Total submissions: 23
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000570507 | SCV000675343 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-02-23 | criteria provided, single submitter | clinical testing | The p.Y220N pathogenic mutation (also known as c.658T>A), located in coding exon 5 of the TP53 gene, results from a T to A substitution at nucleotide position 658. The tyrosine at codon 220 is replaced by asparagine, 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 (IARC TP53 database: 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 (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 amino acid position (p.Y220C) has been reported in multiple individuals and families with classic Li-Fraumeni syndrome (Birch et al. Cancer Res. 1994 Mar 1;54(5):1298-304; Monti et al. Clin Cancer Res. 2007 Jul 1;13(13):3789-95; Melham-Bertrand et al. Cancer. 2012 Feb 15;118(4):908-13). Based on internal structural analysis, p.Y220N destabilizes a residue in an indicated functional domain to a greater degree than multiple pathogenic variants in the region (Cho Y et al. Science 1994 Jul;265:346-55). 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Invitae | RCV001313857 | SCV001504365 | uncertain significance | Li-Fraumeni syndrome | 2023-08-17 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 376688). 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, 29979965, 30224644). This variant disrupts the p.Tyr220 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8118819, 10432928, 15977174, 18307025, 19101993, 19556618). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 220 of the TP53 protein (p.Tyr220Asn). |
Gene |
RCV001575028 | SCV001801938 | likely pathogenic | not provided | 2020-10-15 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as a germline pathogenic or benign variant to our knowledge; This variant is associated with the following publications: (PMID: 31105275, 31990523, 12826609, 26619011, 14559903, 29979965) |
Myriad Genetics, |
RCV004022254 | SCV004931135 | 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: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. |
Database of Curated Mutations |
RCV000424584 | SCV000510247 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434427 | SCV000510248 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443812 | SCV000510249 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427847 | SCV000510250 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438068 | SCV000510251 | likely pathogenic | Papillary renal cell carcinoma type 1 | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419523 | SCV000510252 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426310 | SCV000510253 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437403 | SCV000510254 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419702 | SCV000510255 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429130 | SCV000510256 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439357 | SCV000510257 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419021 | SCV000510258 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429300 | SCV000510259 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438679 | SCV000510260 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421037 | SCV000510261 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432093 | SCV000510262 | likely pathogenic | Uterine carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438838 | SCV000510263 | likely pathogenic | Papillary renal cell carcinoma, sporadic | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423767 | SCV000510264 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434035 | SCV000510265 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only |