ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.763A>T (p.Ile255Phe)

dbSNP: rs1057519995
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001301950 SCV001491135 uncertain significance Li-Fraumeni syndrome 2020-06-14 criteria provided, single submitter clinical testing This variant has been reported to affect TP53 protein function (PMID: 12826609, 29979965, 30224644, 30840781). This sequence change replaces isoleucine with phenylalanine at codon 255 of the TP53 protein (p.Ile255Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376621). This variant disrupts the p.Ile255 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21761402, Invitae). 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.
Ambry Genetics RCV002392946 SCV002670637 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-13 criteria provided, single submitter clinical testing The p.I255F variant (also known as c.763A>T), located in coding exon 6 of the TP53 gene, results from an A to T substitution at nucleotide position 763. The isoleucine at codon 255 is replaced by phenylalanine, an amino acid with highly similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient 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 alteration has been reported in a cohort of individuals diagnosed with breast cancer (Alsner J et al. Clin. Cancer Res. 2000 Oct;6(10):3923-31), and has numerous somatic observations (cancerhotspots.org; IARCTP53 database). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Database of Curated Mutations (DoCM) RCV000436676 SCV000508688 likely pathogenic B-cell chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444896 SCV000508689 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425759 SCV000508690 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436027 SCV000508691 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418615 SCV000508692 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428426 SCV000508693 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435616 SCV000508694 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785451 SCV000924023 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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