ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.760A>G (p.Ile254Val) (rs746601313)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000477424 SCV000545356 uncertain significance Li-Fraumeni syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 254 of the TP53 protein (p.Ile254Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs746601313, ExAC 0.001%). This variant has been reported in three individuals affected with lung cancer (PMID: 27242894), in a family with suspected Li-Fraumeni syndrome (PMID: 21348412), in individuals affected with uveal melanoma (PMID: 29769598), and in two individuals undergoing genetic testing unselected for cancer history (PMID: 28861920). ClinVar contains an entry for this variant (Variation ID: 406605). This variant has been reported not to substantially affect TP53 protein function (PMID: 12826609, 30224644, 29979965). This variant disrupts the p.Ile254 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29070607). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. 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 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted TP53 c.760A>G at the cDNA level, p.Ile254Val (I254V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant has been observed in at least one family suggestive of Li-Fraumeni syndrome (Foretova 2010). TP53 Ile254Val is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Ile254Valwas not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Ile254Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573924 SCV000664384 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-07 criteria provided, single submitter clinical testing The p.I254V variant (also known as c.760A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 760. The isoleucine at codon 254 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in one family with a "certain probability of having LFS," however, no details were provided regarding this family's medical history (Foretova L et al. Klin Onkol 2010;23(6):388-400). This alteration has also been reported as a somatic alteration in a variety of tumor types (Foulkes WD et. al. Ann. Oncol. 2000 Mar;11(3):307-13; Chiaretti S et al. Haematologica 2013 May;98(5):e59-61; Starr JS et al. J. Clin. Oncol. 2015 Jun; 33(17):e74-6). In addition, a similar alteration at this position, p.I254T, was reported in a woman from a LFS family with breast cancer at age 36 (Patrier-Sallebert S et al. J. Med. Genet. 2015 Mar;52(3):145-6). The p.I254V variant is in the DNA binding domain of the TP53 protein and is predicted to affect several p53 isoforms; however, it is reported to have functional transactivation capacity (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additionally, studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000573924 SCV000686769 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-13 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, 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 non-small cell lung cancer (PMID: 27242894) and uveal melanoma (PMID: 29769598), as well as in control individuals unaffected with cancer (PMID: 28861920). 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; 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

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