rs55819519

Positions:

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

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]

TP53 links:

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/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.869G>T	p.Arg290Leu	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 linkuse as main transcript	c.869G>T	p.Arg290Leu	missense_variant	8/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 30, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 29, 2020

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. Experimental studies have shown that this variant does not substantially affect TP53 protein function (PMID: 12826609, 30224644, 29979965). This variant 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). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 290 of the TP53 protein (p.Arg290Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. -

Bone marrow failure syndrome 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2020

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

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2021

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

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

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

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

MutationAssessor

Benign

1.8

.;.;.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.21

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over