Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001527084 | SCV001737923 | likely pathogenic | Li-Fraumeni syndrome 1 | 2022-06-27 | reviewed by expert panel | curation | This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a partially functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3_Moderate; PMID: 12826609, 30224644). This variant has been reported in 2 probands meeting Chompret criteria (PS4_Supporting; Invitae, GeneDx/NIH). In summary, TP53 c.569C>T (p.Pro190Leu) meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PM1, PS3_Moderate, PS4_Supporting. |
| Myriad Genetics, |
RCV001527084 | SCV004043214 | likely pathogenic | Li-Fraumeni syndrome 1 | 2023-09-28 | 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: 37562436, 35974385, 32658383]. Functional studies indicate this variant impacts protein function [PMID: 29979965]. |
| Ambry Genetics | RCV002350050 | SCV002647488 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-04-21 | criteria provided, single submitter | clinical testing | The p.P190L variant (also known as c.569C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 569. The proline at codon 190 is replaced by leucine, an amino acid with similar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (IARC TP53 database, personal communication). This variant is in the DNA binding domain of the TP53 protein and is reported to have a partial loss of transactivation capacity in two different yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9, Jordan JJ, Mol. Cancer Res. 2010 May; 8(5):701-16). 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 alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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 majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000551566 | SCV000629842 | pathogenic | Li-Fraumeni syndrome | 2025-12-29 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 190 of the TP53 protein (p.Pro190Leu). 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 syndrome (PMID: 17311302, 32658383, 32817165; internal data). ClinVar contains an entry for this variant (Variation ID: 418517). 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, 20407015, 23713777, 29979965, 30224644). This variant disrupts the p.Pro190 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 26787237, 28499267). 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. |
| Gene |
RCV000484792 | SCV000565623 | pathogenic | not provided | 2024-05-01 | 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; This variant is associated with the following publications: (PMID: 29979965, 12826609, 20407015, 30224644, 12124823, 32817165, 34863587, 32658383, 35974385, 15510160, 37562436) |