Submissions for variant NM_032043.3(BRIP1):c.1873T>C (p.Ser625Pro)

gnomAD frequency: 0.00001  dbSNP: rs935011040

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000758992	SCV000566988	uncertain significance	not provided	2015-06-25	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.1873T>C at the cDNA level, p.Ser625Pro (S625P) at the protein level, and results in the change of a Serine to a Proline (TCA>CCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Ser625Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRIP1 Ser625Pro occurs at a position that is conserved across species and is located in the helicase domain (Cantor 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRIP1 Ser625Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000568571	SCV000666238	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-30	criteria provided, single submitter	clinical testing	The p.S625P variant (also known as c.1873T>C), located in coding exon 12 of the BRIP1 gene, results from a T to C substitution at nucleotide position 1873. The serine at codon 625 is replaced by proline, an amino acid with similar 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	RCV000568571	SCV000684164	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 625 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 BRIP1-related disorders in the literature. This variant has been identified in 1/251450 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758992	SCV000887987	uncertain significance	not provided	2018-04-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002605	SCV001160579	uncertain significance	Fanconi anemia complementation group J	2019-06-06	criteria provided, single submitter	clinical testing	The BRIP1 c.1873T>C; p.Ser625Pro variant (rs935011040), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 419290). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 625 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001224574	SCV001396779	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 625 of the BRIP1 protein (p.Ser625Pro). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 419290). 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.