ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.742C>G (p.Arg248Gly) (rs121912651)

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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences 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 (DoCM) RCV000425782 SCV000509334 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436038 SCV000509335 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418362 SCV000509336 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425100 SCV000509337 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435353 SCV000509338 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417693 SCV000509339 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) 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 (DoCM) RCV000441711 SCV000509341 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420498 SCV000509342 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430735 SCV000509343 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441010 SCV000509344 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423297 SCV000509345 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433611 SCV000509346 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440334 SCV000509347 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422668 SCV000509348 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432931 SCV000509349 likely pathogenic Myelodysplastic syndrome 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444519 SCV000509350 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425394 SCV000509351 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432207 SCV000509352 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444427 SCV000509353 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424776 SCV000509354 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435050 SCV000509355 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444356 SCV000509356 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427544 SCV000509357 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437882 SCV000509358 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only

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