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rs1131691043

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000546.6(TP53):c.514G>T(p.Val172Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V172D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

13
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 5.05
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 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 chr17-7675097-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 836761.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant 17-7675098-C-A is Pathogenic according to our data. Variant chr17-7675098-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428909.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TP53NM_000546.6 linkuse as main transcriptc.514G>T p.Val172Phe missense_variant 5/11 ENST00000269305.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TP53ENST00000269305.9 linkuse as main transcriptc.514G>T p.Val172Phe missense_variant 5/111 NM_000546.6 P1P04637-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461890
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
727248
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Feb 14, 2024This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJul 27, 2022The p.V172F pathogenic mutation (also known as c.514G>T), located in coding exon 4 of the TP53 gene, results from a G to T substitution at nucleotide position 514. The valine at codon 172 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in an individual meeting LFL-Birch criteria as well as a family meeting classic LFS criteria (Siddiqui R et al. Fam Cancer, 2005;4:177-81; Ricker CA et al. Cold Spring Harb Mol Case Stud, 2021 02;7:). This alteration is located in the highly conserved domain III of the TP53 DNA binding domain. This alteration was shown to have a loss of transactivation capacity in yeast-based functional studies (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 deficient at growth suppression and has a 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 variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This alteration has also 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly 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 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJun 14, 2023In 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 21343334). 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. ClinVar contains an entry for this variant (Variation ID: 428909). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 15951970, 33436392). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 172 of the TP53 protein (p.Val172Phe). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
Cadd
Benign
22
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.82
D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.84
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-4.6
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G
Pathogenic
0.0010
D;D;D;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
0.79
MutPred
0.84
Loss of MoRF binding (P = 0.0898);Loss of MoRF binding (P = 0.0898);.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0898);.;Loss of MoRF binding (P = 0.0898);Loss of MoRF binding (P = 0.0898);Loss of MoRF binding (P = 0.0898);.;.;Loss of MoRF binding (P = 0.0898);.;.;.;.;
MVP
0.99
MPC
1.9
ClinPred
1.0
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.72

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1131691043; hg19: chr17-7578416; COSMIC: COSV52672812; COSMIC: COSV52672812; API