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

gnomAD frequency: 0.00001  dbSNP: rs746601313

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV001724015	SCV001949914	likely benign	Li-Fraumeni syndrome 1	2021-08-03	reviewed by expert panel	curation	This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has been observed in 7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). In summary, TP53 c.760A>G (p.Ile254Val) 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: PP3, BS3, BS2_Supporting.
Invitae	RCV000477424	SCV000545356	uncertain significance	Li-Fraumeni syndrome	2024-01-11	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; Invitae). ClinVar contains an entry for this variant (Variation ID: 406605). 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, 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.
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)
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.
Color Diagnostics, LLC DBA Color Health	RCV000573924	SCV000686769	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	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.
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
Genetic Services Laboratory, University of Chicago	RCV001821241	SCV002067548	uncertain significance	not specified	2018-10-24	criteria provided, single submitter	clinical testing
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.
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.