ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1009C>T (p.Arg337Cys) (rs587782529)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131726 SCV000186766 pathogenic Hereditary cancer-predisposing syndrome 2018-11-29 criteria provided, single submitter clinical testing ​The p.R337C mutation (also known as c.1009C>T) is located in coding exon 9 of the TP53 gene. This alteration results from a C to T substitution at nucleotide position 1009. The arginine at codon 337 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration is in the tetramerization domain of the TP53 protein, is reported to have loss of transactivation capacity, and has been reported as a somatic mutation in 20 tumors and as a germline mutation in numerous Li-Fraumeni syndrome (LFS) patients (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). A broad spectrum of tumors were reported within these families including of the breast, bone, pancreas, and other soft tissues. This mutation has also been reported in two children with adrenocortical carcinomas (Bougeard G et al. J Clin Oncol. 2015 Jul 20;33(21):2345-52) and in a Chinese breast cancer cohort (Li JY et al. Int. J. Cancer. 2018 May). A functional study has reported this mutation to result in partial activity affecting the oligomerization domain of TP53 (Lomax et al. Oncogene (1997) 14, 1869 - 1874). Another study concurred that this mutation retains partial TP53 activity, yet leads to a predisposition to cancer. At physiological temperatures, a majority of the mutant protein appears to be in a presumably inactive state (Davison et al. Oncogene (1998) 17, 651 - 656). A more recent study classified p.R337C as a severe deficiency allele based on a residual transactivation activity of less than 25% compared with wild-type (Monti et al. Mol Cancer Res. 2011 March ; 9(3): 271–279). Of note, the similar p.R337H mutation in the TP53 gene has been reported to predispose to mainly adrenocortical carcinomas in pediatric patients, and also to a wide spectrum of other LFS tumors (Achatz et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102). Based on the available evidence, p.R337C is classified as a pathogenic mutation.
Invitae RCV000475086 SCV000545330 pathogenic Li-Fraumeni syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 337 of the TP53 protein (p.Arg337Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587782529, ExAC 0.01%). This sequence change has been reported in many individuals and families with Li-Fraumeni like syndrome with some evidence of segregation with disease (PMID: 17606709, 9150393, 20478780, 9452042, 18511570). ClinVar contains an entry for this variant (Variation ID: 142536). Experimental studies using model organisms and mammalian cells have shown that this sequence change partially disrupts TP53 protein function (PMID: 12826609, 9150393, 20128691, 21343334, 9704931, 9704930). A different missense substitution at this codon (p.Arg337His) has been determined to be pathogenic (PMID: 20407015, 12826609, 9704930, 16033918, 10864200). This suggests that the arginine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000131726 SCV001354213 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-19 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 337 in the tetramerization domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a partial loss of transactivation function of TP53 protein in yeast (PMID: 9150393, 12826609, 14559903, 20407015, 21343334) and mammalian cells (PMID: 9766574, 10653977, 19454241, 20128691, 20505364). This variant has been reported in individuals diagnosed with classic or Chompret Li-Fraumeni syndrome (PMID 9150393, 9452042, 18511570, 20478780) and in an individual with early-onset breast cancer (PMID: 29752822) This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg337His, have been reported as disease-causing (ClinVar variation ID: 12379), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310211 SCV001499817 likely pathogenic Li-Fraumeni syndrome 1 2020-04-02 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785479 SCV000924051 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.