Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000544036 | SCV001142548 | likely pathogenic | Li-Fraumeni syndrome | 2024-08-05 | reviewed by expert panel | curation | The NM_000546.6: c.538G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 180 (p.Glu180Lys). This variant has been reported in 12 unrelated families meeting Revised Chompret criteria and reported in 1 individual with a HER2+ breast cancer. Based on this evidence, this variant scores 7 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 35974385, 33178583, 25584008, 8118819; Internal lab contributors: SCV000629836.7, SCV000581143.5, SCV000292772.10). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.262; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4; PM2_Supporting, PS3_Moderate; PP3. (Bayesian Points: 8; VCEP specifications version 2.0; 7/24/2024) |
| Myriad Genetics, |
RCV006633910 | SCV007517562 | likely pathogenic | Li-Fraumeni syndrome 1 | 2025-12-15 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35974385, 9242456, 33178583, 25584008]. |
| Department of Clinical Genetics, |
RCV000544036 | SCV005689587 | likely pathogenic | Li-Fraumeni syndrome | 2025-02-04 | criteria provided, single submitter | clinical testing | PS4; PM2_SUP, PS3_MOD; PP3. |
| Labcorp Genetics |
RCV000544036 | SCV000629836 | pathogenic | Li-Fraumeni syndrome | 2024-05-23 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 180 of the TP53 protein (p.Glu180Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TP53-related conditions (PMID: 8118819, 25584008; Invitae). ClinVar contains an entry for this variant (Variation ID: 245711). 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: 12826609, 20128691, 20471942, 21343334). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV000492319 | SCV000581143 | pathogenic | Hereditary cancer-predisposing syndrome | 2025-05-01 | criteria provided, single submitter | clinical testing | The p.E180K variant (also known as c.538G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 538. The glutamic acid at codon 180 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in individuals diagnosed with pediatric adrenocortical carcinoma (Birch JM et al. Cancer Res. 1994 Mar;54:1298-304; Wasserman JD et al. J Clin Oncol, 2015 Feb;33:602-9; Miele E et al. Front Oncol, 2020 Oct;10:554388). This alteration has also been reported in an individual diagnosed with high-risk breast cancer (Kharaziha P et al. Clin Genet, 2019 09;96:216-225). This variant is in the DNA binding domain of the TP53 protein and its position is involved in a dimer-stabilizing salt-bridge (Kitayner M et al. Mol. Cell. 2006 Jun;22:741-53). Multiple functional assays in yeast have shown this variant leads to at least partial deficiency in transactivation activity compared to wild type (Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Campomenosi P et al. Oncogene. 2001 Jun;20:3573-9). This alteration also demonstrated a reduced ability to bind DNA in functional protein microarray studies (Malcikova J et al. Biol. Chem. 391:197-205; Boutell JM et al. Proteomics. 2004 Jul;4:1950-8). Additional studies in human cell lines show this alteration is deficient in cell growth suppression (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-138). An in vivo assay in mice showed that a functionally equivalent variant (E180R) leads to a reduction in dimerization and DNA binding, and an inability to induce apoptosis (Timofeev O et al. Cell Rep. 2013 May;3:1512-25). This amino acid position is highly 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. |
| Gene |
RCV000235571 | SCV000292772 | likely pathogenic | not provided | 2023-12-05 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate partially functional transactivation and conflicting results with respect to apoptosis and growth suppression abilities (PMID: 20128691, 11429705, 10206274, 21343334, 24814347, 30224644, 29979965, 12826609); Identified in several children with adrenocortical carcinoma and other individuals with early-onset breast cancer, but also in unaffected adults, suggesting that this variant may confer reduced penetrance and may not result in classic Li-Fraumeni syndrome (PMID: 33178583, 35974385, 31081129, 9242456, 25584008, 8118819); This variant is associated with the following publications: (PMID: 8118819, 11948487, 10607740, 11044641, 23665223, 20128691, 11896595, 11429705, 17606709, 11429700, 15308588, 10206274, 17947339, 20471942, 16983711, 21343334, 15538112, 29058986, 12082526, 24814347, 25584008, 16035029, 15221755, 9242456, 29979965, 31081129, 30720243, 30840781, 31105275, 33300245, 30224644, 34273903, 12826609, 15510160, 12067251, 22768918, 33178583, 35974385) |
| Clinical Genetics and Genomics, |
RCV004797607 | SCV005419147 | likely pathogenic | TP53-related disorder | 2024-10-01 | no assertion criteria provided | clinical testing |