ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.818G>T (p.Arg273Leu)

dbSNP: rs28934576
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Total submissions: 32
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568814 SCV000665156 pathogenic Hereditary cancer-predisposing syndrome 2023-01-12 criteria provided, single submitter clinical testing The p.R273L pathogenic mutation (also known as c.818G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 818. The arginine at codon 273 is replaced by leucine, an amino acid with dissimilar properties. This mutation occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain. Several other mutations have been described at this position and are associated with a classic LFS-associated tumor spectrum (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum Mutat. 2007 Jun;28(6):622-9). This specific alteration has been reported in a family meeting Chompret criteria for Li-Fraumeni Syndrome, and has been identified as a de novo mutation in a patient diagnosed with adrenaocortical carcinoma and rhabdomyosarcoma at 1 year of age (Bougeard Get al. J. Clin. Oncol. 2015 Jul; 33(21):2345-52; Chompret A et al. Br. J. Cancer 2000 Jun; 82(12):1932-7). Functional assays conducted in both yeast and human cells have shown a loss of transactivation capacity and a dominant negative phenotype (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; Dearth Let al. Carcinogenesis 2007 Feb; 28(2):289-98). 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). Based on crystal structure analysis, this position has been shown to be involved in DNA contact and binding (Martin A et al. Hum. Mutat. 2002 Feb; 19(2):149-64). 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). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, p.R273L is classified as a pathogenic mutation.
Invitae RCV000822080 SCV000962866 pathogenic Li-Fraumeni syndrome 2023-09-10 criteria provided, single submitter clinical testing This variant disrupts the p.273 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565144, 9242456, 17540308, 20693561, 21484931, 21552135). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 273 of the TP53 protein (p.Arg273Leu). This variant is present in population databases (rs28934576, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni-associated cancers (PMID: 10864200, 26014290). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376655). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 9407971, 12826609, 21343334, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001539823 SCV001757640 pathogenic not provided 2022-12-23 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of apoptotic activity, and exhibits a dominant-negative effect (Monti et al., 2007; Monti et al., 2011; Giacomelli et al., 2018; Kotler et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 10519380, 16322298, 9738975, 12792784, 16000567, 8336941, 10753186, 9546439, 8062826, 11429705, 30840781, 15510160, 29922827, 9407971, 17606709, 21343334, 30720243, 29752319, 10864200, 29092957, 17311302, 32658383, 16861262, 21484931, 21552135, 8649776, 17540308, 15161705, 27813088, 15037740, 11793474, 9242456, 30224644, 26619011, 20693561, 12826609, 1565144, 29979965, 26014290)
Genome-Nilou Lab RCV000568814 SCV002582451 pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002289534 SCV002583113 pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002502455 SCV002784210 pathogenic Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5 2022-05-24 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000423981 SCV000509434 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434695 SCV000509435 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444989 SCV000509436 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427314 SCV000509437 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437048 SCV000509438 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444109 SCV000509439 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426132 SCV000509440 likely pathogenic Adrenal cortex carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436818 SCV000509441 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418738 SCV000509442 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429444 SCV000509443 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435767 SCV000509444 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418536 SCV000509445 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428692 SCV000509446 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438507 SCV000509447 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421259 SCV000509448 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431067 SCV000509449 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441792 SCV000509450 likely pathogenic Uterine carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423633 SCV000509451 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434296 SCV000509452 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442241 SCV000509453 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423490 SCV000509454 likely pathogenic B-cell chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433315 SCV000509455 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444782 SCV000509456 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425890 SCV000509457 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Genome Sciences Centre, British Columbia Cancer Agency RCV000515526 SCV000611151 likely pathogenic Metastatic pancreatic neuroendocrine tumours 2017-11-01 no assertion criteria provided research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785524 SCV000924096 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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