TP53 NM_000546.5:c.589G>A, Val197Met

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. 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: 16494995, 23259501, 31321604; Myriad internal data].

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 197 of the TP53 protein (p.Val197Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni (PMID: 16494995, 31321604; internal data). ClinVar contains an entry for this variant (Variation ID: 188060). 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: 21343334). This variant disrupts the p.Val197 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 33818021), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

The p.V197M variant (also known as c.589G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 589. The valine at codon 197 is replaced by methionine, an amino acid with highly similar properties. This variant has been identified in individuals with features consistent with Li-Fraumeni or Li-Fraumeni-Like criteria (Achatz M et al., Cancer Lett. 2007 Jan; 245(1-2):96-102; Fortes F et al. Braz. J. Med. Biol. Res. 2015 Jul;48(7):610-5; external communication). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation capacity in yeast based assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant has been detected in at least one individual 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 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.