ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.472C>T (p.Arg158Cys) (rs587780068)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000508084 SCV000149632 uncertain significance not provided 2015-06-08 criteria provided, single submitter clinical testing This variant is denoted TP53 c.472C>T at the cDNA level, p.Arg158Cys (R158C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was observed in the germline of a male patient with a history of adrenocortical carcinoma and teratocarcinoma of the testis where loss of heterozygosity of the wild-type allele and negative staining of the p53 protein via immunohistochemistry were observed in the adrenal tumor tissue (Herrmann 2011). In vitro yeast-based assays have demonstrated this variant to be temperature sensitive and to inhibit transactivation (Shiraishi 2004, Monti 2003). TP53 Arg158Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Arg158Cys occurs at a position that is not conserved, with Cysteine being the naturally occurring amino acid at this position in one mammal, and is located in the DNA binding domain and region of interaction with HIPK1, ZNF385A, FBXO42 and AXIN1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether TP53 Arg158Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115723 SCV000185723 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-10 criteria provided, single submitter clinical testing ​The p.R158C variant (also known as c.472C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 472. The arginine at codon 158 is replaced by cysteine, an amino acid with highly dissimilar properties. The R158 codon is located in the core DNA-binding domain of the TP53 protein. Functional studies with this variant in yeast have shown temperature sensitivity, and a significantly reduced transactivation capacity compared to wild type (Shiraiski K et al. J. Biol. Chem. 2004 Jan;279(1):348-55; Monti P et al. Oncogene. 2003 Aug;22(34):5252-60; IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9). This variant was reported in a patient with adrenocortical cancer and a family history of various cancers; the patient's tumor showed LOH of the wild-type TP53 allele, as well as negative p53 staining on immunohistochemistry (Herrmann LJ et al. J. Clin. Endocrinol. Metab. 2012 Mar;97(3):E476-85). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science 1994 Jul; 265(5170):346-55). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508084 SCV000602273 likely pathogenic not provided 2016-09-28 criteria provided, single submitter clinical testing
Invitae RCV000533951 SCV000629824 uncertain significance Li-Fraumeni syndrome 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 158 of the TP53 protein (p.Arg158Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587780068, ExAC 0.003%). This variant has been observed in an individual affected with adrenocortical carcinoma and testicular cancer (PMID: 22170717), and an individual affected with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 127812). Experimental studies have shown that this variant does not substantially affect TP53 protein function (PMID: 12826609, 29979965, 12826609, 12917626, 14559903). Different missense substitutions at this codon (p.Arg158His and p.Arg158Leu) have been determined to be pathogenic (PMID: 10486318, 23894400, 20455025, 20522432, 25584008, 21343334, 10229196, 16861262, 12725534). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000115723 SCV000908793 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-28 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 158 in the DNA binding domain 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 partially functional in yeast transactivation assays (IARC database and PMID: 12826609) and functional in human cell proliferation assay (PMID: 29979965). The variant impact on function was inconclusive in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with adrenocortical carcinoma with a family history of leukemia, lung cancer and adrenocortical carcinoma (PMID: 22170717) and in an individual affected with breast cancer with a family history of fibrosarcoma, breast cancer and lung cancer (PMID: 29958926). This variant has also been observed in individuals affected with pancreatic cancer and colorectal cancer (PMID: 23200980, 29844874). This variant has been identified in 2/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same position, p.Arg158His, is known to be pathogenic (Clinvar variation ID: 141963). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000533951 SCV001429673 uncertain significance Li-Fraumeni syndrome 2019-10-11 criteria provided, single submitter clinical testing Data included in classification: UK family 1: Proband ACC at 11. Unaffected mother carries variant, maternal great uncle possible brain tumour and another maternal great-uncle in died in 20s (meets Chompret criteria). Literature/IARC case 1: ACC at 39 and testicular ca at 20. Herrmann et al, 2012 (PMID: 22170717, IARC ref 261) (meets Chompret criteria) (PS4_sup). The variants p.Arg158His and p.Arg158Leu at the same codon are considered likely pathogenic/pathogenic (PM5_mod). Variant is class 65 on AlignGVGD and Bayes del score 0.51 (PP3_mod). Data not included in classification: Variant observed in 2/125,638 gnomAD controls. Multiple reports of variant on IARC database with limited clinical information. Literature/IARC family 2: Proband breast cancer age 49 (Er+ve, PR +ve, Her2 -ve), fibrosarcoma at 59 in FDR, breast cancer at 50 in SDR, Lung cancer at 70 in SDR, cancer of unknown primary at 47 in SDR (Meiss et al. 2018, PMID: 29958926, IARC Ref 422). Kato et al. 2003 (PMID 12826609): Transactivation class partially functional, Giacomelli et al. 2018 (PMID 30224644) Combined model score: 123.6556. IARC classification: unclassified.
Institute of Medical Sciences, Banaras Hindu University RCV001255633 SCV001432169 pathogenic Lip and oral cavity carcinoma 2019-04-30 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000508084 SCV001551841 uncertain significance not provided no assertion criteria provided clinical testing The TP53 p.Arg158Cys variant was identified in 1 of 206 proband chromosomes (frequency: 0.005) from an individual with adrenocortical cancer and testicular cancer (Herrmann 2011). The variant was also identified in the following databases: dbSNP (ID: rs587780068) as "With Likely pathogenic allele ", ClinVar (2x uncertain significance, 2x likely pathogenic), Clinvitae (3x uncertain significance), Cosmic (23x, confirmed somatic, in cancer of the large intestine, urinary tract, lung, endometrium, haematopoietic, and lymphoid system), IARC TP53 Database (21x somatic, partially functional transcriptional activity), and the UMD TP52 Mutation Database. The variant was not identified in GeneInsight-COGR, LOVD 3.0, or the Database of Germline p53 Mutations. The variant was identified in control databases in 2 of 246112 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European in 2 of 111580 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro yeast based functional assays have demonstrated this variant inhibits transactivation and is temperature sensitive (Monti 2003, Shiraishi 2004). Different missense substitutions at this codon have been determined to be pathogenic (Ruijis 2009, Wasserman 2015). The p.Arg158 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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