ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.869G>A (p.Arg290His) (rs55819519)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115740 SCV000187277 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148914 SCV000190660 uncertain significance Li-Fraumeni syndrome 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Color RCV000115740 SCV000910675 benign Hereditary cancer-predisposing syndrome 2015-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000213061 SCV000149649 uncertain significance not specified 2016-09-07 criteria provided, single submitter clinical testing This variant is denoted TP53 c.869G>A at the cDNA level, p.Arg290His (R290H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). The variant has been reported in at least three individuals with Li-Fraumeni syndrome (LFS) or from a Li-Fraumeni-like family as well as in individuals with sporadic glioblastoma, uterine serous carcinoma, and early-onset colon cancer whose family histories were not suggestive of LFS (Quesnel 1999, Pinto 2009, Rodriguez-Hernandez 2013, Pennington 2013, Yurgelun 2015). The LFS proband, with a rhabdomyosarcoma and a brain tumor in childhood, also carried a pathogenic TP53 variant in trans. Although TP53 Arg290His did not appear to affect protein activity in vitro, it did result in lower protein levels, leading the authors to suggest that maybe this allele contributed to the severe phenotype in this child (Quesnel 1999). TP53 Arg290His was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project or 1000 Genomes. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. TP53 Arg290His occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the DNA binding domain and region of interaction with multiple binding partners (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, we consider TP53 Arg290His to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000620742 SCV000693679 uncertain significance Li-Fraumeni syndrome 1 2017-12-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000213061 SCV000920323 uncertain significance not specified 2018-12-28 criteria provided, single submitter clinical testing Variant summary: The variant, TP53 c.869G>A (p.Arg290His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 277,220 control chromosomes (gnomAD). The observed variant frequency is approximately 3.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05), strongly suggesting that the variant is benign. The variant, c.869G>A has been reported in the literature in individuals affected with Li-Fraumeni Syndrome, Li-Fraumeni like Syndrome, Hematopoietic malignancies, Colorectal cancer, breast cancer and uterine serous carcinoma (Quesnel_1999, Pinto_2013, Portwine_2000, Qian_2018, Drazer_2018, Yurgelun_2017, Arcand_2015, Pennington_2012). These data indicate that the variant is likely to be associated with disease. There have been experimental evidence evaluating the impact of this variant on protein function. This variant did not affect Tp53 expression, transcriptional activity or cell proliferation, however, it may affect the expression of p21WAF1/CIP1 (Quesnel_1999, Zerdoumi_2017). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000148914 SCV000254643 uncertain significance Li-Fraumeni syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 290 of the TP53 protein (p.Arg290His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs55819519, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in families affected with Li-Fraumeni-like syndrome (PMID: 10435620, 16437140, 21601526, 19468865, 26086041), and in individuals without a personal or family history of TP53-related disease (PMID: 22811390, 17541742, 26086041). This variant is also known as c.473G>A (p.Arg158His) or p.Arg251His in the literature. ClinVar contains an entry for this variant (Variation ID: 127825). Experimental studies have shown that this missense change can result in a modest reduction in TP53 transactivation activity, classifying this variant as a partial deficiency allele (PMID: 10435620, 21343334, 17606709). However, the results are not consistent across each of the assays, and the clinical significance of these results is uncertain. In addition, another study reported normal mRNA levels for this missense variant in transfected cells (PMID: 24076587). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000213061 SCV000540572 uncertain significance not specified 2017-01-25 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 8 papers, including at least 3 individuals with Li-Fraumeni syndrome as well as individuals with other cancers. The variant has a Max MAF of 0.02% in ExAC (16 alleles) and 0.03% in gnomAD (9 Finnish alleles and 26 non-Finnish European alleles). It is classified with 1 star in ClinVar as VUS by Invitae, Ambry, GeneDx and CSER_CC_NCGL, and as Pathogenic by UCLA. 14 mammals and 2 non-mammals have a His at this position.
Mendelics RCV000148914 SCV000839107 uncertain significance Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000760102 SCV000889884 uncertain significance not provided 2018-07-04 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000115740 SCV000805309 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-19 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000148914 SCV000886455 likely benign Li-Fraumeni syndrome 2018-03-28 criteria provided, single submitter research The TP53 variant designated as NM_000546.5:c.896G>A (p.R290H) is classified as likely benign in the context of 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. Computational programs predict that this variant is likely to be tolerated. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign in the context of Li-Fraumeni syndrome. Additionaly, the familial germline TP53 variant (NM_000546.5:c.869G>A, p.R290H) was detected in breast tumor tissue without evidence of loss of heterozygosity. No second somatic mutation was identified in TP53. The absence of loss of heterozygosity or second TP53 mutation in the tumor provides some evidence that the TP53 variant is more likely to be benign. We cannot rule out the possibility that this variant does cause some increased risk for breast cancer. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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