Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Center for Genomic Medicine, |
RCV006273051 | SCV007129833 | oncogenic | Neoplasm | 2025-12-29 | criteria provided, single submitter | clinical testing | |
| Institute for Genomic Medicine |
RCV006253480 | SCV007105083 | tier ii - potential | Pleomorphic xanthoastrocytoma | 2024-03-21 | criteria provided, single submitter | clinical testing | Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in pleomorphic xanthoastrocytoma, 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). 4) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 32619305, 30051528, 11523567, 12484572, 8834542). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001221969 | SCV005725719 | pathogenic | Li-Fraumeni syndrome | 2024-11-26 | criteria provided, single submitter | clinical testing | Variant summary: TP53 c.814G>T (p.Val272Leu) results in a conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250892 control chromosomes. c.814G>T has been reported in the literature in individuals affected with features of Li-Fraumeni Syndrome (example, Felix_1992, Bally_2014, Jasek_2010, Internal data). These data indicate that the variant may be associated with disease. At-least one somatic co-occurrence with other pathogenic germline variant(s) has been reported (BRCA1 c.181T>G, p.Cys61Gly) (Amikura_2006). Multiple publications report experimental evidence evaluating an impact on protein function (example, Monti_2011, Malcikova_2010, Fischer_2018, Kato_2003). The most pronounced variant effect results in considerably reduced DNA binding activity of p53 compared to wild type (Malcikova_2010) and non-functional/reduced based on transcriptional activity (Kato_2003, Fischer_2018). The following publications have been ascertained in the context of this evaluation (PMID: 16337994, 24836762, 23246812, 15221755, 27895058, 1737852, 16818505, 30089713, 11782540, 22915647, 26230955, 21519010, 19759556, 20407015, 27463065, 20128691, 30327374, 17606709, 21343334, 26585234, NCCN_AML, NCCN_MDS, NCCN_MPN, 25952993, 27276561, 22186996, 27680515, 27959731, 15523690, 12826609, Internal data). ClinVar contains an entry for this variant (Variation ID: 12358). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Myriad Genetics, |
RCV000013152 | SCV004931523 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-20 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 20128691, 29979965]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 1737852]. |
| Genetics and Molecular Pathology, |
RCV000013152 | SCV002761563 | likely pathogenic | Li-Fraumeni syndrome 1 | 2020-08-10 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001221969 | SCV001394046 | pathogenic | Li-Fraumeni syndrome | 2025-07-27 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 272 of the TP53 protein (p.Val272Leu). 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 (PMID: 1737852; internal data). ClinVar contains an entry for this variant (Variation ID: 12358). 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.Val272 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18511570, 23175693, 25584008, 29070607). 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 | RCV000164988 | SCV000215682 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-11-02 | criteria provided, single submitter | clinical testing | The p.V272L variant (also known as c.814G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 814. The valine at codon 272 is replaced by leucine, an amino acid with highly similar properties. This mutation was first described in a proband with childhood-onset acute lymphoblastic leukemia (ALL) whose family history was suggestive of Li-Fraumeni syndrome (Felix CA J. Clin. Invest. 1992 Feb;89(2):640-7). 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 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 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). Another variant at the same codon, p.V272M (c.814G>A), has been described in individuals with features consistent with Li-Fraumeni syndrome (Bougeard G et al. J. Med. Genet. 2008 Aug;45(8):535-8; Raymond VM et al. J. Clin. Endocrinol. Metab. 2013 Jan; 98(1):E119-25; Renaux-Petel M et al. J. Med. Genet. 2017 Oct 25). This amino acid position is not well 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. |
| OMIM | RCV000013152 | SCV000033399 | pathogenic | Li-Fraumeni syndrome 1 | 1992-08-01 | no assertion criteria provided | literature only |