TP53 NM_000546.6:c.1010G>T, Arg337Leu

The p.R337L pathogenic mutation (also known as c.1010G>T), located in coding exon 9 of the TP53 gene, results from a G to T substitution at nucleotide position 1010. The arginine at codon 337 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (Ambry internal data). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has no dominant negative effect (Giacomelli AO et al. Nat Genet, 2018 Oct;50:1381-1387). This variant is reported to have non-functional transactivation in yeast-based assays (Kato S et al. Proc Natl Acad Sci U S A, 2003 Jul;100:8424-9). This variant is in the tetramerization domain of the TP53 protein and was not able to form tetramers (Kawaguchi T et al. Oncogene. 2005 Oct;24:6976-81). A thermal denaturation study predicted that several tetramerization domain mutants, including p.R337L, are thermally unstable at or near body temperature, and the authors note that earlier studies showed that p53 proteins with the p.R337L mutation exhibit an overall decrease in DNA-binding and transactivation activity (Kamada, R et al. J Biol Chem. 2011 Jan 7;286(1):252-8). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Based on internal structural analysis, this alteration is structurally deleterious (Ambry internal data). Other variant(s) at the same codon, p.R337H (c.1010G>A), have been identified in individual(s) with features consistent with Li-Fraumeni syndrome (Garritano et al. Hum Mutat. 2010 Feb;31(2):143-50; Ribeiro RC et al. Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9330-5; Giacomazzi J et al, PLoS ONE 2014 ; 9(6):e99893). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this variant is interpreted as a disease-causing mutation.

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9766574, 16007150, 19454241, 9704930, 10653977, 9704931, 20978130]. This variant is expected to disrupt protein structure [Myriad internal data, PMID: 20978130].