Menu
GeneBe

rs28934575

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000546.6(TP53):c.733G>T(p.Gly245Cys) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G245S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Consequence

TP53
NM_000546.6 missense

Scores

15
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:23

Conservation

PhyloP100: 7.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 13 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 chr17-7674230-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12365.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 17-7674230-C-A is Pathogenic according to our data. Variant chr17-7674230-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TP53NM_000546.6 linkuse as main transcriptc.733G>T p.Gly245Cys missense_variant 7/11 ENST00000269305.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TP53ENST00000269305.9 linkuse as main transcriptc.733G>T p.Gly245Cys missense_variant 7/111 NM_000546.6 P1P04637-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:23
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJun 18, 2022- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 15, 1992- -
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJun 18, 2022- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 13, 2022The p.G245C pathogenic mutation (also known as c.733G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 733. The glycine at codon 245 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was first described in a patient diagnosed with an osteosarcoma at age 11, and two first degree relatives that developed sarcomas at ages 19 and 58 (Malkin et al. Science. 1990 Nov 30;250(4985):1233-8.) 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 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). Another group showed the p.G245C mutation leading to greatly reduced DNA binding ability compared to wild-type p53 (Malcikova et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). In addition, this site is a mutation hotspot, with multiple other alterations at this same codon being described in individuals with Li-Fraumeni Syndrome (Srivastava S et al. Nature. 1990 Dec.; 348(6303):747-9; Wong P et al. Gastroenterology. 2006 Jan; 130(1):73-9; Xu J et al. Sci Rep. 2014 ; 4():4223). 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 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 17, 2023This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 245 of the TP53 protein (p.Gly245Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 1978757, 10922393, 23406775, 25584008, 26681312). ClinVar contains an entry for this variant (Variation ID: 12349). 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: 1631137, 12826609, 20128691, 21343334, 26205489). This variant disrupts the p.Gly245 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565143, 12826609, 12917626, 15722483, 17311302, 20128691, 21343334, 24122735). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Glioblastoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingCZECANCA consortiumJun 11, 2019- -
Prostate adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Carcinoma of esophagus Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Gastric adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Breast neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Squamous cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 13, 2019Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25584008, 17311302, 25743702, 24122735, 29489754, 20128691, 17606709, 26681312, 15722483, 12826609, 1631137, 29752319, 27323394, 1978757, 22803791, 23406775, 1565143, 21343334, 10629033, 16337994, 29979965, 16401470, 24573247, 30720243, 30840781) -
Ovarian serous cystadenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Brainstem glioma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Uterine carcinosarcoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Pancreatic adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Neoplasm of brain Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Transitional cell carcinoma of the bladder Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Squamous cell carcinoma of the head and neck Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -
Neoplasm of the large intestine Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 31, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
Cadd
Pathogenic
28
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;D;.;.;.;.;D;D;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.79
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
0.70
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.90
D
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-8.4
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G
Pathogenic
0.0
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
0.90
MutPred
0.99
Loss of disorder (P = 0.0891);Loss of disorder (P = 0.0891);.;.;.;.;.;.;.;Loss of disorder (P = 0.0891);.;Loss of disorder (P = 0.0891);Loss of disorder (P = 0.0891);Loss of disorder (P = 0.0891);.;.;Loss of disorder (P = 0.0891);.;.;.;.;
MVP
0.99
MPC
0.40
ClinPred
1.0
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
0.85

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: rs28934575; hg19: chr17-7577548; COSMIC: COSV52661744; COSMIC: COSV52661744; API