Submissions for variant NM_032043.3(BRIP1):c.2329C>G (p.Arg777Gly)

dbSNP: rs768555161

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695760	SCV000824278	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 777 of the BRIP1 protein (p.Arg777Gly). This variant is present in population databases (rs768555161, gnomAD 0.003%). 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: 573953). 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	RCV001015205	SCV001176015	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-09	criteria provided, single submitter	clinical testing	The p.R777G variant (also known as c.2329C>G), located in coding exon 15 of the BRIP1 gene, results from a C to G substitution at nucleotide position 2329. The arginine at codon 777 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001015205	SCV001734755	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 777 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 been reported in a breast and ovarian cancer case-control study where the variant was absent in the cases and observed in three population controls (PMID: 29368626). This variant has been identified in 3/251302 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.