Total submissions: 30
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000991149 | SCV001142561 | pathogenic | Li-Fraumeni syndrome | 2019-08-28 | reviewed by expert panel | curation | This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). It is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in 1 family meeting classic Li-Fraumeni syndrome and 1 proband meeting Chompret criteria (PS4_Supporting; PMID: 1359493, 25584008). In summary, TP53 c.743G>T; p.Arg248Leu meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PM2_Supporting, PP3_Moderate, PS3, PS4_Supporting. |
Ambry Genetics | RCV000219834 | SCV000273723 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-01-30 | criteria provided, single submitter | clinical testing | The p.R248L variant (also known as c.743G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 743. The arginine at codon 248 is replaced by leucine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and has been shown to be involved in DNA binding through crystal structures (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). Yeast based functional studies have demonstrated p.R248L to be devoid of transactivation activity and have a dominant negative phenotype (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Dearth LR et al. Carcinogenesis. 2007 Feb; 28(2):289-98; Jordan JJ et al. Mol. Cancer Res. 2010 May; 8(5):701-16). The p.R248L variant has been reported in a cohort of Chinese individuals at an high risk for breast cancer (Li JY et al. Int. J. Cancer. 2019 Jan;144:281-289). In addition, several other alterations at the same codon (p.R248Q, p.R248W, and p.R248G) have been classified as pathogenic mutations. 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 majority of available evidence to date, this variant is likely to be pathogenic. |
Invitae | RCV000991149 | SCV001392992 | likely pathogenic | Li-Fraumeni syndrome | 2023-06-16 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 9290701, 12826609, 20407015, 25584008). 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: 230253). This missense change has been observed in individual(s) with breast cancer (PMID: 29752822). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 248 of the TP53 protein (p.Arg248Leu). |
Color Diagnostics, |
RCV000219834 | SCV002052387 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-10-06 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with leucine at codon 248 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). Functional studies have shown that the mutant protein is non-functional in transactivation assay (PMID: 12826609, 25584008, 29786075) and in human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 1359493), adrenocortical carcinoma (PMID 25584008) and early-onset breast cancer (PMID: 29752822). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg248Gln and p.Arg248Trp, are known to be disease-causing (Clinvar variation ID: 12356 and 12347), indicating that arginine at this position is important for TP53 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. |
Baylor Genetics | RCV003475005 | SCV004204257 | likely pathogenic | Adrenocortical carcinoma, hereditary | 2023-03-08 | criteria provided, single submitter | clinical testing | |
Database of Curated Mutations |
RCV000439516 | SCV000509284 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422303 | SCV000509285 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433237 | SCV000509286 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445266 | SCV000509287 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423159 | SCV000509288 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433865 | SCV000509289 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443630 | SCV000509290 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427307 | SCV000509291 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437940 | SCV000509292 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443712 | SCV000509293 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424394 | SCV000509294 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435101 | SCV000509295 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417894 | SCV000509296 | likely pathogenic | Uterine carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428586 | SCV000509297 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435726 | SCV000509298 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418531 | SCV000509299 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429221 | SCV000509300 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439901 | SCV000509301 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422821 | SCV000509302 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430044 | SCV000509303 | likely pathogenic | B-cell chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440686 | SCV000509304 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423468 | SCV000509305 | likely pathogenic | Medulloblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434177 | SCV000509306 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445145 | SCV000509307 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424119 | SCV000509308 | likely pathogenic | Myelodysplastic syndrome | 2016-05-31 | no assertion criteria provided | literature only |