Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute for Genomic Medicine |
RCV006254187 | SCV007104764 | tier i - strong | Embryonal rhabdomyosarcoma | 2022-11-22 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644, 29979965). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24436047, 34166060, 24332040, 25768946, 26138366). |
| Myriad Genetics, |
RCV002290550 | SCV004930576 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-14 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Genome- |
RCV002290550 | SCV002583040 | likely pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV001024094 | SCV002582379 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001206963 | SCV001378298 | pathogenic | Li-Fraumeni syndrome | 2023-11-15 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 181 of the TP53 protein (p.Arg181Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni Syndrome (PMID: 15925506, 29360161). ClinVar contains an entry for this variant (Variation ID: 825729). 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, 20407015, 21343334, 23149933). This variant disrupts the p.Arg181 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1591732, 1631137, 11429705, 20128691, 21059199, 21343334, 23175693). 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. |
| Ambry Genetics | RCV001024094 | SCV001186052 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-08-31 | criteria provided, single submitter | clinical testing | The p.R181P pathogenic mutation (also known as c.542G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 542. The arginine at codon 181 is replaced by proline, an amino acid with dissimilar properties. This alteration was identified in the germline of a 1y/o child diagnosed with choroid plexus carcinoma and an individual with multiple primary malignancies and a family history consistent with Li Fraumeni syndrome (Krutilkova V et al. Eur. J. Cancer, 2005 Jul;41:1597-603; Dudley B et al. Cancer, 2018 04;124:1691-1700). Multiple yeast-based functional studies have shown a loss of transactivation capacity and evidence of dominant negative activity (Marutani M et al. Cancer Res., 1999 Oct;59:4765-9; Jordan JJ et al. Mol. Cancer Res., 2010 May;8:701-16; Monti P et al. Mol. Cancer Res., 2011 Mar;9:271-9). Additional studies conducted in human cell lines indicate this alteration has dominant negative activity 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 variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |