Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000164195 | SCV000214816 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-03-07 | criteria provided, single submitter | clinical testing | The p.A138V variant (also known as c.413C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 413. The alanine at codon 138 is replaced by valine, an amino acid with similar properties. This alteration was detected in a Chinese breast cancer patient diagnosed at 33y as well as her sister affected with breast cancer at 33y and uterine leimyosarcoma at 43y (Lee DS, Breast Cancer Res. 2012 ; 14(2):R66). Analysis of a breast tumor from this family did demonstrate TP53 LOH associated with this alteration. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially reduced transactivation capacity compared to wild type in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Zhao K et al, 2001 Apr;276:12120-7). 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. |
| Labcorp Genetics |
RCV000813957 | SCV000954344 | uncertain significance | Li-Fraumeni syndrome | 2023-09-21 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 7761089, 12826609, 20407015, 22923379, 27533082, 27657329, 29979965, 30224644). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 184863). This missense change has been observed in individual(s) with breast cancer, pancreatic cancer, sarcoma, and/or stomach cancer (PMID: 22507745, 32552660). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 138 of the TP53 protein (p.Ala138Val). |
| Baylor Genetics | RCV003474852 | SCV004204281 | uncertain significance | Adrenocortical carcinoma, hereditary | 2022-04-06 | criteria provided, single submitter | clinical testing | |
| Myriad Genetics, |
RCV004019963 | SCV004931397 | pathogenic | Li-Fraumeni syndrome 1 | 2024-02-13 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7761089, 7624116]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22507745]. |
| Key Laboratory of Carcinogenesis and Cancer Invasion, |
RCV003995323 | SCV004046829 | likely pathogenic | Adrenal cortex carcinoma | no assertion criteria provided | clinical testing |