rs770374782
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS2_SupportingBS3
This summary comes from the ClinGen Evidence Repository: Transactivation assays show retained function according to Kato, et al (PMID:12826609) and there is no evidence of a dominant negative effect or loss of function according to Giacomelli et al. (PMID:30224644) and Kotler et al. (PMID:29979965) (BS3). Additionally, this variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C15 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). In summary, TP53 c.868C>T; p.Arg290Cys meets criteria to be classified as Likely Benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3; BP4; BS2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA001448/MONDO:0007903/009
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.868C>T | p.Arg290Cys | missense_variant | 8/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.868C>T | p.Arg290Cys | missense_variant | 8/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 152088Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251486Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135918
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727244
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 152088Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74290
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 26, 2023 | This missense variant replaces arginine with cysteine at codon 290 of the TP53 protein. Computational prediction suggests that this variant may impact protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to function normally in yeast transactivation assays (PMID: 12826609) and human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with early-onset breast cancer (PMID: 25503501) and osteosarcoma (PMID: 25512523). This variant has been identified in 4/282870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 290 of the TP53 protein (p.Arg290Cys). This variant is present in population databases (rs770374782, gnomAD 0.005%). This missense change has been observed in individual(s) with breast cancer and/or osteosarcoma (PMID: 25503501, 25512523). ClinVar contains an entry for this variant (Variation ID: 216472). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 17311302, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 09, 2019 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12909720, 25589618, 8338955, 24729566, 23718828, 24113472, 21159888, 22205265, 22568511, 18843282, 17311302, 23200980, 19533719, 21643842, 25256751, 21118481, 22678923, 27101868, 28502725, 28861920, 30483911, 25503501, 25512523, 29625052, 29979965, 30720243, 30840781) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 16, 2023 | In the published literature, it has been reported individuals with early-onset breast cancer patient (PMID: 25503501 (2015)), lung cancer (PMID: 29625052 (2018)), and pancreatic cancer (PMID: 23200980 (2013)). Functional studies have shown the variant to retain transactivation activity and retaining anti-proliferative activity (IARC TP53 (https://p53.iarc.fr/), PMID: 12826609 (2003), 17311302 (2007), 29979965 (2018)). The frequency of this variant in the general population, 0.000014 (4/282870 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 12, 2023 | This missense variant replaces arginine with cysteine at codon 290 of the TP53 protein. Computational prediction suggests that this variant may impact protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to function normally in yeast transactivation assays (PMID: 12826609) and human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with early-onset breast cancer (PMID: 25503501) and osteosarcoma (PMID: 25512523). This variant has been identified in 4/282870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 04, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Li-Fraumeni syndrome 1 Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | May 13, 2021 | Transactivation assays show retained function according to Kato, et al (PMID: 12826609) and there is no evidence of a dominant negative effect or loss of function according to Giacomelli et al. (PMID: 30224644) and Kotler et al. (PMID: 29979965) (BS3). Additionally, this variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C15 (BP4). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). In summary, TP53 c.868C>T; p.Arg290Cys meets criteria to be classified as Likely Benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3; BP4; BS2_supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at