TP53 NM_000546.5:c.1010G>C, Arg337Pro

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces arginine with proline at codon 337 of the TP53 protein (p.Arg337Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 20426520). ClinVar contains an entry for this variant (Variation ID: 177879). This variant has been reported to affect TP53 protein function (PMID: 12826609, 19454241, 29955864). This variant disrupts the p.Arg337 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10864200, 16033918, 16494995, 21192060). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

The p.R337P variant (also known as c.1010G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide position 1010. The arginine at codon 337 is replaced by proline, an amino acid with dissimilar properties. This alteration was identified in a 5 year old patient with acute lymphoblastic leukemia and adrenocortical carcinoma, as well as several family members with cancer (Karakas Z et al. Pediatr Hematol Oncol, 2010 May;27:297-305). This variant is in the oligomerization domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays, and loss of tetramer formation in studies conducted in human cell lines (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Fischer NW et al. J. Natl. Cancer Inst., 2018 12;110:1418-1421). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.