ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.847C>T (p.Arg283Cys) (rs149633775)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000200641 SCV001142525 uncertain significance Li-Fraumeni syndrome 2019-09-16 reviewed by expert panel curation This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). However, transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.847C>T; p.Arg283Cys is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PP3 and BS3.
GeneDx RCV000585912 SCV000149648 likely benign not provided 2020-10-27 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22652532, 19367569, 17289876, 25527155, 21343334, no PMID, 15173255, 30224644, 29979965, 31016814, 23018556, 22710932, 17224268, 25980754, 23894400, 24728327, 21288114, 21512767, 25637381, 19558493, 21232794, 16487937, 19714488, 11040944, 26086041, 24868540, 12826609, 11793474, 8198984, 9865903, 11391594, 17727479, 28125078, 28861920, 15580553, 8203469, 29785153, 29300620, 21761402, 30840781, 31159747, 30374176, 29945567, 31786208, 31749828, 33300245, 32658383)
Ambry Genetics RCV000115739 SCV000183772 likely benign Hereditary cancer-predisposing syndrome 2020-09-03 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Other strong data supporting benign classification
Invitae RCV000200641 SCV000254640 likely benign Li-Fraumeni syndrome 2020-12-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000122178 SCV000272533 uncertain significance not specified 2019-01-31 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg283Cys variant in TP53 has been reported in multiple individuals with cancer who did not meet Li-Fraumeni diagnostic criteria, and as a somatic variant in at least 7 tumors (Faille 1994, Diller 1995, Rugge 2000, Prescott 2001, Keller 2004, Libe 2007, Manoukian 2007, Ryu 2007, Pekova 2011, Melhem-Bertandt 2012, Schulz 2012, Boyault 2012, Mitchell 2013, Yurgelun 2015, Brohl 2017). It has also been identified in 17/129154 European chromosomes by the Genome Aggregation Database (GnomAD, Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, though in vitro functional studies provide some evidence that the p.Arg283Cys variant may impact protein function (Monti 2011, Pekova 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg283Cys variant is uncertain.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000238755 SCV000297015 uncertain significance Li-Fraumeni syndrome 1 2015-08-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000122178 SCV000597522 uncertain significance not specified 2017-04-17 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115739 SCV000686778 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-29 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 283 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that the mutant protein harboring this variant is functional in yeast transactivation assay (PMID: 12826609), human cell proliferation assay (PMID: 29979965), and human cell growth suppression assay (PMID: 30224644). This variant has been reported in individuals affected with breast cancer, colorectal cancer, diffuse gastric cancer, glioblastoma, lymphocytic leukemia, adult-onset sarcoma and leiomyosarcoma (PMID: 15173255, 17224268, 21761402, 23894400, 25527155, 26086041, 26692951). This variant has been reported in an individual affected with breast cancer and leiomyosarcoma, who also carried a pathogenic truncation variant in the BRCA2 gene (PMID: 17224268). This variant has also been observed in healthy individuals (PMID: 21232794, 24728327). This variant has been reported to be likely benign in the context of Li-Fraumeni syndrome based on cosegregation likelihood ratios (PMID: 30374176). This variant has been identified in 21/282828 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, while this variant has been observed in individuals affected with cancer, it also occurs at an appreciable frequency in the general population. In addition, the available functional studies indicate that this variant has no significant impact on TP53 protein function. Additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000122178 SCV000697452 uncertain significance not specified 2019-11-11 criteria provided, single submitter clinical testing Variant summary: TP53 c.847C>T (p.Arg283Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251440 control chromosomes (gnomAD). The observed variant frequency is approximately 2-folds over the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome (LFS) phenotype (4e-05), strongly suggesting that the variant is benign. c.847C>T has been reported in the literature in patients with CLL, early-onset colorectal cancer, breast cancer, gastric carcinoma, pancreatic, and brain tumor as a germline or somatic variant, but most of the patients did not fulfill LFS criteria (e.g. Gaidano_1994, Yurgelun_2015, Manoukian_2007, Keller_2004, Melhem-Bertrandt_2012, Mitchell_2013, Schulz_2012, Wang_2013, Abe_2019, Mai_2017, Momozawa_2018, Tsaousis_2019, Young_2018). In addition, one patient who was affected with metachronous breast cancers and a subsequent leiomyosarcoma carried TP53 c.847C>T variant and a pathogenic BRCA2 variant (p.Arg2394X); however TP53 c.847C>T did not segregate with disease in her family, as it was absent in an astrocytoma patient (Manoukian_2007). