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

dbSNP: rs730882008

Total submissions: 27

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