Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001217442 | SCV001389282 | pathogenic | Familial cancer of breast; Fanconi anemia complementation group J | 2025-01-20 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 626 of the BRIP1 protein (p.Glu626Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 23285130). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 946555). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BRIP1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002411805 | SCV002721119 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-12-23 | criteria provided, single submitter | clinical testing | The p.E626D variant (also known as c.1878A>C), located in coding exon 12 of the BRIP1 gene, results from an A to C substitution at nucleotide position 1878. The glutamic acid at codon 626 is replaced by aspartic acid, an amino acid with highly similar properties. A similar alteration, c.1878A>T, which results in the same amino acid change,p.E626D, is reported in the homozygous state in three siblings affected with Fanconi anemia; analysis of lymphoblastoid cell lines from these individuals demonstrated microsatellite instability (Knies K et al. PLoS ONE 2012;7(12):e52648; Matsuzaki K et al. Genes Dev. 2015 Dec;29(24):2532-46). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 120000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is still limited at this time, the clinical significance of p.E626D remains unclear. |