17-7674893-C-G

Variant summary

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

The NM_000546.6(TP53):​c.638G>C​(p.Arg213Pro) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TP53
NM_000546.6 missense

Scores

13
5
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) 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 chr17-7674893-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 17-7674893-C-G is Pathogenic according to our data. Variant chr17-7674893-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 231214.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
TP53NM_000546.6 linkc.638G>C p.Arg213Pro missense_variant Exon 6 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.638G>C p.Arg213Pro missense_variant Exon 6 of 11 1 NM_000546.6 ENSP00000269305.4 P04637-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2
Jan 12, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R213P pathogenic mutation (also known as c.638G>C), located in coding exon 5 of the TP53 gene, results from a G to C substitution at nucleotide position 638. The arginine at codon 213 is replaced by proline, an amino acid with dissimilar properties. This alteration was first described segregating with disease in a family satisfying clinical criteria for classic Li-Fraumeni syndrome (LFS) (Dockhorn-Dworniczak B et al, Eur. J. Cancer 1996 Jul; 32A(8):1359-65). Tumor analyses from p.R213P-carriers in this family revealed increased nuclear p53 staining as well as somatic loss-of-heterozygosity (LOH). 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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al., Science 1994 Jul; 265(5170):346-55). In addition, another alteration at the same codon, p.R213Q, has been identified in multiple suspected-LFS patients and is considered pathogenic (Achatz MI et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102; Becherini et al. Neuropathol Appl Neurobiol. 2008 Oct;34(5):564-8; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

- -

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

- -

Li-Fraumeni syndrome Pathogenic:1
May 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 213 of the TP53 protein (p.Arg213Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni Syndrome (PMID: 8869100). It has also been observed to segregate with disease in related individuals. This variant is also known as CGA to CCA transversion. ClinVar contains an entry for this variant (Variation ID: 231214). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg213 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 6736287, 16494995, 17541742, 18208484, 19468865, 20522432, 23259501). 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. -

not specified Pathogenic:1
Nov 02, 2016
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Sep 17, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: non-functional transactivation and dominant negative effect (PMID: 21343334, 17606709, 12826609, 29979965, 30224644); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12826609, 15510160, 18208484, 29979965, 8023157, 17541742, 33990091, 17606709, 21343334, 8869100, 16494995, 19468865, 20522432, 26619011, AndersonJE2018[Article], 33671606, 37437600, 30840781, 11920788, 24549055, 25584008, 31105275, 34863587, 32817165, 34273903, 30224644) -

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
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.64
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
0.95
D
MutationAssessor
Pathogenic
3.3
.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-6.6
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G
Uncertain
0.0020
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
0.98
MutPred
0.98
Gain of glycosylation at S215 (P = 0.0483);Gain of glycosylation at S215 (P = 0.0483);.;.;.;.;.;.;.;Gain of glycosylation at S215 (P = 0.0483);.;Gain of glycosylation at S215 (P = 0.0483);Gain of glycosylation at S215 (P = 0.0483);Gain of glycosylation at S215 (P = 0.0483);.;.;Gain of glycosylation at S215 (P = 0.0483);.;.;.;.;
MVP
1.0
MPC
2.0
ClinPred
1.0
D
GERP RS
4.3
Varity_R
1.0
gMVP
0.92

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: rs587778720; hg19: chr17-7578211; COSMIC: COSV52693072; COSMIC: COSV52693072; API