TP53 NM_000546.5:c.1009C>T, Arg337Cys

Variant summary: TP53 c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change located in the p53, tetramerisation domain (IPR010991) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250834 control chromosomes (gnomAD). c.1009C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (e.g. Renaux-Petel_2017, Fischer_2018, Frone_2021). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (e.g. Lomax_1997, Kato_2003, Imagawa_2009, Fischer_2018). These studies indicate that the variant results in a substantial decrease in transcriptional activity compared to the WT protein and a reduction in tumor suppression functions including increased colony formation, decreased growth arrest, and impaired apoptotic response. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9150393, 20478780]. This variant is expected to disrupt protein structure [PMID: 20978130]. Functional studies indicate this variant impacts protein function [PMID: 9704930, 10653977, 9704931, 20978130, 9766574, 19454241, 9150393].

The p.R337C pathogenic mutation (also known as c.1009C>T), located in coding exon 9 of the TP53 gene, results from a C to T substitution at nucleotide position 1009. The arginine at codon 337 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with TP53-related disease (Ambry internal data). In addition, this variant has been detected in several individuals at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant in the tetramerization domain is reported as non-functional in yeast based assays of transactivation (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). A study conducted in human cell lines indicates that this alteration is deficient at growth suppression but has no dominant negative effect (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). 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, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 337 of the TP53 protein (p.Arg337Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni like syndrome (PMID: 9150393, 9452042, 17606709, 18511570, 20478780). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142536). 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: 9150393, 9704930, 9704931, 12826609, 20128691, 21343334). 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: 9704930, 10864200, 12826609, 16033918, 20407015). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.