Total submissions: 14
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Center for Genomic Medicine, |
RCV006273577 | SCV007129907 | oncogenic | Neoplasm | 2025-12-29 | criteria provided, single submitter | clinical testing | |
| Institute for Genomic Medicine |
RCV006253848 | SCV007105570 | tier ii - potential | Rhabdomyosarcoma | 2024-10-17 | criteria provided, single submitter | clinical testing | Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 29979965, 30224644). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 30181563, 34782706, 35705560). |
| Institute for Genomic Medicine |
RCV006253850 | SCV007105470 | tier i - strong | Diffuse midline glioma, H3 K27M-mutant | 2023-09-13 | 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: 12826609, 30224644, 29979965). 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). |
| Institute for Genomic Medicine |
RCV006253849 | SCV007104644 | tier i - strong | Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype | 2023-12-12 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, 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. 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 31481512, 28966033). |
| Ce |
RCV000161024 | SCV005891689 | likely pathogenic | not provided | 2025-02-01 | criteria provided, single submitter | clinical testing | TP53: PM2, PM5, PS4:Moderate, PS3:Supporting |
| Myriad Genetics, |
RCV004019945 | SCV004932421 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-13 | 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]. |
| Baylor Genetics | RCV003474836 | SCV004204273 | likely pathogenic | Adrenocortical carcinoma, hereditary | 2022-09-21 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003162681 | SCV003878902 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2025-06-30 | criteria provided, single submitter | clinical testing | The p.S127F variant (also known as c.380C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 380. The serine at codon 127 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was detected in a cohort of 295 women considered at high risk for breast cancer (Guindalini RSC et al. Clin Cancer Res, 2019 Mar;25:1786-1794). 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 U S A, 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). Another alteration at the same codon, p.S127T (c.379T>A), has been shown to also have non-functional transactivation in yeast based assays, be deficient at growth suppression, and have a dominant negative effect (Ambry internal data; 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic. |
| Mendelics | RCV000606528 | SCV002516106 | likely pathogenic | not specified | 2023-05-19 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000633384 | SCV000754606 | pathogenic | Li-Fraumeni syndrome | 2023-10-04 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 127 of the TP53 protein (p.Ser127Phe). 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 and/or Li-Fraumeni syndrome (PMID: 32817165, 34240179; Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182928). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16000567, 16322298, 29979965, 30224644). This variant disrupts the p.Ser127 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29470806; Invitae). 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 |
RCV000161024 | SCV000211743 | pathogenic | not provided | 2021-10-07 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: reduced transcriptional activation for multiple p53 response elements, loss of growth suppression activity, non-functional transactivation (Kato 2003, Dekairelle 2005, Bally 2015, Kotler 2018); Observed in individuals with TP53-related cancers referred for genetic testing at GeneDx in published literature (Guindalini 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25308272, 30312528, 16322298, 16000567, 24280411, 25033756, 21747090, 26271412, 15195137, 16094622, 12826609, 29085664, 29979965, 30154229, 15510160) |
| University Health Network, |
RCV000785332 | SCV001738483 | pathogenic | Ovarian neoplasm | 2021-03-19 | no assertion criteria provided | clinical testing | |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785332 | SCV000923900 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research | |
| Laboratory for Molecular Medicine, |
RCV000606528 | SCV000712629 | uncertain significance | not specified | 2016-11-22 | flagged submission | clinical testing | The p.Ser127Phe variant in TP53 has not been previously reported in individuals with Li-Fraumeni syndrome or in large population studies. Computational predicti on tools and conservation analysis suggest that the p.Ser127Phe variant may impa ct the protein, though this information is not predictive enough to determine pa thogenicity. In summary, the clinical significance of the p.Ser127Phe variant is uncertain. |