Submissions for variant NM_032043.3(BRIP1):c.1972C>T (p.Arg658Trp)

gnomAD frequency: 0.00003  dbSNP: rs786203170

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166362	SCV000217151	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-20	criteria provided, single submitter	clinical testing	The p.R658W variant (also known as c.1972C>T), located in coding exon 13 of the BRIP1 gene, results from a C to T substitution at nucleotide position 1972. The arginine at codon 658 is replaced by tryptophan, an amino acid with dissimilar properties. In one study, this variant was observed in 0/3236 invasive epithelial ovarian cancer patients and in 1/3431 control patients of European origin; this control was heterozygous for the variant (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). This alteration has also been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient had acute lymphoblastic leukemia (Zhang J et al. N. Engl. J. Med. 2015 Dec;373:2336-46). This amino acid position is well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205396	SCV000261198	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 658 of the BRIP1 protein (p.Arg658Trp). This variant is present in population databases (rs786203170, gnomAD 0.007%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 186720). 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.
Counsyl	RCV000411903	SCV000490095	uncertain significance	Fanconi anemia complementation group J	2016-11-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000409454	SCV000490096	uncertain significance	Ovarian neoplasm	2016-11-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166362	SCV000684174	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 658 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 ovarian cancer (PMID: 26329992), but also in unaffected individuals (PMID: 26315354, 26329992). This variant has been identified in 1/31396 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001169900	SCV001251962	uncertain significance	Familial cancer of breast	2020-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001557438	SCV001779201	uncertain significance	not provided	2023-11-13	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; Observed in an individual with acute lymphocytic leukemia (PMID: 26580448); Not observed in any cases, but was observed in unaffected controls in a serous ovarian cancer study (PMID: 26315354); This variant is associated with the following publications: (PMID: 26580448, 26315354)
Myriad Genetics, Inc.	RCV001169900	SCV004019373	uncertain significance	Familial cancer of breast	2023-02-28	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.