17-7676040-C-G
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1PM1PM2PM5PP3PP5_Very_Strong
The NM_000546.6(TP53):c.329G>C(p.Arg110Pro) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R110H) has been classified as Likely benign.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.329G>C | p.Arg110Pro | missense_variant | 4/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.329G>C | p.Arg110Pro | missense_variant | 4/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 13, 2024 | This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 24076587, 29979965]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21552135, 23894400, 29070607]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 17, 2023 | The p.R110P pathogenic mutation (also known as c.329G>C), located in coding exon 3 of the TP53 gene, results from a G to C substitution at nucleotide position 329. The arginine at codon 110 is replaced by proline, an amino acid with dissimilar properties. This variant has been reported in two male individuals from separate families with Li-Fraumeni syndrome, one with gastric cancer at 32 years of age, and the other with two primary sarcomas at 37 and 44 years of age (Mitchell G et al. PLoS ONE. 2013; 8(7):e69026; Masciari S et al. Genet. Med. 2011 Jul; 13(7):651-7). This variant has also been reported and confirmed de novo in an individual with 2 soft tissue sarcomas, diagnosed at age 38 years and 44 years (Renaux-Petel M et al. J. Med. Genet. 2018 Mar;55(3):173-180). Multiple functional studies have demonstrated that this alteration is deficient in transcriptional activation, DNA binding, and induction of apoptosis (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Wang B et al. Cell Death Differ. 2014 Apr; 21(4):521-32). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition, 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Li-Fraumeni syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 110 of the TP53 protein (p.Arg110Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with classical Li-Fraumeni syndrome (LFS) (PMID: 21552135, 23894400, 29070607; Invitae). ClinVar contains an entry for this variant (Variation ID: 233627). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 23897043, 24076587). This variant disrupts the p.Arg110 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16778209, 21445056, 24076587; Invitae). 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. - |
Adrenocortical carcinoma, hereditary Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 25, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at