ClinVar Genomic variation as it relates to human health

This variant is denoted TP53 c.701A>G at the cDNA level and p.Tyr234Cys (Y234C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC) in exon 7. This TP53 Tyr234Cys has previously been identified in over 100 tumors as a somatic mutation, most frequently in tumors of the lung, ovaries, brain, breast, and bladder (Petitjean 2007). In addition, this mutation has been observed as a germline mutation in at least one patient with Li Fraumeni syndrome (Pepper 2003). Functional studies have shown loss of transcriptional activation, loss of growth arrest, and loss of induction of apoptosis for this mutation as compared to wild type (Smith 1999, Monti 2007, Monti 2011). Smith et al. (1999) identified that this mutation failed to suppress oncogenic transformation and instead acts as a gain of function mutation, enhancing oncogenic transformation. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Variant Server, suggesting it is not a common benign variant in these populations. This variant is a non-conservative amino acid, altering a position that is well conserved throughout evolution, and is located in the DNA domain which interacts with HIPK1, ZNF385A, FOXO42, and AXIN1 (UniProt). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. We therefore consider this mutation to be pathogenic. This variant has been seen apparently mosaic. The variant is found in ENDOM-HEREDIC panel(s).

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 234 of the TP53 protein (p.Tyr234Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of TP53-related conditions (PMID: 12695689, 26556299, 28724667; Invitae). ClinVar contains an entry for this variant (Variation ID: 127820). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 10229196, 16861262, 17606709, 21343334). For these reasons, this variant has been classified as Pathogenic.

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 10229196, 20505364].

The p.Y234C pathogenic mutation (also known as c.701A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 701. The tyrosine at codon 234 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with a personal history of B-CLL and leiomyosarcoma, and a family history of sarcoma, breast cancer, and leukemia (Pepper C et al. Cell Cycle. 2003 Jan-Feb;2(1):53-8). This alteration was also detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). This alteration has been shown to be deficient in transactivation and exhibits dominant negative properties in studies conducted in both yeast and mammalian cells (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). In addition, two other alterations at this position (p.Y234D, p.Y234H) have been identified in patients meeting criteria for Li-Fraumeni syndrome (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). 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.