17-7673751-C-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BS2BS3
This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.869G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 290 (p.Arg290His). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000187277.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.09; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BP4 (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000468/MONDO:0018875/009
Frequency
Consequence
ENST00000269305.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.869G>A | p.Arg290His | missense_variant | 8/11 | ENST00000269305.9 | NP_000537.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.869G>A | p.Arg290His | missense_variant | 8/11 | 1 | NM_000546.6 | ENSP00000269305 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152122Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251482Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135912
GnomAD4 exome AF: 0.000224 AC: 328AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.000226 AC XY: 164AN XY: 727246
GnomAD4 genome AF: 0.000131 AC: 20AN: 152240Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11AN XY: 74436
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome Uncertain:1Benign:4
Benign, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Aug 05, 2024 | The NM_000546.6: c.869G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 290 (p.Arg290His). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000187277.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.09; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BP4 (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024) - |
Likely benign, criteria provided, single submitter | research | University of Washington Department of Laboratory Medicine, University of Washington | Mar 28, 2018 | 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. - |
Benign, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 03, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | Low GERP score may suggest that this variant may belong in a lower pathogenicity class - |
not provided Uncertain:1Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 21, 2020 | 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) - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | TP53: PM5, BS3:Supporting, BS1, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 21, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 14, 2020 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2021 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 20, 2020 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | True Health Diagnostics | Mar 19, 2018 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 23, 2021 | - - |
not specified Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 25, 2017 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 23, 2022 | 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. - |
Li-Fraumeni syndrome 1 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 01, 2020 | The TP53 c.869G>A variant is classified as Benign (BS2, BS3, BP4, BP6) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 28, 2017 | - - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jul 18, 2019 | - - |
Familial ovarian cancer Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
TP53-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 12, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at