NM_000546.6:c.358A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000546.6(TP53):​c.358A>C​(p.Lys120Gln) variant causes a missense change. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K120E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TP53
NM_000546.6 missense

Scores

12
6
1

Clinical Significance

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

Conservation

PhyloP100: 6.45
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 Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 16 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 chr17-7676011-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141098.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TP53NM_000546.6 linkc.358A>C p.Lys120Gln missense_variant Exon 4 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.358A>C p.Lys120Gln missense_variant Exon 4 of 11 1 NM_000546.6 ENSP00000269305.4 P04637-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Jun 02, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.K120Q variant (also known as c.358A>C), located in coding exon 3 of the TP53 gene, results from an A to C substitution at nucleotide position 358. The lysine at codon 120 is replaced by glutamine, an amino acid with similar properties. 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. USA. 2003 Jul;100:8424-9). 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

- -

Li-Fraumeni syndrome Uncertain:1
Feb 05, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamine at codon 120 of the TP53 protein (p.Lys120Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 423255). This variant has been reported to have conflicting or insufficient data to determine the effect on TP53 protein function (PMID: 12826609, 15781620, 27341992, 24219989, 26851285). 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. -

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

- -

not provided Uncertain:1
Jan 30, 2017
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is denoted TP53 c.358A>C at the cDNA level, p.Lys120Gln (K120Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAG>CAG). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in a breast carcinoma (Végran 2007). The p53 Lys120 residue is acetylated in response to DNA damage, a process that promotes apoptosis (Sykes 2006). Although TP53 Lys120Gln mimics Lys120 acetylation, apoptotic activity resulting from this variant alone has not been found to differ from wild-type, but was elevated compared to wild-type after exposure to UV radiation (Chang 2013, Yun 2016). While TP53 Lys120Gln is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database, other studies have either found normal transactivation or only observed an impact for a few pro-apoptotic targets (Kato 2003, Kakudo 2005, Chang 2013, Monteith 2016, Yun 2016). TP53 Lys120Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Lys120Gln occurs at a position that is conserved across species and is located in the DNA binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether TP53 Lys120Gln is pathogenic or benign. We consider it to be a variant of uncertain significance. -

TP53-related disorder Uncertain:1
Jun 13, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The TP53 c.358A>C variant is predicted to result in the amino acid substitution p.Lys120Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.26
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
D;D;.;D;.;.;.;.;.;.;D;.;D;D;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
3.3
.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.3
D;D;.;D;.;.;D;D;.;.;D;.;D;.;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0070
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;.
Polyphen
1.0
D;.;.;D;.;D;D;D;.;.;D;.;D;.;.
Vest4
0.72
MutPred
0.69
Loss of ubiquitination at K120 (P = 0.0155);Loss of ubiquitination at K120 (P = 0.0155);.;Loss of ubiquitination at K120 (P = 0.0155);.;Loss of ubiquitination at K120 (P = 0.0155);Loss of ubiquitination at K120 (P = 0.0155);Loss of ubiquitination at K120 (P = 0.0155);.;.;Loss of ubiquitination at K120 (P = 0.0155);.;Loss of ubiquitination at K120 (P = 0.0155);Loss of ubiquitination at K120 (P = 0.0155);Loss of ubiquitination at K120 (P = 0.0155);
MVP
0.98
MPC
1.7
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.94
gMVP
0.74

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: rs121912658; hg19: chr17-7579329; COSMIC: COSV53685479; COSMIC: COSV53685479; API