rs1057520008
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.613T>G(p.Tyr205Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,832 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y205C) has been classified as Likely 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 AF: 0.00000659 AC: 1AN: 151832Hom.: 0 Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461890Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 727248
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151832Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74122
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:1Uncertain:1
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]. -
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Li-Fraumeni syndrome Pathogenic:1
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 205 of the TP53 protein (p.Tyr205Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with sarcoma (PMID: 29070607). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376686). Invitae Evidence Modeling incorporating data from in vitro 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: 12826609, 29979965, 30224644). This variant disrupts the p.Tyr205 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10922393, 12826609, 16861262, 17724467, 20505364, 21356188, 29324801, 29979965, 30224644). 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 provided Pathogenic:1
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression ability (Kato et al., 2003; Giacomelli et al., 2018; Kotler et al., 2018); 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: 15510160, 20505364, 17724467, 16861262, 12826609, 26619011, 30224644, 29979965, 29070607, 10922393, 29324801, 21356188, 30840781) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at