rs483352697

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000546.6(TP53):​c.587G>T​(p.Arg196Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R196Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TP53
NM_000546.6 missense

Scores

13
5
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 7.91
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 Pathogenic. Variant got 10 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;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-7674944-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TP53NM_000546.6 linkuse as main transcriptc.587G>T p.Arg196Leu missense_variant 6/11 ENST00000269305.9 NP_000537.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TP53ENST00000269305.9 linkuse as main transcriptc.587G>T p.Arg196Leu missense_variant 6/111 NM_000546.6 ENSP00000269305 P1P04637-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Uncertain significance, flagged submissionliterature onlyRichard Lifton Laboratory, Yale University School of Medicine-- -
Likely pathogenic, no assertion criteria providedliterature onlyRichard Lifton Laboratory, Yale University School of Medicine-- -
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 04, 2018The p.R196L variant (also known as c.587G>T), located in coding exon 5 of the TP53 gene, results from a G to T substitution at nucleotide position 587. The arginine at codon 196 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported as a somatic mutation two times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum. Mutat. 2007 Jun;28:622-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 04, 2024This missense variant replaces arginine with leucine at codon 196 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant has a neutral effect on TP53 protein function (PMID: 29979965, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Li-Fraumeni syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchDepartment of Pediatrics, Memorial Sloan Kettering Cancer CenterDec 15, 2020- -
Li-Fraumeni syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 05, 2022In 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. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 100814). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 196 of the TP53 protein (p.Arg196Leu). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.9
.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-6.6
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen
1.0
D;.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D
Vest4
0.94
MutPred
0.93
Loss of disorder (P = 0.0701);Loss of disorder (P = 0.0701);.;.;.;.;.;.;.;Loss of disorder (P = 0.0701);.;Loss of disorder (P = 0.0701);Loss of disorder (P = 0.0701);Loss of disorder (P = 0.0701);.;.;Loss of disorder (P = 0.0701);.;.;.;.;
MVP
1.0
MPC
1.8
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.99
gMVP
0.84

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: rs483352697; hg19: chr17-7578262; COSMIC: COSV52667931; COSMIC: COSV52667931; API