Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000535418 | SCV000629844 | uncertain significance | Li-Fraumeni syndrome | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 194 of the TP53 protein (p.Leu194Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 376633). 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: 12509279, 12826609, 20407015, 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. |
Ambry Genetics | RCV000561306 | SCV000676299 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-10-25 | criteria provided, single submitter | clinical testing | The p.L194R variant (also known as c.581T>G), located in coding exon 5 of the TP53 gene, results from a T to G substitution at nucleotide position 581. The leucine at codon 194 is replaced by arginine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of 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 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 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Institute of Biochemistry, |
RCV001270270 | SCV001450486 | pathogenic | Colorectal cancer | criteria provided, single submitter | case-control | ||
Myriad Genetics, |
RCV004022229 | SCV004932075 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-15 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 12509279, 15077194]. This variant is expected to disrupt protein structure [Myriad internal data]. |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV004764786 | SCV005374679 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2024-05-14 | criteria provided, single submitter | curation | According to the ClinGen ACMG TP53 v1.4.0 criteria we chose these criteria: PS3 (strong pathogenic): Giacomelli 2018: DNE and LOF, Kato 2003: non funct ClinGen-TP3-PS3-str: transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a low functioning allele (<= 20% activity) AND: Evidence of dominant negative effect (DNE) + evidence of LOF from Giacomelli, et al data , PM1 (medium pathogenic): This rule can be applied to variants in hot spots (codons 175, 245, 248, 249, 273, 282), but not to variants within functional domains. Use transcript NM_000546.4. Also use rule for variants with ≥10 somatic observations cancerhotspots.org (v2) L194: 49x in cancerhotspots, PM2 (supporting pathogenic): 1X in gnomAD, PP3 (medium pathogenic): BayesDel (no AF): 0.582962 AlignGVGD: C65 |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785551 | SCV000924123 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research | |
Clinical Genetics and Genomics, |
RCV004797609 | SCV005419148 | likely pathogenic | TP53-related disorder | 2024-10-01 | no assertion criteria provided | clinical testing |