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
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
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. -
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Li-Fraumeni syndrome 1 Pathogenic:1
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Li-Fraumeni syndrome Pathogenic:1
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
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not provided Pathogenic:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at