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

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

TP53
ENST00000269305.9 missense

Scores

1
3
15

Clinical Significance

Benign reviewed by expert panel U:7B:14

Conservation

PhyloP100: -0.383
Variant links:
Genes affected
TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
For more information check the summary or visit ClinGen Evidence Repository.
BS2
For more information check the summary or visit ClinGen Evidence Repository.
BS3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TP53NM_000546.6 linkuse as main transcriptc.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
TP53ENST00000269305.9 linkuse as main transcriptc.869G>A p.Arg290His missense_variant 8/111 NM_000546.6 ENSP00000269305 P1P04637-1

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152122
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000155
AC:
39
AN:
251482
Hom.:
0
AF XY:
0.000155
AC XY:
21
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.000416
Gnomad NFE exome
AF:
0.000211
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000224
AC:
328
AN:
1461892
Hom.:
0
Cov.:
33
AF XY:
0.000226
AC XY:
164
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.000300
Gnomad4 NFE exome
AF:
0.000261
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152240
Hom.:
0
Cov.:
31
AF XY:
0.000148
AC XY:
11
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000161
Hom.:
0
Bravo
AF:
0.000128
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000157
AC:
19
EpiCase
AF:
0.000218
EpiControl
AF:
0.000237

ClinVar

Significance: Benign
Submissions summary: Uncertain:7Benign:14
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1Benign:4
Benign, reviewed by expert panelcurationClinGen TP53 Variant Curation Expert Panel, ClinGenAug 05, 2024The 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 submitterresearchUniversity of Washington Department of Laboratory Medicine, University of WashingtonMar 28, 2018The 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 submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalSep 03, 2020- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Uncertain significance, criteria provided, single submitterresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
not provided Uncertain:1Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxFeb 21, 2020In 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2023TP53: PM5, BS3:Supporting, BS1, BS2 -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoSep 21, 2020- -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 14, 2020- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 08, 2021This 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 20, 2020- -
Uncertain significance, no assertion criteria providedclinical testingTrue Health DiagnosticsMar 19, 2018- -
Likely benign, criteria provided, single submittercurationSema4, Sema4Apr 23, 2021- -
not specified Uncertain:1Benign:2
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 25, 2017Variant 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 23, 2022Variant 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 submitterclinical testingGenetics and Molecular Pathology, SA PathologyJul 01, 2020The TP53 c.869G>A variant is classified as Benign (BS2, BS3, BP4, BP6) -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 28, 2017- -
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJul 18, 2019- -
Familial ovarian cancer Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment 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 providedclinical testingPreventionGenetics, part of Exact SciencesNov 12, 2021This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Uncertain
0.035
T
BayesDel_noAF
Uncertain
0.090
CADD
Benign
8.6
DANN
Benign
0.92
DEOGEN2
Benign
0.023
T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.31
N
LIST_S2
Benign
0.82
T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T
M_CAP
Benign
0.066
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Benign
1.0
.;.;.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Benign
0.20
T
PROVEAN
Benign
-2.2
N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N
REVEL
Uncertain
0.58
Sift
Benign
0.10
T;.;.;.;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T
Sift4G
Benign
0.11
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.0, 0.0010
.;.;.;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.
Vest4
0.54
MVP
0.98
MPC
0.075
ClinPred
0.017
T
GERP RS
-1.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.26
gMVP
0.23

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs55819519; hg19: chr17-7577069; COSMIC: COSV52683585; COSMIC: COSV52683585; API