Total submissions: 25
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 |
RCV000424235 | SCV000509136 | likely pathogenic | Nasopharyngeal Neoplasms | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430584 | SCV000509137 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441260 | SCV000509138 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421436 | SCV000509139 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432105 | SCV000509140 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444111 | SCV000509141 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421238 | SCV000509142 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432831 | SCV000509143 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444080 | SCV000509144 | likely pathogenic | Carcinoma of gallbladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425355 | SCV000509145 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000443278 | SCV000509147 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426938 | SCV000509148 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436759 | SCV000509149 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419625 | SCV000509150 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430740 | SCV000509151 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437498 | SCV000509152 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420706 | SCV000509153 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430935 | SCV000509154 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438570 | SCV000509155 | likely pathogenic | Medulloblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420923 | SCV000509156 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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, |
RCV000785486 | SCV000924058 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |