ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV001527097 SCV001737940 likely benign Li-Fraumeni syndrome 1 2020-09-17 reviewed by expert panel curation This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). 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 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). In summary, TP53 c.105G>C (p.Leu35Phe) 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: BP4, BS3, BS2_supporting.
Ambry Genetics RCV000131759 SCV000186802 likely benign Hereditary cancer-predisposing syndrome 2019-12-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes)
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 Health, Inc 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 2020-09-09 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). This variant has been reported not to substantially affect TP53 protein function (PMID: 12826609, 30840781). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002101 SCV001159948 uncertain significance not specified 2018-09-24 criteria provided, single submitter clinical testing The TP53 c.105G>C; p.Leu35Phe variant (rs121912661) has been reported in the germline of an individual with breast cancer who had loss of the alternative allele in breast tumor and no concurrent mutations in BRCA1/BRCA2 (Davies 2017, Supplementary Table 4). It has also been reported in the tumor of a patient with hepatocellular carcinoma (Nishida 1993). This variant is reported in the IARC TP53 database as having functional transactivation activity (see link). It is classified as uncertain by multiple laboratories in ClinVar (Variation ID: 142562), and found in the general population with a low overall allele frequency of 0.003% (1/30928 alleles) in the Genome Aggregation Database. The leucine at codon 35 is weakly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Leu35Phe variant is uncertain at this time. REFERENCES Link to IARC database: http://p53.iarc.fr/TP53GeneVariations.aspx Davies H et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med. 2017 Apr;23(4):517-525. Nishida N et al. Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma. Cancer Res. 1993 Jan 15;53(2):368-72.

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