TP53 NM_000546.5:c.1031T>C, Leu344Pro

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9704930, 9704931, 27754743]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8649785].

The p.L344P pathogenic mutation (also known as c.1031T>C), located in coding exon 9 of the TP53 gene, results from a T to C substitution at nucleotide position 1031. The leucine at codon 344 is replaced by proline, an amino acid with some similar properties. This alteration occurs at a well-characterized residue involved in the tetramerization of the p53 protein (Mateu and Fersht, EMBO J. 1998 May; 17(10):2748-58). This alteration has been identified in families meeting clinical criteria for Li-Fraumeni syndrome with a tumor spectrum including osteosarcomas, leiomyosarcomas, and early onset breast cancer (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9;Varley J et al., Oncogene 1996 Jun; 12(11):2437-42 ). Evidence from both functional and structural analyses indicate that this alteration is structurally unstable and unable to form tetramers (Ishioka C et al., Oncogene 1995 Apr; 10(8):1485-92; Davison T et al., Oncogene 1998 Aug; 17(5):651-6). Additional functional studies conducted in both yeast and mammalian cells have demonstrated that this alteration produces a protein that cannot activate transcription, is defective in DNA binding, suppression of cell growth, and induction of apoptosis (Monti P et al., Mol. Cancer Res. 2011 Mar; 9(3):271-9. Malcikova Jet al., Biol. Chem. ; 391(2-3):197-205; Lomax M et al., Oncogene 1998 Aug; 17(5):643-9). Based on the available evidence, p.L344P is classified as a pathogenic mutation.

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 344 of the TP53 protein (p.Leu344Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 8649785, 17606709, 20522432). ClinVar contains an entry for this variant (Variation ID: 12375). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 10064694, 17606709, 20128691). For these reasons, this variant has been classified as Pathogenic.