rs746601313
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. BS2PP3PM2_SupportingPM1_SupportingBS3
This summary comes from the ClinGen Evidence Repository: The NM_000546.6:c.760A>G variant in TP53 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 254 (p.Ile254Val). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: ClinVar SCV000545356.10). This variant has an allele frequency of 0.000006821 (11/1612700 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). 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). Computational predictor scores (BayesDel = 0.1708; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID:30311369) (PM1_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: BS2_Moderate, PM2_Supporting, BS3, PP3, PM1_Supporting. (Bayesian Points: -3; VCEP specifications version 2.2; 1/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA001720/MONDO:0018875/009
Frequency
Genomes: ๐ 0.0000066 ( 0 hom., cov: 30)
Exomes ๐: 0.0000068 ( 0 hom. )
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
9
5
5
Clinical Significance
Conservation
PhyloP100: 8.02
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 Likely_benign. Variant got -5 ACMG points.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
BS2
For more information check the summary or visit ClinGen Evidence Repository.
BS3
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000659 AC: 1AN: 151808Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251476Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
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GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460892Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726838
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GnomAD4 genome 0.00000659 AC: 1AN: 151808Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74150
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ClinVar
Significance: Likely benign
Submissions summary: Uncertain:7Benign:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome Uncertain:2Benign:1
| Likely benign, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Jan 16, 2025 | The NM_000546.6:c.760A>G variant in TP53 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 254 (p.Ile254Val). This variant has been observed in 4-7 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Moderate; Internal lab contributor: ClinVar SCV000545356.10). This variant has an allele frequency of 0.000006821 (11/1612700 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). 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). Computational predictor scores (BayesDel = 0.1708; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_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: BS2_Moderate, PM2_Supporting, BS3, PP3, PM1_Supporting. (Bayesian Points: -3; VCEP specifications version 2.2; 1/16/2025). - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 254 of the TP53 protein (p.Ile254Val). This variant is present in population databases (rs746601313, gnomAD 0.003%). This missense change has been observed in individual(s) with TP53-related conditions (PMID: 21348412, 27242894, 28861920, 29769598, 32817165; internal data). ClinVar contains an entry for this variant (Variation ID: 406605). 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 | Sep 17, 2023 | This missense variant replaces isoleucine with valine at codon 254 of the TP53 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that this variant does not impair TP53 protein function (PMID: 12826609, 29979965, 30224644). This variant is said to be reported in a family affected with Li-Fraumeni syndrome but detailed clinical findings were not provided for evaluation (PMID: 21348412). This variant has been reported in individuals affected with breast cancer (PMID: 33471991), non-small cell lung cancer (PMID: 27242894), and uveal melanoma (PMID: 29769598), as well as in control individuals unaffected with cancer (PMID: 28861920, 33471991). Other variants at this position have been classified as pathogenic (ClinVar Variation ID: 856299) suggesting the amino acid residue is important for function. This variant has been identified in 4/251476 individuals 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. - |
not provided Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 12, 2022 | The frequency of this variant in the general population, 0.000035 (4/113752 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in families suspected of Li-Fraumeni Syndrome (LFS) (PMID: 21348412 (2010), 32817165 (2020)), in individuals with acute lymphocytic leukemia (ALL) (PMID: 23403321 (2013)), non-small cell lung cancer (NSCLC) (PMID: 27242894 (2016)), uveal melanoma (PMID: 29769598 (2018)), and pancreatic cancer (PMID: 35047863 (2022)). It has also been reported in a large breast cancer association study in affected and unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/TP53). Functional studies found this variant did not have an effect on TP53 protein function (PMID: 12826609 (2003), 29979965 (2018), 30224644 (2018)). 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21348412, 16596195, 10225439, 22634756, 25612911, 10811497, 14559903, 24663046, 23403321, 15370252, 25675526, 27242894, 25801821, 28975018, 27930734, 29979965, 28861920, 29769598, 30840781) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2022 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 06, 2023 | This missense variant replaces isoleucine with valine at codon 254 of the TP53 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that this variant does not impair TP53 protein function (PMID: 12826609, 29979965, 30224644). This variant is said to be reported in a family affected with Li-Fraumeni syndrome but detailed clinical findings were not provided for evaluation (PMID: 21348412). This variant has been reported in individuals affected with breast cancer (PMID: 33471991), non-small cell lung cancer (PMID: 27242894), and uveal melanoma (PMID: 29769598), as well as in control individuals unaffected with cancer (PMID: 28861920, 33471991). Other variants at this position have been classified as pathogenic (ClinVar Variation ID: 856299) suggesting the amino acid residue is important for function. This variant has been identified in 4/251476 individuals 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. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 24, 2018 | - - |
Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0585442:Bone osteosarcoma;C0699790:Carcinoma of colon;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Malignant glioma Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Laboratory of Medical Genetics Unit, Bambino Gesรน Children's Hospital | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
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
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;.;.;.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N
REVEL
Pathogenic
Sift
Pathogenic
D;T;.;.;.;.;.;.;.;T;.;.;T;T;.;.;T;.;.;D
Sift4G
Pathogenic
D;T;T;T;T;T;T;T;T;D;T;T;T;T;T;T;D;T;D;T
Polyphen
D;.;.;.;.;.;.;.;.;P;.;P;B;P;.;.;P;.;.;.
Vest4
MVP
MPC
0.26
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at