ClinVar Miner

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

dbSNP: rs730882008
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Total submissions: 27
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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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000709402 SCV000953105 pathogenic Li-Fraumeni syndrome 2022-12-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg282 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565143, 1565144, 11370630, 19468865, 21305319, 21761402, 22672556, 25584008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 376659). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 27616075, 29070607). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 282 of the TP53 protein (p.Arg282Pro).
Mendelics RCV000442220 SCV001140248 likely pathogenic Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000492764 SCV001349811 likely pathogenic Hereditary cancer-predisposing syndrome 2023-06-13 criteria provided, single submitter clinical testing This missense variant replaces arginine with proline at codon 282 in the DNA binding domain of the TP53 protein. Computational prediction tool 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 impairs TP53 protein function. The mutant protein has been shown to be non-functional in yeast transactivation assays (PMID: 12826609), human cell growth suppression assays (PMID: 30224644) and human cell proliferation assay (PMID: 29979965). This variant has been reported in an individual affected with bone cancer at age 29, breast cancer at age 50, with family history of skin cancer, leukemia, cerebral tumor and Hodgkin lymphoma (PMID: 27616075); a female individual who was affected with breast and ovarian cancer in her twenties, with family history of early-onset breast cancer in the first and second degree relatives (Color Health internal data); as well as in a cohort with Li-Fraumeni syndrome and non-small-cell lung carcinoma (DOI:https://doi.org/10.1016/j.annonc.2022.07.1809). This variant has also been detected de novo in the germline of a female individual who was affected with choroid plexus carcinoma at age 17 and breast sarcoma at age 24 (PMID: 28369373, 29070607). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Genome-Nilou Lab RCV000492764 SCV002582344 likely pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002289536 SCV002583006 likely pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002502456 SCV002807846 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 2021-12-10 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV002289536 SCV004933284 likely pathogenic Li-Fraumeni syndrome 1 2024-02-21 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28472496, 27616075, 29070607].
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 Papillary renal cell carcinoma type 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 Prostate adenocarcinoma 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 Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only

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