Submissions for variant NM_032043.3(BRIP1):c.887A>G (p.Glu296Gly)

gnomAD frequency: 0.00003  dbSNP: rs878855158

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226821	SCV000291060	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 296 of the BRIP1 protein (p.Glu296Gly). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 241663). 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.
Mendelics	RCV000709556	SCV000839390	uncertain significance	Fanconi anemia complementation group J	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001018433	SCV001179671	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-28	criteria provided, single submitter	clinical testing	The p.E296G variant (also known as c.887A>G), located in coding exon 6 of the BRIP1 gene, results from an A to G substitution at nucleotide position 887. The glutamic acid at codon 296 is replaced by glycine, an amino acid with similar properties. This variant identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration was also detected in a cohort of 1,663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284465	SCV001470275	uncertain significance	not provided	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001284465	SCV004169799	uncertain significance	not provided	2023-05-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or prostate cancer (Matejcic et al., 2020; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 35264596, 32832836)
Color Diagnostics, LLC DBA Color Health	RCV001018433	SCV004362960	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 296 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 BRIP1-related disorders in the literature. This variant has been identified in 5/282294 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.