Total submissions: 10
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000548853 | SCV007113936 | pathogenic | Li-Fraumeni syndrome | 2025-12-05 | reviewed by expert panel | curation | The NM_000546.6: c.473G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 158 (p.Arg158Pro). This variant received a total of 0.5 points in 1 proband on literature search only (internal data not obtained). (PS4 not met; PMID: 35974385). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Another missense variant (c.473G>T, p.Arg158Leu) (ClinVar ID: 528248), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). This variant has 11 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). Computational predictor scores (BayesDel = 0.575563; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3_moderate, PM1, PM5, PM2_Supporting. (Bayesian Points: 11; VCEP specifications version 2.3) |
| Center for Genomic Medicine, |
RCV006273689 | SCV007129889 | oncogenic | Neoplasm | 2025-12-29 | criteria provided, single submitter | clinical testing | |
| Institute for Genomic Medicine |
RCV006253926 | SCV007105634 | tier i - strong | IDH-wildtype glioblastoma | 2025-10-14 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in IDH-wildtype glioblastoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24120142, 29802247, 26919320, 9284834, 17498554, 26443480, 30861589, 32642724, 34952640). |
| Ambry Genetics | RCV002288932 | SCV005522112 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-09-17 | criteria provided, single submitter | clinical testing | The p.R158P pathogenic mutation (also known as c.473G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 473. The arginine at codon 158 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported in a Li Fraumeni syndrome family (Morgan JE et al. Hum Mutat, 2010 Apr;31:484-91). It has also been reported in a pediatric patient meeting Chompret criteria with a personal history of rhabdomyosarcoma and osteosarcoma (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). This alteration has also been reported in a patient with acute myeloid leukemia (Zuo Z et al. Leuk Res Rep, 2023 Aug;20:100385). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |
| Myriad Genetics, |
RCV002288931 | SCV004931212 | 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- |
RCV002288931 | SCV002583052 | likely pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV002288932 | SCV002582390 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000989719 | SCV001140261 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000548853 | SCV000629825 | likely pathogenic | Li-Fraumeni syndrome | 2025-04-23 | 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 158 of the TP53 protein (p.Arg158Pro). 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: 20127978, 35974385; internal data). ClinVar contains an entry for this variant (Variation ID: 246118). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Gene |
RCV000236862 | SCV000293524 | likely pathogenic | not provided | 2018-11-13 | criteria provided, single submitter | clinical testing | This variant is denoted TP53 c.473G>C at the cDNA level, p.Arg158Pro (R158P) at the protein level, and results in the change of an Arginine to a Proline (CGC>CCC). This variant has been observed in at least one individual reported to have Li-Fraumeni syndrome (Morgan 2010). On functional interrogation, TP53 Arg158Pro has been shown to impact transactivation, growth suppression, and cause a dominant-negative effect (Brachmann 1996, Dearth 2007, Kotler 2018). Consistent with these results, this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg158Pro was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider TP53 Arg158Pro to be a likely pathogenic variant. |