Submissions for variant NM_032043.3(BRIP1):c.759C>G (p.His253Gln)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003019607	SCV003321434	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-07-08	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 253 of the BRIP1 protein (p.His253Gln).
Ambry Genetics	RCV003170887	SCV003868799	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-28	criteria provided, single submitter	clinical testing	The p.H253Q variant (also known as c.759C>G), located in coding exon 6 of the BRIP1 gene, results from a C to G substitution at nucleotide position 759. The histidine at codon 253 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. 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	RCV003170887	SCV004362965	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 253 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 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.