Total submissions: 20
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000216410 | SCV000274927 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-05-28 | criteria provided, single submitter | clinical testing | The p.R196P pathogenic mutation (also known as c.587G>C), located in coding exon 5 of the TP53 gene, results from a G to C substitution at nucleotide position 587. The arginine at codon 196 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported as a germline mutation in two individuals with Li-Fraumeni syndrome, including a male with a brain tumor at age 1 and osteosarcoma at age 16 (Rines RD et al. Carcinogenesis 1998 Jun;19(6):979-84; Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). This alteration was also reported in a proband with breast cancer at age 28 whose mother had breast cancer at age 29 (Bonache S et al. J. Cancer Res. Clin. Oncol. 2018 Dec;144(12):2495-2513). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and a dominant negative effect in yeast based assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P, Mol. Cancer Res. 2011 Mar; 9(3):271-9). 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Sema4, |
RCV000216410 | SCV002530470 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-12-08 | criteria provided, single submitter | curation | |
Invitae | RCV003114386 | SCV003784963 | pathogenic | Li-Fraumeni syndrome | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 196 of the TP53 protein (p.Arg196Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni Syndrome (PMID: 10922393, 16401470, 30306255; Invitae). ClinVar contains an entry for this variant (Variation ID: 231165). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. |
Color Diagnostics, |
RCV000216410 | SCV004359998 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-05-02 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with proline at codon 196 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant disrupted function and exhibited dominant-negative effect in yeast transactivation assays (PMID: 12826609, 21343334) and human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in families affected with classic Li-Fraumeni syndrome (PMID: 9667734, 10922393, 16401470; ClinVar Accession: SCV003784963.1) as well as in individuals affected with early-onset breast cancer (PMID: 30306255; DOI: 10.1158/1538-7445.SABCS21-P3-07-07; Color Health internal data). 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. |
Database of Curated Mutations |
RCV000433800 | SCV000509180 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440531 | SCV000509181 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423798 | SCV000509182 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434064 | SCV000509183 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443813 | SCV000509184 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427483 | SCV000509185 | likely pathogenic | Papillary renal cell carcinoma type 1 | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431695 | SCV000509186 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443927 | SCV000509187 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425092 | SCV000509188 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435372 | SCV000509189 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418400 | SCV000509190 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426017 | SCV000509191 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436292 | SCV000509192 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419494 | SCV000509193 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429772 | SCV000509194 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440866 | SCV000509195 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only |