Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000461678 | SCV000549849 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2016-08-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with lysine at codon 1694 of the BRCA2 protein (p.Arg1694Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The lysine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Genetics and Molecular Pathology, |
RCV002272244 | SCV002556392 | likely benign | Breast-ovarian cancer, familial, susceptibility to, 2 | 2021-06-25 | criteria provided, single submitter | clinical testing | The BRCA2 c.5081G>A variant is classified as Likely Benign (BP1, BP4) The BRCA2 c.5081G>A variant is a single nucleotide change in the BRCA2 gene, which is predicted to change the amino acid arginine at position 1694 in the protein to lysine. Disease causing variants in BRCA2 are predominantly trucating variants and this variant is a missense variant (BP1). Multiple lines of computational evidence suggest this variant has no impact on the gene or gene product (BP4). The variant has been reported as Uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 409591). It has not been reported in dbSNP or HGMD. |
| University of Washington Department of Laboratory Medicine, |
RCV003157551 | SCV003846975 | 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). |
| Ambry Genetics | RCV003157551 | SCV004005372 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-20 | criteria provided, single submitter | clinical testing | The p.R1694K variant (also known as c.5081G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5081. The arginine at codon 1694 is replaced by lysine, an amino acid with highly similar properties. This amino acid position is not 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. |
| MGZ Medical Genetics Center | RCV003607288 | SCV004543896 | likely benign | Familial cancer of breast | 2024-02-09 | criteria provided, single submitter | clinical testing | ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP |