ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.817C>A (p.Arg273Ser) (rs121913343)

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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561782 SCV000664439 pathogenic Hereditary cancer-predisposing syndrome 2017-04-05 criteria provided, single submitter clinical testing The p.R273S pathogenic mutation (also known as c.817C>A), located in coding exon 7 of the TP53 gene, results from a C to A substitution at nucleotide position 817. The arginine at codon 273 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. This alteration occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain, and has repededly shown loss of transactivation capacity in yeast-based functional studies (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Mitsumoto Y et al. Hum. Pathol., 2004 Mar;35:350-6; Monti P et al. Oncogene, 2003 Aug;22:5252-60; Monti P et al. Mol. Cancer Res., 2011 Mar;9:271-9). This pathogenic mutation has been reported as a germline mutation in 1 of 235 unselected pediatric patients with osteosarcoma (McIntyre JF et al. J. Clin. Oncol., 1994 May;12:925-30). This alteration has been described as “oncomorphic”, or gain-of-function, secondary to functional analysis indicating a loss of interaction with the microprocessing Drosha complex (Brachova P et al. J Cancer Ther, 2014 Jun;5:506-516). Further, crystal structure analysis indicates this position is involved in DNA contact and binding (Martin A et al., Hum. Mutat. 2002 Feb; 19(2):149-64). Based on the available evidence, p.R273S is classified as a pathogenic mutation.
Invitae RCV000698744 SCV000827427 likely pathogenic Li-Fraumeni syndrome 2019-12-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 273 of the TP53 protein (p.Arg273Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs121913343, ExAC 0.006%). This variant has been observed in an individual affected with osteosarcoma and in two families with Li-Fraumeni syndrome (PMID: 8164043, 18685109, 25584008). ClinVar contains an entry for this variant (Variation ID: 376656). Experimental studies have shown that this missense change significantly impairs the transcriptional transactivation activity of the TP53 protein and was shown to interfere with wild-type TP53 protein function in a dominant-negative manner (PMID: 12826609, 12917626, 15017592, 21343334). The p.Arg273 amino acid residue in TP53 has been determined to be clinically significant (PMID: 2826609, 8479749, 21535297, 21552135, 17606709, 17540308, 9242456, 21484931, 1565144). This suggests that variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Database of Curated Mutations (DoCM) RCV000436543 SCV000509458 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444595 SCV000509459 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425669 SCV000509460 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435480 SCV000509461 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418085 SCV000509462 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427884 SCV000509463 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435074 SCV000509464 likely pathogenic Adrenocortical carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420482 SCV000509465 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431180 SCV000509466 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440997 SCV000509467 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420280 SCV000509468 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430119 SCV000509469 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440794 SCV000509470 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422795 SCV000509471 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433489 SCV000509472 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439774 SCV000509473 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422550 SCV000509474 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432372 SCV000509475 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445287 SCV000509476 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424918 SCV000509477 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431455 SCV000509478 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445314 SCV000509479 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427515 SCV000509480 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438218 SCV000509481 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only

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