ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.760A>G (p.Ile254Val)

gnomAD frequency: 0.00001  dbSNP: rs746601313
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000477424 SCV001949914 likely benign Li-Fraumeni syndrome 2025-01-16 reviewed by expert panel curation 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).
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000573924 SCV006059710 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-20 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital RCV004776285 SCV005382088 uncertain significance Malignant glioma criteria provided, single submitter research
All of Us Research Program, National Institutes of Health RCV000477424 SCV004823767 uncertain significance Li-Fraumeni syndrome 2023-09-17 criteria provided, single submitter clinical testing 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485986 SCV004221373 uncertain significance not provided 2022-12-12 criteria provided, single submitter clinical testing 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.
Genetic Services Laboratory, University of Chicago RCV001821241 SCV002067548 uncertain significance not specified 2018-10-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000765398 SCV000896673 uncertain significance Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000573924 SCV000686769 uncertain significance Hereditary cancer-predisposing syndrome 2024-07-08 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this variant does not impair function in yeast based transcriptional transactivation studies, and human cell proliferation and growth supression assays (PMID: 12826609, 29979965, 30224644). This variant was reported in a family suspected of Li-Fraumeni syndrome (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 (p.Ile254Asn; 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.
Ambry Genetics RCV000573924 SCV000664384 likely benign Hereditary cancer-predisposing syndrome 2022-07-11 criteria provided, single submitter clinical testing 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.
GeneDx RCV000485986 SCV000566316 likely benign not provided 2019-06-24 criteria provided, single submitter clinical testing 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)
Labcorp Genetics (formerly Invitae), Labcorp RCV000477424 SCV000545356 uncertain significance Li-Fraumeni syndrome 2024-12-19 criteria provided, single submitter clinical testing 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.

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