rs786204041

Positions:

• chr17-7674942-C-A
• chr17-7674942-C-G
• chr17-7674942-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP3_Strong

The NM_000546.6(TP53):​c.589G>T​(p.Val197Leu) variant causes a missense change. 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 Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.04

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_000546.6 (TP53) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.589G>T	p.Val197Leu	missense_variant	6/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.589G>T	p.Val197Leu	missense_variant	6/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 12, 2019

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 missense change reduces p53 transcriptional activity in yeast and acts as a temperature-sensitive mutant in a glioblastoma cell line, but the clinical significance of these findings is unclear (PMID: 12826609, 11668476). This variant has been observed in a family affected with suspected Li-Fraumeni syndrome (PMID: 18511570). ClinVar contains an entry for this variant (Variation ID: 216468). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 197 of the TP53 protein (p.Val197Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2015

The p.V197L variant (also known as c.589G>T), located in coding exon 5 of the TP53 gene, results from a G to T substitution at nucleotide position 589. The valine at codon 197 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported as a somatic mutation 4 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(6):622-9). This variant is in the DNA binding domain of the TP53 protein and is reported to have reduced transactivation capacity but no dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Marutani M et al. Cancer Res. 1999 Oct; 59(19):4765-9). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 125000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D;D;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	Uncertain	2.5	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N;N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.052	T;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G	Benign	0.089	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;B;.;P;P;P;.;.;B;.;.;.;D
Vest4		0.86
MutPred		0.91		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;.;.;.;.;.;Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;Loss of sheet (P = 0.1158);.;.;.;.;
MVP		0.97
MPC		1.6
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.90
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs786204041; hg19: chr17-7578260; COSMIC: COSV52927251; COSMIC: COSV52927251;