Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000483594 | SCV000572301 | uncertain significance | not provided | 2016-11-17 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA2 c.4558A>G at the cDNA level, p.Thr1520Ala (T1520A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). Using alternate nomenclature, this variant would be defined as BRCA2 4786A>G. This variant was reported in an apparently homozygous state in an individual with a personal and/or family history of breast and/or ovarian cancer; however, specific clinical details for this individual were not provided (Hernan 2012). BRCA2 Thr1520Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Thr1520Ala occurs at a position that is not conserved and is located within the BRC4 domain and the binding domain of POLH and RAD51 (Cole 2011, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Thr1520Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Labcorp Genetics |
RCV001316741 | SCV001507376 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2020-10-01 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine with alanine at codon 1520 of the BRCA2 protein (p.Thr1520Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 51673). 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 not expected to disrupt BRCA2 protein function. 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. |
| University of Washington Department of Laboratory Medicine, |
RCV003156775 | SCV003850607 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-23 | criteria provided, single submitter | curation | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). |
| Breast Cancer Information Core |
RCV000113320 | SCV000146447 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2003-12-23 | no assertion criteria provided | clinical testing |