ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.105G>C (p.Leu35Phe) (rs121912661)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131759 SCV000186802 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
GeneDx RCV000481187 SCV000566581 uncertain significance not provided 2017-11-20 criteria provided, single submitter clinical testing This variant is denoted TP53 c.105G>C at the cDNA level, p.Leu35Phe (L35F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTC). This variant has been reported in the tumors of individuals with hepatocellular carcinoma and lymphoma (Nishida 1993, Churchill 2015). This variant 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 Leu35Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. TP53 Leu35Phe is located in the transactivation domain (Bode 2004, Pessoa 2014). In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Leu35Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000131759 SCV000686716 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-20 criteria provided, single submitter clinical testing
Invitae RCV000633325 SCV000754547 uncertain significance Li-Fraumeni syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 35 of the TP53 protein (p.Leu35Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 28288110). ClinVar contains an entry for this variant (Variation ID: 142562). An experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.