Submissions for variant NM_032043.3(BRIP1):c.1637A>G (p.Asp546Gly)

dbSNP: rs2077612367

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001205772	SCV001377046	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 546 of the BRIP1 protein (p.Asp546Gly). 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: 936872). 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 not expected to disrupt BRIP1 protein function with a negative 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.
Color Diagnostics, LLC DBA Color Health	RCV001806043	SCV002052519	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 546 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 been reported in an individual affected with breast cancer, but also in a control individual in the literature (PMID: 26921362). 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.
Ambry Genetics	RCV001806043	SCV002709260	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	clinical testing	The p.D546G variant (also known as c.1637A>G), located in coding exon 11 of the BRIP1 gene, results from an A to G substitution at nucleotide position 1637. The aspartic acid at codon 546 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate 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 alteration remains unclear.