rs587782620

chr17-7675185-C-Achr17-7675185-C-Gchr17-7675185-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000546.6(TP53):c.427G>T(p.Val143Leu) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V143A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.26

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain 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 chr17-7675184-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 804214.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.427G>T	p.Val143Leu	missense_variant	5/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.427G>T	p.Val143Leu	missense_variant	5/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 05, 2021	The p.V143L variant (also known as c.427G>T), located in coding exon 4 of the TP53 gene, results from a G to T substitution at nucleotide position 427. The valine at codon 143 is replaced by leucine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have partial loss of transactivation capacity (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 21, 2022

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 143 of the TP53 protein (p.Val143Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 185729). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. 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. -

Li-Fraumeni syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D;D
Eigen	Benign	0.0076
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;T;D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N;.
REVEL	Uncertain	0.61
Sift	Benign	0.089	T;T;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T;D;T;.
Sift4G	Benign	0.088	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;T
Polyphen		0.77	P;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.;B;.;.
Vest4		0.32
MutPred		0.71		Loss of catalytic residue at V143 (P = 0.047);Loss of catalytic residue at V143 (P = 0.047);.;.;.;.;Loss of catalytic residue at V143 (P = 0.047);.;Loss of catalytic residue at V143 (P = 0.047);Loss of catalytic residue at V143 (P = 0.047);Loss of catalytic residue at V143 (P = 0.047);.;.;Loss of catalytic residue at V143 (P = 0.047);.;.;.;.;Loss of catalytic residue at V143 (P = 0.047);.;
MVP		0.93
MPC		1.6
ClinPred		0.89	D
GERP RS		4.5
Varity_R		0.56
gMVP		0.46

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

Other links and lift over

dbSNP: rs587782620; hg19: chr17-7578503; COSMIC: COSV53025766; COSMIC: COSV53025766;