Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Myriad Genetics, |
RCV002289527 | SCV004931404 | pathogenic | Li-Fraumeni syndrome 1 | 2024-02-14 | criteria provided, single submitter | clinical testing | This variant is considered 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: 33840814, 19556618]. |
| Ambry Genetics | RCV001293868 | SCV002643411 | pathogenic | Hereditary cancer-predisposing syndrome | 2015-06-25 | criteria provided, single submitter | clinical testing | The p.H179Q pathogenic mutation (also known as c.537T>G), located in coding exon 4 of the TP53 gene, results from a T to G substitution at nucleotide position 537. The histidine at codon 179 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a French family with a clinical history suggestive of Li-Fraumeni syndrome (LFS) (Bougeard G et al. J Med Genet. 2008 Aug;45(8):535-8), and a woman with breast cancer at 27 years of age (Sheng S et al. Int. J. Cancer, 2020 01;146:487-495). A similar nucleotide alteration, c.537T>A, which results in the same p.H179Q amino acid alteration was detected in a child diagnosed with two classic LFS cancers and was confirmed to be a de novo mutation (Gonzalez KD et al. J Med Genet. 2009 Oct;46(10):689-93). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and 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). 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 available evidence, p.H179Q is classified as a pathogenic mutation. |
| Genome- |
RCV002289527 | SCV002583042 | likely pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV001293868 | SCV002582382 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV002264935 | SCV002547072 | likely pathogenic | not provided | 2022-10-14 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity, and a dominant-negative effect (Unger et al., 2003; Waddell et al., 2001; Kotler et al., 2018; Kato et al., 2003; Giacomelli et al., 2018); 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; Identified in a child with rhabdomyosarcoma as well as an individual with breast cancer (Wagener et al., 2021; Sun et al., 2017); This variant is associated with the following publications: (PMID: 34972722, 30337059, 32923889, 30840781, 30720243, 22540896, 19759556, 28724667, 15510160, 10802655, 8336941, 8355677, 15848166, 16474844, 29979965, 30224644, 12826609, 11593407, 33840814, 11435891, 26619011) |
| Department of Pediatric Oncology, |
RCV001293868 | SCV001482286 | pathogenic | Hereditary cancer-predisposing syndrome | criteria provided, single submitter | research | ||
| Labcorp Genetics |
RCV000815181 | SCV000955628 | pathogenic | Li-Fraumeni syndrome | 2025-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 179 of the TP53 protein (p.His179Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer or acute myeloid leukemia (PMID: 19556618, 26230955, 28724667). ClinVar contains an entry for this variant (Variation ID: 376607). 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, 29979965, 30224644). This variant disrupts the p.His179 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19556618). 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. |