17-7675146-G-T

Variant names:

• chr17-7675146-G-T
• NM_000546.6:c.466C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000546.6(TP53):​c.466C>A​(p.Arg156Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00200

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 6 ACMG points.

• PM1: In a strand (size 9) in uniprot entity P53_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr17-7675145-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.466C>A	p.Arg156Ser	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.466C>A	p.Arg156Ser	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 05, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R156S variant (also known as c.466C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 466. The arginine at codon 156 is replaced by serine, an amino acid with dissimilar properties. This variant impacts an exposed residue in the DNA binding domain of the TP53 protein and is reported to have partial loss of transactivation capacity and predicted to affect several p53 isoforms. (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). 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 0.0005% (greater than 200000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is poorly 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 p.R156S remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.38	T;T;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.85	D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.64	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	2.0	.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.15	N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.062	T;T;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T;T;D
Sift4G	Benign	0.083	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		0.80	P;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.;P;.
Vest4		0.47
MutPred		0.64		Loss of methylation at R156 (P = 0.0183);Loss of methylation at R156 (P = 0.0183);.;.;.;.;Loss of methylation at R156 (P = 0.0183);.;Loss of methylation at R156 (P = 0.0183);Loss of methylation at R156 (P = 0.0183);Loss of methylation at R156 (P = 0.0183);.;.;Loss of methylation at R156 (P = 0.0183);.;.;.;.;Loss of methylation at R156 (P = 0.0183);
MVP		0.89
MPC		1.7
ClinPred		0.47	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7578464; COSMIC: COSV53119766; COSMIC: COSV53119766;