rs55819519

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000546.6(TP53):​c.869G>T​(p.Arg290Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

6
4
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TP53NM_000546.6 linkc.869G>T p.Arg290Leu missense_variant Exon 8 of 11 ENST00000269305.9 NP_000537.3 P04637-1K7PPA8Q53GA5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TP53ENST00000269305.9 linkc.869G>T p.Arg290Leu missense_variant Exon 8 of 11 1 NM_000546.6 ENSP00000269305.4 P04637-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461890
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 30, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: TP53 c.869G>T (p.Arg290Leu) 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 was absent in 251482 control chromosomes. c.869G>T has been reported in the literature in two individuals from the same family affected with Li-Fraumeni Syndrome (e.g., Anensen_2006). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, however with conflicting results. One study found no induction of p53 during therapy in patient cells (e.g., Anensen_2006), while other studies have shown that the variant maintains wild-type p53-like anti-proliferative capacity in vitro (e.g., Kotler_2018). The following publications have been ascertained in the context of this evaluation (PMID: 16437140, 35425963, 29979965). ClinVar contains an entry for this variant (Variation ID: 633445). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Li-Fraumeni syndrome Uncertain:1
Aug 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 290 of the TP53 protein (p.Arg290Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li Fraumeni syndrome (PMID: 16437140). ClinVar contains an entry for this variant (Variation ID: 633445). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). 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. -

Bone marrow failure syndrome 5 Uncertain:1
Feb 23, 2020
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Hereditary cancer-predisposing syndrome Uncertain:1
Dec 14, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R290L variant (also known as c.869G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 869. The arginine at codon 290 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a 51-year-old female with a personal history of breast cancer, three soft tissue sarcomas and anal carcinoma, the first sarcoma being diagnosed at the age of 28. This alteration was also reported in the woman's son, who had a rhabdomyosarcoma and died from acute leukemia at age 12 (Anensen N et al. Leukemia, 2006 Apr;20:734-6). This variant is in the DNA binding domain of the TP53 protein and is reported to have functional transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). 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). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Benign
7.9
DANN
Uncertain
0.98
DEOGEN2
Benign
0.068
T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.73
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.85
T;T;D;T;T;D;T;.;.;.;T;T;.;D;T;T;T;T;T
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.8
.;.;.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.
PrimateAI
Benign
0.21
T
PROVEAN
Uncertain
-4.2
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL
Pathogenic
0.65
Sift
Uncertain
0.011
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G
Uncertain
0.051
T;T;T;T;T;T;T;T;T;T;T;T;T;D;D;T;T;T;T
Polyphen
0.0, 0.0020
.;.;.;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.
Vest4
0.65
MutPred
0.80
Gain of catalytic residue at R290 (P = 0.0054);.;.;.;.;.;.;.;Gain of catalytic residue at R290 (P = 0.0054);.;Gain of catalytic residue at R290 (P = 0.0054);Gain of catalytic residue at R290 (P = 0.0054);Gain of catalytic residue at R290 (P = 0.0054);.;.;Gain of catalytic residue at R290 (P = 0.0054);.;.;.;
MVP
0.99
MPC
0.076
ClinPred
0.43
T
GERP RS
-1.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.46
gMVP
0.34

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: COSV53296796; COSMIC: COSV53296796; API