ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.845G>C (p.Arg282Pro) (rs730882008)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492764 SCV000581142 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-29 criteria provided, single submitter clinical testing The p.R282P variant (also known as c.845G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 845. The arginine at codon 282 is replaced by proline, an amino acid with dissimilar properties. This variant has been detected in a German individual diagnosed with bone cancer at age 29 and breast cancer at age 50 and whose family history consisted of skin cancer, leukemia, cerebral tumors, and Hodgkin lymphoma (Kraus C et al. Int. J. Cancer. 2017 Jan;140:95-102). This alteration has been reported in a female patient with choroid plexus carcinoma diagnosed at 17 and a breast sarcoma diagnosed at 24 (Zerdoumi Y et al. Hum. Mol. Genet., 2017 Mar). Further, Zerdoumi et al. conducted a functional assay in lymphocytes from this individual and showed a drastic reduction in p53 transcriptional activity similar to that observed in well characterized dominant-negative missense mutations. The p.R282P variant is located in the functionally critical DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast-based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression in vitro (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Two other alterations (p.R282W and p.R282G) have been described in the same codon in families meeting criteria for Li-Fraumeni syndrome (LFS) or suspected of having LFS (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Mendelics RCV000709402 SCV000839108 likely pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Invitae RCV000709402 SCV000953105 pathogenic Li-Fraumeni syndrome 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 282 of the TP53 protein (p.Arg282Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 27616075, 29070607), being de novo in one of them (PMID: 29070607). ClinVar contains an entry for this variant (Variation ID: 376659). An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). Variants that disrupt the p.Arg282 amino acid residue in TP53 have been observed in affected individuals (PMID: 19468865, 29070607, 25584008, 21305319, 21761402, 1565143, 11370630, 1565144). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000442220 SCV001140248 likely pathogenic Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000492764 SCV001349811 likely pathogenic Hereditary cancer-predisposing syndrome 2019-02-22 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000419006 SCV000509631 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427957 SCV000509632 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438637 SCV000509633 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417919 SCV000509634 likely pathogenic Non-Hodgkin lymphoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428608 SCV000509635 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441023 SCV000509636 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423789 SCV000509637 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434763 SCV000509638 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440221 SCV000509639 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423005 SCV000509640 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433722 SCV000509641 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442220 SCV000509642 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425389 SCV000509643 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432620 SCV000509644 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441861 SCV000509645 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426071 SCV000509646 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435036 SCV000509647 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417824 SCV000509648 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424978 SCV000509649 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only

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