Submissions for variant NM_032043.3(BRIP1):c.2189G>A (p.Gly730Glu)

gnomAD frequency: 0.00004  dbSNP: rs748616469

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573512	SCV000666236	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-09	criteria provided, single submitter	clinical testing	The p.G730E variant (also known as c.2189G>A), located in coding exon 14 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2189. The glycine at codon 730 is replaced by glutamic acid, an amino acid with similar properties. 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 limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000573512	SCV000684192	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 730 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been identified in 2/282582 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636134	SCV000757566	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 730 of the BRIP1 protein (p.Gly730Glu). This variant is present in population databases (rs748616469, gnomAD 0.008%). 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: 481651). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRIP1 protein function. 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.
GeneDx	RCV001566458	SCV001789975	uncertain significance	not provided	2022-04-19	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; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001821669	SCV002068099	uncertain significance	not specified	2020-04-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRIP1 gene demonstrated a sequence change, c.2189G>A, in exon 15 that results in an amino acid change, p.Gly730Glu. This sequence change has been described in the gnomAD database with a low population frequency of 0.00071% (dbSNP 748616469). The p.Gly730Glu change affects a highly conserved amino acid residue located in a domain of the BRIP1 protein that is known to be functional. The p.Gly730Glu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with BRIP1-related disorders. Due to the lack of functional studies, the clinical significance of the p.Gly730Glu change remains unknown at this time.
Baylor Genetics	RCV003459322	SCV004214740	uncertain significance	Familial cancer of breast	2023-09-26	criteria provided, single submitter	clinical testing