Submissions for variant NM_032043.3(BRIP1):c.170T>G (p.Leu57Arg)

gnomAD frequency: 0.00001  dbSNP: rs1435822764

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001189622	SCV001356936	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-13	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 57 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001863001	SCV002121600	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 57 of the BRIP1 protein (p.Leu57Arg). 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: 926810). 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 with a positive 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.
Ambry Genetics	RCV001189622	SCV005101040	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-19	criteria provided, single submitter	clinical testing	The p.L57R variant (also known as c.170T>G), located in coding exon 2 of the BRIP1 gene, results from a T to G substitution at nucleotide position 170. The leucine at codon 57 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.