Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001013776 | SCV001174403 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-25 | criteria provided, single submitter | clinical testing | The p.G649D variant (also known as c.1946G>A), located in coding exon 13 of the BRIP1 gene, results from a G to A substitution at nucleotide position 1946. The glycine at codon 649 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV001013776 | SCV001341602 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-12-09 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with aspartic acid at codon 649 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251286 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Invitae | RCV001238342 | SCV001411146 | uncertain significance | Familial cancer of breast; Fanconi anemia complementation group J | 2022-09-01 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs746066323, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 649 of the BRIP1 protein (p.Gly649Asp). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 820382). 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. 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 BRIP1 protein function. |