ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.869G>A (p.Arg290His) (rs55819519)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000148914 SCV001142524 benign Li-Fraumeni syndrome 2019-09-16 reviewed by expert panel curation This variant has a minor allele frequency of 0.0003583 (0.03%, 9/25,120 alleles) in the European Finnish subpopulation of the gnomAD cohort (BS1). Transactivation assays show super transactivation 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). Additionally, this variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Finally, this variant has been observed in at least 7 60+ year old females without a cancer diagnosis (BS2_Supporting; FLOSSIES database - https://whi.color.com). In summary, TP53 c.869G>A; p.Arg290His meets criteria to be classified as benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS1, BS3, BP4, BS2_Supporting.
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.
Ambry Genetics RCV000115740 SCV000187277 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-10 criteria provided, single submitter clinical testing The p.R290H variant (also known as c.869G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 869. The arginine at codon 290 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in two suspected Li-Fraumeni syndrome (LFS) families. In the first family, p.R290H was detected in a child with a severe LFS phenotype who was also found to carry two other TP53 alterations in trans with p.R290H (p.[R156H;R267Q]). Segregation studies showed that p.R290H was inherited from an unaffected father; however, no extended paternal family history was available. In a second family, p.R290H was detected in a child with a brain tumor diagnosed at age 9 whose family history included unaffected parents, a paternal grandfather with a brain tumor (died at age 40) and a paternal first cousin with a rhabdomyosarcoma (died at age 4) (Quesnel S et al. Oncogene. 1999 Jul;18:3970-8). The p.R290H alteration has also been reported in patients with personal history of uterine serous carcinoma, CNS malignancies, Ewing's sarcoma, pancreatic neuroendocrine tumor, and early-onset breast or colorectal cancer (Arcand SL et al. Breast Cancer Res. Treat. 2008 Apr;108:399-408; Pinto C et al. Fam. Cancer. 2009 May;8:383-90; Pennington KP et al. Cancer. 2013 Jan;119:332-338; Yurgelun MB et al. JAMA Oncol. 2015 May;1:214-21; Zhang J et al. N. Engl. J. Med. 2015 Dec 10;373(24):2336-2346; Scarpa A et al. Nature. 2017 Mar 2;543(7643):65-71), as well as in unaffected individuals (de Andrade KC et al. Hum. Mutat. 2017 Dec;38(12):1723-1730). Functional assays in both yeast cells and human lymphocytes have demonstrated this alteration has transactivation capability similar to, or greater than, wildtype p53 protein (Kato S et al. <span style="font-family:arial,sans-serif">Proc. <span style="font-family:arial,sans-serif">Natl. Acad<span style="font-family:arial,sans-serif">. <span style="font-family:arial,sans-serif">Sci. USA. 2003 Jul;100:8424-9; Monti P et al. <span style="font-family:arial,sans-serif">Mol. Cancer Res. 2011 Mar;9:271-9; Zerdoumi Y et al. <span style="font-family:arial,sans-serif">Hum. Mol. Genet. 2017 Jul;26:281), and another functional study conducted in mammalian cells demonstrated the R290H variant was proficient in transcriptional activation, DNA binding, and activation of apoptosis (Wang B et al. <span style="font-family:arial,sans-serif">Cell Death Differ. 2014 Apr;21:521-32). Additional studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). An internal family study revealed that an affected individual inherited this alteration from an unaffected 77-year-old father (Ambry internal data). This alteration has been seen numerous times by our laboratory, frequently in unaffected individuals (Ambry internal data). This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
CSER _CC_NCGL, University of Washington 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
Invitae RCV000148914 SCV000254643 benign Li-Fraumeni syndrome 2020-12-03 criteria provided, single submitter clinical testing
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.
Genetic Services Laboratory, University of Chicago RCV000620742 SCV000693679 uncertain significance Li-Fraumeni syndrome 1 2017-12-28 criteria provided, single submitter clinical testing
Mendelics RCV000148914 SCV000839107 uncertain significance Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter 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 analyze.myvariant.org (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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000760102 SCV000889884 uncertain significance not provided 2019-03-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115740 SCV000910675 likely benign Hereditary cancer-predisposing syndrome 2020-05-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Mendelics RCV000989708 SCV001140247 uncertain significance Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000148914 SCV001439185 benign Li-Fraumeni syndrome 2020-09-03 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357075 SCV001552412 uncertain significance Familial ovarian cancer no assertion criteria provided clinical testing The TP53 p.Arg290His variant was identified in 4 of 1586 proband chromosomes (frequency: 0.003) from French Canadian, Spanish, Portuguese, and American individuals or families with BRCA1/2-negative breast or endometrial cancer, Li-Fraumeni syndrome (Arcand 2008, Pennington 2012, Pinto 2009, Bonache 2018) and in 26 of 127,966 (frequency: 0.0002) chromosomes from individuals in an unselected population (de Andrade 2017). The variant was identified in dbSNP (ID: rs55819519) as “With Uncertain significance, other allele”, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, and five other submitters; and as likely benign by University of Washington Department of Laboratory Medicine). The variant was not identified in LOVD 3.0. The variant was also identified in control databases in 42 of 277220 chromosomes at a frequency of 0.0002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24030 chromosomes (freq: 0.00008), Other in 3 of 6466 chromosomes (freq: 0.0005), Latino in 2 of 34420 chromosomes (freq: 0.00006), European in 26 of 126714 chromosomes (freq: 0.0002), East Asian in 1 of 18868 chromosomes (freq: 0.00005), Finnish in 7 of 25790 chromosomes (freq: 0.0003), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while it was not observed in the Ashkenazi Jewish population. The variant was identified in a patient with BRCA1/2-negative breast cancer who did not have a family history consistent with LFS (Arcand 2008) and a patient with LFS who presented in early childhood with multiple primary cancers, as co-occurring in trans with two TP53 variants on the other allele (p.R156H and p.R267Q); family history information was not available for the side of the family where the p.Arg290His variant segregated (Quesnel 1999). In vitro assays of cellular growth suppression and transcriptional activation demonstrated ambiguous results with the variant demonstrating complete loss of function, partial function, or function comparable to wildtype (Quesnel 1999, Zerdoumi 2017, Monti 2011). The p.Arg290 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the His variant impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Altogether, data from family histories, population frequencies, and functional assays are inconsistent and could represent either a benign variant identified in affected individuals as a result of increased population frequency or a pathogenic, hypomorphic variant with reduced penetrance. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.