ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.523C>G (p.Arg175Gly) (rs138729528)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459914 SCV000545325 pathogenic Li-Fraumeni syndrome 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 175 of the TP53 protein (p.Arg175Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families with Li-Fraumeni syndrome and hereditary breast and/or ovarian cancer (PMID: 11370630, 17606709, 25927356). ClinVar contains an entry for this variant (Variation ID: 376649). This variant is located in a known mutation hotspot within the central DNA binding domain of TP53 (PMID: 23263379, 20516128, 24573247, 12007217). Experimental studies using yeast as well as mammalian cells have shown that this missense change severely disrupts TP53 protein function (PMID: 12826609, 21343334, 8062826, 9546439). A different missense substitution at this codon (p.Arg175His) has been determined to be pathogenic (PMID: 8825920, 8164043, 21761402, 22006311, 16401470, 23792586, 23263379, 15607980, 15607981). This suggests that the arginine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000573315 SCV000664381 pathogenic Hereditary cancer-predisposing syndrome 2019-08-21 criteria provided, single submitter clinical testing The p.R175G pathogenic mutation (also known as c.523C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 523. The arginine at codon 175 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in a French family meeting Li-Fraumeni syndrome criteria, where the proband had osteosarcoma at 18, and two primary breast cancers at 27 and 29 (Bougeard G et al. J. Med. Genet., 2001 Apr;38:253-7). Multiple functional studies in both yeast and mammalian cells have shown a loss of transactivation activity for this variant (Monti P et al. Mol. Cancer Res., 2011 Mar;9:271-9; Ory K et al. EMBO J., 1994 Aug;13:3496-504; Flaman JM et al. Oncogene, 1998 Mar;16:1369-72; IARC TP53 database: Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Zerdoumi Y et al. Hum. Mol. Genet., 2017 07;26:2591-2602). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition, another alteration at this same amino acid position (p.R175H) is a well characterized TP53 hotspot mutation (Soussi T et al. Cell Death Differ., 2015 Aug;22:1239-49). This amino acid position is highly conserved in available vertebrate species, and is predicted to be deleterious by in silico analysis. As such, this alteration is interpreted as a disease-causing mutation.
Database of Curated Mutations (DoCM) RCV000424235 SCV000509136 likely pathogenic Nasopharyngeal Neoplasms 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430584 SCV000509137 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441260 SCV000509138 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421436 SCV000509139 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432105 SCV000509140 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444111 SCV000509141 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421238 SCV000509142 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432831 SCV000509143 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444080 SCV000509144 likely pathogenic Carcinoma of gallbladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425355 SCV000509145 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436078 SCV000509146 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443278 SCV000509147 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426938 SCV000509148 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436759 SCV000509149 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419625 SCV000509150 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430740 SCV000509151 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437498 SCV000509152 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420706 SCV000509153 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430935 SCV000509154 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438570 SCV000509155 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420923 SCV000509156 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428548 SCV000509157 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785486 SCV000924058 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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