Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000217131 | SCV000277077 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-07-17 | criteria provided, single submitter | clinical testing | The p.K752R variant (also known as c.2255A>G), located in coding exon 14 of the BRIP1 gene, results from an A to G substitution at nucleotide position 2255. The lysine at codon 752 is replaced by arginine, an amino acid with highly similar properties. 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 0.002% (greater than 65000 alleles tested) in our clinical cohort. This amino acid position is well conserved however, arginine is the reference amino acid in several fish 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 variant remains unclear. |
| Labcorp Genetics |
RCV001248527 | SCV001422021 | uncertain significance | Familial cancer of breast; Fanconi anemia complementation group J | 2019-11-10 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 232832). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 752 of the BRIP1 protein (p.Lys752Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. 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 arginine amino acid residue is 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 and their clinical significance is uncertain. 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. |