Manoukian 2007). Functional studies have identified both normal and reduced transcriptional activity for a variety of reporters, with no evidence for a dominant-negative effect (Pekova 2011, Monti 2011, Jagosova 2012). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg283Cys was observed at an allele frequency of 0.02% (20/126,682) in individuals of European ancestry 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, it is unclear whether TP53 Arg283Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115739 SCV000183772 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000200641 SCV000254640 uncertain significance Li-Fraumeni syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 283 of the TP53 protein (p.Arg283Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs149633775, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with breast cancer, colorectal cancer, diffuse gastric cancer, lymphocytic leukemia, and adult-onset sarcoma (PMID: 15173255, 17224268, 21761402, 23894400, 25527155, 26086041). This variant was also observed in healthy individuals (PMID: 21232794, 24728327). ClinVar contains an entry for this variant (Variation ID: 127824). In vitro experimental studies report conflicting results with regard to the effect of this variant on TP53 protein transcriptional transactivation activity (PMID: 12826609, 21343334, 22710932). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000122178 SCV000272533 uncertain significance not specified 2015-09-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg283Cys variant in TP53 has been reported in 5 individuals with Li-Fraumeni syndrome-as sociated cancers, and as a somatic variant in at least 7 tumors (myeloid neoplas ms, gastric cancer, breast cancer, bladder carcinoma, and adrenocortical tumors; Faille 1994, Rugge 2000, Prescott 2001, Keller 2004, Libe 2007, Ryu 2007, Melhe m-Bertandt 2012, Schulz 2012, Boyault 2012, Mitchell 2013, Yurgelun 2015). It ha s also been identified in 3/10364 African and 11/66452 European chromosomes by t he Exome Aggregation Consortium (ExAC,; dbSNP rs1 49633775). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein, though in vitro funct ional studies provide some evidence that the p.Arg283Cys variant may impact prot ein function (Monti 2011). In summary, while there is some suspicion for a patho genic role, the clinical significance of the p.Arg283Cys variant is uncertain.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000238755 SCV000297015 uncertain significance Li-Fraumeni syndrome 1 2015-08-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000122178 SCV000597522 uncertain significance not specified 2017-04-17 criteria provided, single submitter clinical testing
Color RCV000115739 SCV000686778 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000585912 SCV000697452 uncertain significance not provided 2016-11-18 criteria provided, single submitter clinical testing Variant summary: The TP53 c.847C>T (p.Arg283Cys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (MutationTaster was not captured due to low p-value). 2/5 splice prediction tools and at least one literature (Kouidou_2009) predict that this variant may create a novel 5' splicing donor site. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant has been reported in patients with CLL, Early-Onset Colorectal Cancer, breast cancer, gastric carcinoma, brain tumor as germline or somatic variant. One patient with metachronous breast cancers and a subsequent leiomyosarcoma carries this variant and a pathogenic BRCA2 variant (p.Arg2394X). This variant was found in 14/120734 control chromosomes at a frequency of 0.000116, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000469). However, some occurrences in control population may be somatic occurrences in cancer patients, thus the possibility that this variant is pathogenic can not be ruled out based on the allele frequency in controls. Two functional studies in yeast provide conflicting results (no defect/Pekova_2011 and partially defect/Monti_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
GeneKor MSA RCV000115739 SCV000822209 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000200641 SCV000886456 likely benign Li-Fraumeni syndrome 2018-03-28 criteria provided, single submitter research The TP53 variant designated as NM_000546.5:c.847C>T (p.Arg283Cys) is classified as likely benign in the context of Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of less than 0.005 to 1 (Thompson et al., 2013, PMID:12900794) in the context of Li-Fraumeni syndrome. This indicates that the TP53 variant is very unlikely to increase the risks of cancer to the extent reported in Li-Fraumeni syndrome. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign in the context of Li-Fraumeni syndrome. Additionally, the familial germline TP53 variant was detected in a family member's breast tumor tissue without evidence of loss of heterozygosity. It was unclear whether there was a second hit. The absence of loss of heterozygosity in the tumor may provide some evidence that the TP53 variant is more likely to be benign. We cannot rule out the possibility that this variant does cause some increased risk for breast cancer. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585912 SCV000889883 uncertain significance not provided 2018-01-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585912 SCV000892470 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765397 SCV000896672 uncertain significance Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
ITMI RCV000122178 SCV000086393 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148912 SCV000190658 likely pathogenic Neoplasm of stomach 2014-06-01 no assertion criteria provided research

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