Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000045272 | SCV000073285 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2022-09-01 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2545 of the BRCA2 protein (p.Val2545Ile). This variant is present in population databases (rs80358990, gnomAD 0.004%). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (HBOC) (PMID: 19043619, 21735045). ClinVar contains an entry for this variant (Variation ID: 52374). 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. |
| Ambry Genetics | RCV000130821 | SCV000185717 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-12 | criteria provided, single submitter | clinical testing | The p.V2545I variant (also known as c.7633G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7633. The valine at codon 2545 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in a set of high-risk families with suspected hereditary breast and ovarian cancer and was found to have no effect on RNA splicing (Menéndez M et al. Breast Cancer Res. Treat. 2012 Apr;132:979-92). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV000212262 | SCV000210437 | uncertain significance | not provided | 2018-08-21 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA2 c.7633G>A at the cDNA level, p.Val2545Ile (V2545I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 7861G>A. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Val2545Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and the FANCD2 binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Val2545Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Mendelics | RCV000045272 | SCV000838859 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000130821 | SCV000911873 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-05-24 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000113799 | SCV001139191 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| MGZ Medical Genetics Center | RCV003607219 | SCV004543916 | likely benign | Familial cancer of breast | 2024-02-09 | criteria provided, single submitter | clinical testing | ACMG codes applied following ENIGMA VCEP rules: BS2_SUP, BP5_MOD, BP4 |
| Breast Cancer Information Core |
RCV000113799 | SCV000147152 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2002-05-29 | no assertion criteria provided | clinical testing |