17-7675142-A-G

Position:

• chr17-7675142-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000546.6(TP53):​c.470T>C​(p.Val157Ala) 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).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.32

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 17-7675142-A-G is Pathogenic according to our data. Variant chr17-7675142-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428887.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.470T>C	p.Val157Ala	missense_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.470T>C	p.Val157Ala	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 08, 2024	The p.V157A pathogenic mutation (also known as c.470T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at nucleotide position 470. The valine at codon 157 is replaced by alanine, an amino acid with similar properties. This variant has been reported in multiple individuals with features consistent with Li-Fraumeni syndrome (Parsons DW et al. JAMA Oncol, 2016 May;2:616-624; Ambry internal data). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Giacomelli AO et al. Nat Genet, 2018 Oct;50:1381-1387). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc Natl Acad Sci U S A, 2003 Jul;100:8424-9). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55; Ambry internal data). Another variant at the same codon, p.V157F (c.469G>T), has been detected in multiple individuals with features consistent with Li-Fraumeni syndrome (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Azzollini J et al. Cancers (Basel), 2020 Sep;12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Li-Fraumeni syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

Adrenal cortex carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Donald Williams Parsons Laboratory, Baylor College of Medicine

May 29, 2013

Likely pathogenicity based on finding it once in this study in a 5-year-old male with adrenocortical carcinoma and 2nd degree relatives on both sides of the family with early-onset adult cancer. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 04, 2022

Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity with a dominant-negative effect (Kato et al., 2003; Giacomelli et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23810757, 30840781, 34607348, 28446506, 15510160, 26822237, 12826609, 30224644) -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 157 of the TP53 protein (p.Val157Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adrenocortical carcinoma (PMID: 26822237, 35306447). ClinVar contains an entry for this variant (Variation ID: 428887). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 22710932). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T;D;T;T;T;.;.;.;D;D;.;T;T;D;D;D;T;T;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.9	.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
Sift4G	Uncertain	0.0030	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		0.65
MutPred		0.78		Gain of disorder (P = 0.0529);Gain of disorder (P = 0.0529);.;.;.;.;Gain of disorder (P = 0.0529);.;Gain of disorder (P = 0.0529);Gain of disorder (P = 0.0529);Gain of disorder (P = 0.0529);.;.;Gain of disorder (P = 0.0529);.;.;.;.;Gain of disorder (P = 0.0529);
MVP		0.97
MPC		1.8
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.57

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: rs1131691023; hg19: chr17-7578460; COSMIC: COSV52722122; COSMIC: COSV52722122;