ClinVar Miner

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

gnomAD frequency: 0.00014  dbSNP: rs55819519
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Total submissions: 20
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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 - 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 RCV000760102 SCV000149649 benign not provided 2020-02-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12610779, 28369373, 30309854, 30514802, 16437140, 24079673, 17606709, 22811390, 15580553, 17541742, 25925845, 21343334, 17318340, 19468865, 26332594, 24829203, 25637381, 10435620, 19643983, 27153395, 26086041, 28472496, 29979965, 28861920, 24076587, 12826609, 21601526, 30352134, 31016814, 30840781, 30374176, 30306255, 33300245)
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 2021-12-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Mass General Brigham 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 (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 2020-09-21 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 benign not specified 2022-05-23 criteria provided, single submitter clinical testing Variant summary: 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 0.00016 in 251482 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00021 in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency (MPAF) for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome phenotype (4e-05). In addition, the variant was reported to be found in the FLOSSIES database in 7/9884 women, who were older than age 70 years and have never had cancer. The frequency in this cohort (0.000354) is ~9-fold higher than MPAF, strongly suggesting that the variant is a benign polymorphism. The variant, c.869G>A, has also been reported in the literature in individuals affected with (suspected) Li-Fraumeni Syndrome and various tumor phenotypes, however, without strong evidence for causality. Multiple publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant overall did not decrease Tp53 expression, transcription activity, and function measured at the cellular level (e.g. Quesnel_1999, Zerdoumi_2017, Kotler_2018). Fifteen other submitters, including one expert panel (ClinGen TP53 Variant Curation Expert Panel) have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=8), likely benign (n=3) / benign (n=4; including the expert panel). Based on the evidence outlined above, the variant was classified as 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
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798340 SCV002042836 uncertain significance Breast and/or ovarian cancer 2019-07-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000760102 SCV002050056 likely benign not provided 2020-11-14 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000115740 SCV002532717 likely benign Hereditary cancer-predisposing syndrome 2021-04-23 criteria provided, single submitter curation
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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000213061 SCV002550936 benign not specified 2022-03-11 no assertion criteria provided clinical testing

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