Total submissions: 28
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genomic Research Center, |
RCV000626118 | SCV000746745 | likely pathogenic | Carcinoma of colon | 2017-12-18 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000633396 | SCV000754618 | likely pathogenic | Li-Fraumeni syndrome | 2019-11-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glycine at codon 248 of the TP53 protein (p.Arg248Gly). 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 not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 376652). Experimental studies in yeast and cancer cell lines have shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 9290701, 22919068, 11920959). Two different missense substitutions at this codon (p.Arg248Gln and p.Arg248Trp) have been determined to be pathogenic (PMID: 17606709, 21601526, 1978757, 21343334). This suggests that the arginine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. 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. |
Ambry Genetics | RCV001026425 | SCV001188805 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-04-08 | criteria provided, single submitter | clinical testing | The p.R248G variant (also known as c.742C>G), located in coding exon 6 of the TP53 gene, results from a C to G substitution at nucleotide position 742. The arginine at codon 248 is replaced by glycine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and was shown 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). This specific alteration has not been reported as a germline finding in the literature, although several other alterations at this same codon (p.R248Q, p.R248W and p.R248L) have been reported in Li-Fraumeni Syndrome, or LFS related cancers (Petitjean A et al. IARC TP53 database [version R15, November 2010]. Hum Mutat. 2007 Jun;28(6):622-9; Rausch T et al., Cell 2012 Jan; 148(1-2):59-71; Toguchida J et al., N. Engl. J. Med. 1992 May; 326(20):1301-8; Rieber J et al., Genes Chromosomes Cancer 2009 Jul; 48(7):558-68). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Database of Curated Mutations |
RCV000425782 | SCV000509334 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436038 | SCV000509335 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418362 | SCV000509336 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425100 | SCV000509337 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435353 | SCV000509338 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417693 | SCV000509339 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427948 | SCV000509340 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441711 | SCV000509341 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420498 | SCV000509342 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430735 | SCV000509343 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441010 | SCV000509344 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423297 | SCV000509345 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433611 | SCV000509346 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440334 | SCV000509347 | likely pathogenic | Medulloblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422668 | SCV000509348 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432931 | SCV000509349 | likely pathogenic | Myelodysplastic syndrome | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444519 | SCV000509350 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425394 | SCV000509351 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432207 | SCV000509352 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444427 | SCV000509353 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424776 | SCV000509354 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435050 | SCV000509355 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444356 | SCV000509356 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427544 | SCV000509357 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437882 | SCV000509358 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only |