ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.998G>A (p.Arg333His) (rs573154688)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000662455 SCV001737937 likely benign Li-Fraumeni syndrome 1 2021-05-06 reviewed by expert panel curation This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Transactivation assays show functional transactivation according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. and normal tetramer formation according to Kawaguchi, et al. (BS3; PMID: 12826609, 30224644,16007150). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Invitae). In summary, TP53 c.998G>A (p.Arg333His) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, BS2_Supporting.
Ambry Genetics RCV000131296 SCV000186268 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-25 criteria provided, single submitter clinical testing The p.R333H variant (also known as c.998G>A), located in coding exon 9 of the TP53 gene, results from a G to A substitution at nucleotide position 998. The arginine at codon 333 is replaced by histidine, an amino acid with highly similar properties. This alteration is located in the tetramerization domain of the p53 protein, and was found to retain transactivation capacity and the ability to form tetramers in yeast based functional studies (Kato S et al. Proc. Natl. Acad. Sci. U.S.A. 2003 Jul;100:8424-9; Kawaguchi T et al. Oncogene. 2005 Oct;24:6976-81). Additional studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been reported with a carrier frequency of 0 in 7051 unselected breast cancer patients and 2 in 11241 female controls of Japanese ancestry (Momozowa Y et al. Nat Commun. 2018 10;9:4083). Based on internal structural analysis, this alteration is anticipated to result in a decrease in structural stability (Clore GM et al. Science, 1994 Jul;265:386-91). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000213064 SCV000211764 uncertain significance not provided 2017-06-21 criteria provided, single submitter clinical testing This variant is denoted TP53 c.998G>A at the cDNA level, p.Arg333His (R333H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant is associated with partial transcriptional activity and retention of the ability to form tetramers (Leroy 2014). However, it 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 Arg333His was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. TP53 Arg333His occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the tetramerization domain (Bode 2004) In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether TP53 Arg333His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227465 SCV000285219 uncertain significance Li-Fraumeni syndrome 2020-10-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 333 of the TP53 protein (p.Arg333His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs573154688, ExAC 0.006%). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 142273). An experimental study using a yeast-based functional assay has shown that this missense change does not affect the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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.
Color Health, Inc RCV000131296 SCV000686790 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-28 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 333 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that the mutant protein is functional in a transactivation assay (PMID 12826609) and in a cell growth suppression assay (PMID: 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 12/281972 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl RCV000662455 SCV000784933 uncertain significance Li-Fraumeni syndrome 1 2017-02-07 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000227465 SCV001429659 uncertain significance Li-Fraumeni syndrome 2019-02-13 criteria provided, single submitter clinical testing Data included in classification: Kato et al 2003: functional on yeast based assay (PMID: 12826609). Giacomelli et al, 2018 IARC No DNE and no LOF (PMID: 30224644). (BS3_strong). Data not included in classification: UK family 1: 40yo female with brain tumour at 32 & breast cancer (ER+, HER2-) at 39, variant found in unaffected mother (aged 62) mat grandmother breast cancer at 55 (deceased). The variant was observed in 6/64,339 GNOMAD NFE controls and 6/76,647 individuals in the remainder of the GNOMAD population. 5 recent classifications of variant as VUS on ClinVar. R333C recorded in an adult onset sarcoma - Mitchell (2013) PloS One 8:e69026. Mutations in tetramerisation domain cause defects in tetramer formation leading to loss of function. Fortuno et al, 2018 Bayesdel -0.092, suggested prediction: benign (PMID: 29775997). In silico tools conflicting.

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.