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Functional studies provide conflicting results ranging from no defect (human cell line) to partially defective in yeasts (Pekova_2011, Monti_2011, Jagosova_2012). In addition, the IARC database indicates the variant to be functional. Twelve ClinVar submissions (evaluation after 2014) cite the variant eleven times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
GeneKor MSA RCV000115739 SCV000822209 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000200641 SCV000886456 uncertain significance Li-Fraumeni syndrome 2018-03-28 criteria provided, single submitter research The TP53 variant designated as NM_000546.5:c.847C>T (p.Arg283Cys) is classified as unlikely to cause fully penetrant Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of less than 0.005 to 1 (Thompson et al., 2013, PMID:12900794) in the context of Li-Fraumeni syndrome. This indicates that the TP53 variant is very unlikely to increase the risks of cancer to the extent reported in Li-Fraumeni syndrome. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity in the context of Li-Fraumeni syndrome. Additionally, the familial germline TP53 variant was detected in a family member's breast tumor tissue without evidence of loss of heterozygosity. It was unclear whether there was a second hit. The absence of loss of heterozygosity in the tumor may provide some evidence that the TP53 variant is more likely to be benign. There have been many reports this variant in patients with cancer. Although it is clear that this variant does not cause classic Li-Fraumeni syndrome, we cannot rule out the possibility that this variant does cause some increased risk for breast and other cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585912 SCV000889883 uncertain significance not provided 2018-01-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585912 SCV000892470 uncertain significance not provided 2019-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765397 SCV000896672 uncertain significance Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000238755 SCV001440887 uncertain significance Li-Fraumeni syndrome 1 2019-01-01 criteria provided, single submitter clinical testing
ITMI RCV000122178 SCV000086393 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148912 SCV000190658 likely pathogenic Neoplasm of stomach 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357872 SCV001553463 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The TP53 p.Arg283Cys variant was identified in 14 of 16242 proband chromosomes (frequency: 0.0009) from individuals or families with gastric cancer, breast cancer, leiomyosarcoma, sarcoma, or colorectal cancer and was present in 2 of 23844 control chromosomes (frequency: 0.00008) from healthy individuals (Keller 2004, Manoukian 2007, Mitchell 2013, Momozawa 2018, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs149633775) as "With Likely pathogenic allele", ClinVar (classified as likely benign by one submitter; as uncertain significance by Invitae, GeneDx, Ambry Genetics and six other submitters; and as likely pathogenic by one submitter), Cosmic (22x in breast, endometrium, pancreatic and other tissues ), and LOVD 3.0 (3x). The variant was identified in control databases in 24 of 277184 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The frequency of the variant in certain populations increases the likelihood that this is a low frequency, benign variant; it was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 1 of 6466 chromosomes (freq: 0.0002), and European in 20 of 126682 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro studies of the variant provide conflicting data: the variant demonstrated weakly temperature-dependent activity, partial deficiency of activity, or activity similar to wild type (Jagosove 2012, Pekova 2011, Monti 2011). The variant was identified in a family meeting criteria for HBOC and Li Fraumeni-like syndrome along with a pathogenic BRCA2 variant (c.7408A>T, p.R2394X). The p.Arg283 residue is conserved in mammals but not in more distantly related organisms, and four out of five 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% 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.
GenomeConnect - Invitae Patient Insights Network RCV000585912 SCV001716320 not provided not provided no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 08-08-2017 by 1197. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory.

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