chr17-7673749-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000546.6(TP53):​c.871A>G​(p.Lys291Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. K291N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.06

Publications

1 publications found
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]
TP53 Gene-Disease associations (from GenCC):
  • breast cancer
    Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
  • Li-Fraumeni syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
  • Li-Fraumeni syndrome 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
  • adrenocortical carcinoma, hereditary
    Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
  • sarcoma
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • bone marrow failure syndrome 5
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • colorectal cancer
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • choroid plexus carcinoma
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 13 uncertain in NM_000546.6
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.42101437).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TP53NM_000546.6 linkc.871A>G p.Lys291Glu missense_variant Exon 8 of 11 ENST00000269305.9 NP_000537.3 P04637-1K7PPA8Q53GA5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TP53ENST00000269305.9 linkc.871A>G p.Lys291Glu missense_variant Exon 8 of 11 1 NM_000546.6 ENSP00000269305.4 P04637-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461894
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
727248
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1112012
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:2
Nov 20, 2023
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces lysine with glutamic acid at codon 291 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant is functional in yeast transcriptional transactivation, human cell growth suprression and proliferation, and apoptosis induction assays (PMID: 15781620, 12826609, 29979965, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Dec 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 291 of the TP53 protein (p.Lys291Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 480951). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 15781620). 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. -

Hereditary cancer-predisposing syndrome Uncertain:2
Jun 18, 2022
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 06, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.K291E variant (also known as c.871A>G), located in coding exon 7 of the TP53 gene, results from an A to G substitution at nucleotide position 871. The lysine at codon 291 is replaced by glutamic acid, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein, was not found to have an effect on transactivation capacity, but is 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). In addition, this variant was shown to induce apoptosis at rates higher than wild-type, however there was no evidence that this alteration had an effect on the protein's ability to transactivate TP53 target genes (Kakudo Y et al. Cancer Res. 2005 Mar 15;65(6):2108-14). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no 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 amino acid position is well conserved in available vertebrate species; however, glutamic acid is the reference amino acid in other 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 this alteration remains unclear. -

Li-Fraumeni syndrome 1 Uncertain:1
Jun 18, 2022
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Adrenocortical carcinoma, hereditary Uncertain:1
Jun 14, 2023
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.025
T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Benign
0.42
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.1
.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
PhyloP100
1.1
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.5
N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N
REVEL
Uncertain
0.56
Sift
Benign
0.15
T;.;.;.;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T
Sift4G
Benign
0.28
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.95, 0.90, 0.98
.;.;.;.;.;.;.;.;P;.;P;D;P;.;.;P;.;.;.
Vest4
0.27
MutPred
0.21
Loss of ubiquitination at K291 (P = 0.0019);.;.;.;.;.;.;.;Loss of ubiquitination at K291 (P = 0.0019);.;Loss of ubiquitination at K291 (P = 0.0019);Loss of ubiquitination at K291 (P = 0.0019);Loss of ubiquitination at K291 (P = 0.0019);.;.;Loss of ubiquitination at K291 (P = 0.0019);.;.;.;
MVP
0.85
MPC
0.29
ClinPred
0.78
D
GERP RS
5.1
PromoterAI
-0.0088
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.59
gMVP
0.69
Mutation Taster
=29/71
disease causing

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

Other links and lift over

dbSNP: rs1555525126; hg19: chr17-7577067; COSMIC: COSV52984891; API