17-7673796-C-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.824G>T(p.Cys275Phe) 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. C275Y) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 31)
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
15
2
2
Clinical Significance
Conservation
PhyloP100: 7.91
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 DNA (size 7) in uniprot entity P53_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr17-7673796-C-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 17-7673796-C-A is Pathogenic according to our data. Variant chr17-7673796-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 376582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 12, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys275 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7887414, 12826609, 14584079, 17606709, 21343334; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 18937320, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 376582). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 17567834, 18937320). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 275 of the TP53 protein (p.Cys275Phe). - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 08, 2024 | The p.C275F pathogenic mutation (also known as c.824G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 824. The cysteine at codon 275 is replaced by phenylalanine, an amino acid with highly dissimilar properties. 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). 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). This alteration was identified in an individual diagnosed with breast cancer at 30 (Trkova M et al. Cancer, 2007 Aug;110:694-702). In addition, this alteration was identified in a family that met classic Li-Fraumeni criteria (Capra V et al. Pediatr Blood Cancer, 2009 Feb;52:303-4). This alteration was also identified in an individual diagnosed with gastric cancer at 35 (Masciari S et al. Genet Med, 2011 Jul;13:651-7). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Another variant at the same codon, p.C275Y (c.824G>A), has been identified in multiple families that were diagnosed with Li-Fraumeni syndrome (Frebourg T et al. Am. J. Hum. Genet. 1995 Mar; 56(3):608-15; Lynch HT et al. Cancer. 2003 Nov 1;98(9):1947-57). 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 variant is interpreted as a disease-causing mutation. - |
Ovarian neoplasm Pathogenic:1
| Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;D;D;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G
Pathogenic
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;.;.;.
Vest4
MutPred
Gain of MoRF binding (P = 0.1412);.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.1412);.;Gain of MoRF binding (P = 0.1412);Gain of MoRF binding (P = 0.1412);Gain of MoRF binding (P = 0.1412);.;.;Gain of MoRF binding (P = 0.1412);.;.;.;
MVP
MPC
0.46
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at