rs121912654

Variant names:

• chr17-7675143-C-A
• rs121912654
• NM_000546.6:c.469G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-7675143-C-A
• chr17-7675143-C-G
• chr17-7675143-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O: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 16 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, 0.948
• PP5: Variant 17-7675143-C-A is Pathogenic according to our data. Variant chr17-7675143-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.469G>T	p.Val157Phe	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.469G>T	p.Val157Phe	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

Feb 14, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]. -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 01, 2020

GeneKor MSA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Oct 01, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Li-Fraumeni syndrome Pathogenic:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 individuals with adrenocortical carcinoma, medulloblastoma and/or breast cancer (PMID: 15564800, 26580448, 29785153, 32899294). ClinVar contains an entry for this variant (Variation ID: 12353). Invitae Evidence Modeling incorporating data from in vitro 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Squamous cell carcinoma Pathogenic:1

Jun 06, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian neoplasm Pathogenic:1

Dec 01, 2018

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hepatocellular carcinoma Pathogenic:1

Apr 04, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
MutationAssessor	Uncertain	2.9	.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
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;