ClinVar Genomic variation as it relates to human health

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30840781, 30720243, 30076369, 29979965, 17606709, 24760004, 25025766, 22575263, 20682393, 25135238, 26230955, 27101868, 26619011, 26851439, 27588476, 14732923, 23121011, 27034009, 14559903, 18765419, 16000567, 18843282, 12826609, 25634208, 26723900, 16827139, 10753186, 9667734, 21343334)

This missense variant replaces tyrosine with cysteine at codon 236 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant is defective in transcriptional transactivation studies, human cell proliferation and growth suppression assays, and nuclear cytoplasmic localization assays (PMID: 12826609, 16827139, 17606709, 21343334, 29979965, 30224644). This variant has been reported in individuals affected with Li Fraumeni syndrome (PMID: 9667734, 17606709). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The p.Tyr236Cys variant in TP53has been reported in 2 individuals with LFS and 1 with Li-Fraumeni-like syndrome (Rines 1998 PMID: 9667734, Haque 2018 PMID: 30076369, Monti 2007 PMID: 17606709). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 376693). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Monti 2007 PMID: 17606709, Monti 2011 PMID: 21343334); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LFS. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting.

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 27813088, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].

The p.Y236C pathogenic mutation (also known as c.707A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 707. The tyrosine at codon 236 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in two unrelated Li-Fraumeni Syndrome families, including one with a history of osteosarcomas, leukemia, and kidney cancer (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9, Rines R et al., Carcinogenesis 1998 Jun; 19(6):979-84). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and a dominant negative effect in yeast based assays (IARC TP53 database; 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, Robert V et al., Carcinogenesis 2000 Apr; 21(4):563-5). 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, based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). Based on the available evidence, this alteration is classified as a pathogenic mutation.

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 236 of the TP53 protein (p.Tyr236Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 9667734, 17606709, 30076369). ClinVar contains an entry for this variant (Variation ID: 376693). 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: 12826609, 16827139, 21343334, 25691460). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.