rs121912654

chr17-7675143-C-Achr17-7675143-C-Gchr17-7675143-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000546.6(TP53):c.469G>T(p.Val157Phe) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V157I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 0.371

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 11 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 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 chr17-7675141-GA-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3148383.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 17-7675143-C-A is Pathogenic according to our data. Variant chr17-7675143-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12353.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.469G>T	p.Val157Phe	missense_variant	5/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.469G>T	p.Val157Phe	missense_variant	5/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461880 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.V157F in TP53 (NM_000546.6) has been reported previously in affected individuals (Zhang J et al,Goidescu IG et al). Functional studies reveal a damaging effect (Dearth LR et al; Calhoun S et al). The variant has been submitted to ClinVar as Pathogenic/Uncertain significance. The p.V157F variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 14, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15077194, 21561095, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change replaces Valine with Phenylalanine at codon 157 of the TP53 protein (p.Val157Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine (Grantham Score 50)This sequence change has been reported in the literature in patients with breast, hepatocellular, and squamous cell carcinoma and adenocarcinoma (22187033 ,1672732 ). This variant is not present in population databases (rs121912654) but there is entries in the mutation database Clinvar (Variation ID: 12353). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 08, 2021	The p.V157F variant (also known as c.469G>T), located in coding exon 4 of the TP53 gene, results from a G to T substitution at nucleotide position 469. The valine at codon 157 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with adrenocortical carcinoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This variant has also been reported as confirmed de novo in a 5 year-old patient who was diagnosed with medulloblastoma (Azzollini J et al. Cancers (Basel), 2020 Sep;12:). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, a dominant negative effect, and is predicted to affect several p53 isoforms in yeast based assays (IARC TP53 databse; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98; Baroni TE et al. Proc. Natl. Acad. Sci. U.S.A., 2004 Apr;101:4930-5; Gorgoulis VG et al. Br. J. Cancer, 1998;77:374-84; Ishii N et al. Oncogene, 1999 Oct;18:5870-8; Obata A et al. Int. J. Cancer, 2000 Mar;89:187-93; Concin N et al. Breast Cancer Res. Treat., 2003 May;79:37-46; Millon R et al. Oral Oncol., 2001 Dec;37:620-31; Fouquet C et al. Clin. Cancer Res., 2004 May;10:3479-89; Schlichtholz B et al. Carcinogenesis, 2004 Dec;25:2319-23; Scian MJ et al. Oncogene, 2004 May;23:4430-43; Mizuarai S et al. Cancer Res., 2006 Jun;66:6319-26; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability of the DNA-binding domain (Kitayner et al. Nat. Struct. Mol. Biol., 2010 Apr;17(4):423-9; Calhoun S et al. Biochemistry, 2011 Jun;50:5345-53). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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 alteration is interpreted as a disease-causing mutation. -

Squamous cell carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research

Jun 06, 2022

- -

Neoplasm of ovary Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Hepatocellular carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 04, 1991

- -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2023

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 157 of the TP53 protein (p.Val157Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adrenocortical carcinoma and/or breast cancer (PMID: 15564800, 26580448, 29785153). ClinVar contains an entry for this variant (Variation ID: 12353). 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: 9472631, 10713666, 16861262). 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	0.93
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.85	T;D;T;T;T;.;.;.;D;D;.;T;T;D;D;D;T;T;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.60	D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.8	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0070	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
Sift4G	Uncertain	0.0050	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		0.78
MutPred		0.72		Loss of MoRF binding (P = 0.0831);Loss of MoRF binding (P = 0.0831);.;.;.;.;Loss of MoRF binding (P = 0.0831);.;Loss of MoRF binding (P = 0.0831);Loss of MoRF binding (P = 0.0831);Loss of MoRF binding (P = 0.0831);.;.;Loss of MoRF binding (P = 0.0831);.;.;.;.;Loss of MoRF binding (P = 0.0831);
MVP		0.98
MPC		1.9
ClinPred		0.98	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.73

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: rs121912654; hg19: chr17-7578461; COSMIC: COSV52667015; COSMIC: COSV52667015;