17-7669655-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM2_SupportingBP4BS3
This summary comes from the ClinGen Evidence Repository: The NM_000546.5:c.1136G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 379 (p.Arg379His). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has a BayesDel score ≤ -0.008 and Align GVGD (Zebrafish) is Class C0 (BP4_moderate). This variant has an allele frequency of 0.00002671 (2/74876 alleles) in the African/African American population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_supporting, BP4_moderate, BS3. (Bayesian Points: -5; VCEP specifications version 2.0, Date of Approval: 1/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584584/MONDO:0018875/009
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251418Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135892
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461826Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727224
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152056Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74276
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2025 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 379 of the TP53 protein (p.Arg379His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with colorectal cancer (PMID: 26086041). ClinVar contains an entry for this variant (Variation ID: 246221). Invitae Evidence Modeling incorporating data from in vitro 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, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 20, 2024 | This missense variant replaces arginine with histidine at codon 379 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported the mutant protein to be functional in yeast transactivation assays (IARC database and PMID: 12826609) and in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 26086041) as well as in individuals without cancer (PMID: 30287823, 32980694). This variant has been identified in 2/282792 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, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Jan 16, 2025 | The NM_000546.5:c.1136G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 379 (p.Arg379His). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has a BayesDel score ≤ -0.008 and Align GVGD (Zebrafish) is Class C0 (BP4_moderate). This variant has an allele frequency of 0.00002671 (2/74876 alleles) in the African/African American population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_supporting, BP4_moderate, BS3. (Bayesian Points: -5; VCEP specifications version 2.0, Date of Approval: 1/16/2025). - |
Li-Fraumeni syndrome 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 11, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 31, 2016 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2015 | This variant is denoted TP53 c.1136G>A at the cDNA level, p.Arg379His (R379H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been identified in at least one individual with early-onset colorectal cancer (Yurgelun 2015). TP53 Arg379His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. TP53 Arg379His occurs at a position that is not conserved and is located in the region of interaction with CARM1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether TP53 Arg379His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 15, 2024 | The TP53 c.1136G>A (p.Arg379His) variant has been reported in the published literature in an individual affected with colorectal cancer (PMID: 26086041 (2015)) as well as reportedly healthy individuals (PMID: 30287823 (2018), 32980694 (2020)). Functional studies reported this variant does not have a damaging effect to protein function (PMID: 12826609 (2003), 30224644 (2018)). The frequency of this variant in the general population, 0.0000071 (2/282792 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 conflicting predictions that this variant is deleterious or benign. 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 | Sep 06, 2022 | This missense variant replaces arginine with histidine at codon 379 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported the mutant protein to be functional in yeast transactivation assays (IARC database and PMID: 12826609) and in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with early-onset colorectal cancer (PMID: 26086041) as well as in individuals without cancer (PMID: 30287823, 32980694). This variant has been identified in 2/282792 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 | Oct 06, 2020 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at