Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000698838 | SCV000827527 | uncertain significance | Familial cancer of breast; Fanconi anemia complementation group J | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 99 of the BRIP1 protein (p.Asp99Glu). This variant is not present in population databases (gnomAD no frequency). 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: 576358). 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 BRIP1 protein function with a negative predictive value of 80%. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781182 | SCV000919064 | uncertain significance | not specified | 2021-12-02 | criteria provided, single submitter | clinical testing | Variant summary: BRIP1 c.297C>G (p.Asp99Glu) results in a conservative amino acid change located in the ATP-binding domain (IPR014001) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251454 control chromosomes (gnomAD). However, the variant has been reported in 1/7325 European American women, who are older than age 70 and cancer free (FLOSSIES database). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.297C>G in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Ambry Genetics | RCV002440496 | SCV002750623 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-04 | criteria provided, single submitter | clinical testing | The p.D99E variant (also known as c.297C>G), located in coding exon 3 of the BRIP1 gene, results from a C to G substitution at nucleotide position 297. The aspartic acid at codon 99 is replaced by glutamic acid, an amino acid with highly similar properties. 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. |