Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Center for Genomic Medicine, |
RCV006273744 | SCV007129846 | oncogenic | Neoplasm | 2025-12-29 | criteria provided, single submitter | clinical testing | |
| Institute for Genomic Medicine |
RCV006254046 | SCV007105630 | tier i - strong | Diffuse midline glioma, H3 K27M-mutant | 2025-10-08 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, 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: 17999388, 15037740). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 22661320, 34796414, 33433639). |
| Ambry Genetics | RCV004948281 | SCV005522071 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-08-21 | criteria provided, single submitter | clinical testing | The p.R249M pathogenic mutation (also known as c.746G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 746. The arginine at codon 249 is replaced by methionine, an amino acid with similar properties. 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 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). 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 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). Two other variants at the same codon, p.R249K (c.746G>A) and p.R249T (c.746G>C), are functionally deficient across functional studies (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; 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. 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, |
RCV004022239 | SCV004933224 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-16 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15037740, 17999388, 25294809, 8001119, 8843196, 12509279]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Labcorp Genetics |
RCV000690948 | SCV000818679 | uncertain significance | Li-Fraumeni syndrome | 2024-09-03 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 249 of the TP53 protein (p.Arg249Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376653). 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, 15037740, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000782360 | SCV000923861 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research | |
| Western Connecticut Health Network, |
RCV000782360 | SCV000902407 | pathogenic | Ovarian neoplasm | 2018-10-15 | no assertion criteria provided | research |