Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV005232191 | SCV005874662 | likely pathogenic | not provided | 2024-08-28 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: non-functional transactivation (PMID: 30224644, 29979965, 12826609); Observed in individuals with high-grade glioma or skin cancer (PMID: 34240179, 34863587); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 23515929, 22768918, 14559903, 10582680, 21575214, 16173033, 18725321, 29979965, 12826609, 15510160, 30224644, 34240179, 34863587) |
| Ambry Genetics | RCV002418782 | SCV002677988 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-07-26 | criteria provided, single submitter | clinical testing | The p.L265Q variant (also known as c.794T>A), located in coding exon 7 of the TP53 gene, results from a T to A substitution at nucleotide position 794. The leucine at codon 265 is replaced by glutamine, an amino acid with dissimilar properties. This variant is located in the highly-conserved DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Another alteration at this same position (p.L265P) was identified in a family with Li Fraumeni Syndrome, and was demonstrated to have reduced DNA binding capability (Cornelis RS et al. Hum. Mutat. 1997;9(2):157-63; Malcikova et al. J. Biol. Chem. 391(2-3):197-205). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91), and 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. |
| Cancer Variant Interpretation Group UK, |
RCV001225765 | SCV001429674 | likely pathogenic | Li-Fraumeni syndrome | 2019-10-11 | criteria provided, single submitter | clinical testing | Data included in classification: Absent from gnomAD (PM2_sup). Align GVGD: Class 65, Revel: 0.964. Bayes del: 0.601. TP53 ConSurf plot shows this residue to be 9 on the conservation scale (predicted to be a highly conserved and buried structural residue). (PP3_mod). Kato et al. 2003 (PMID 12826609) Transactivation class: Non functional. Giacomelli et al. 2018 (PMID 30224644) DNE and LOF variant. Fortuno et al, 2018 (PMID: 29775997) Suggested prediction: non-functional. (PS3_strong). Data not included in classification: UK Family 1: Variant identified in a child with adrenocortical cancer (1 proband meeting Chompret criteria). Pathogenic variant that affects same residue with 2* ClinVar status p.Leu265Pro (BLOSUM62: -3 compared to -2 for current variant). |
| Labcorp Genetics |
RCV001225765 | SCV001398055 | pathogenic | Li-Fraumeni syndrome | 2023-04-24 | criteria provided, single submitter | clinical testing | This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 34240179; Invitae). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 265 of the TP53 protein (p.Leu265Gln). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 953467). 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Leu265 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9067756, 12826609, 16861262, 17606709, 20128691, 20522432, 21343334). 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. |