rs760043106
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000546.6(TP53):c.584T>G(p.Ile195Ser) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I195T) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 9.32
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 11 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 chr17-7674947-A-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97
PP5
Variant 17-7674947-A-C is Pathogenic according to our data. Variant chr17-7674947-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 376619.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 15, 2024 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Hereditary cancer-predisposing syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 03, 2019 | This missense variant replaces isoleucine with serine at codon 195 of the TP53 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. A different variant affecting the same codon, c.584T>C (p.Ile195Thr), is considered to be disease-causing (ClinVar variation ID: 216077), suggesting that isoleucine or similar amino acid at this position is important for the protein function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant to be non-functional in yeast transcription activation assays and in a cell proliferation assay in p53-null mammalian cells (PMID: 12826609, 23897043, 29979965). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, clinical evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
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;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
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;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;.;.;.;.;.;.;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;D;.
Polyphen
D;.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D
Vest4
MutPred
Gain of disorder (P = 0.0013);Gain of disorder (P = 0.0013);.;.;.;.;.;.;.;Gain of disorder (P = 0.0013);.;Gain of disorder (P = 0.0013);Gain of disorder (P = 0.0013);Gain of disorder (P = 0.0013);.;.;Gain of disorder (P = 0.0013);.;.;.;.;
MVP
MPC
2.0
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