Submissions for variant NM_032043.3(BRIP1):c.787C>T (p.Leu263Phe)

gnomAD frequency: 0.00001  dbSNP: rs1060501776

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467138	SCV000547373	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 263 of the BRIP1 protein (p.Leu263Phe). This variant is present in population databases (no rsID available, gnomAD 0.06%). This missense change has been observed in individual(s) with biliary tract cancer, breast cancer, and/or prostate cancer (PMID: 26790966, 31214711, 36243179). ClinVar contains an entry for this variant (Variation ID: 407869). 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. 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	RCV000663200	SCV000786376	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2018-04-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775746	SCV000910178	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 263 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 been reported in individuals affected with breast cancer (PMID: 26790966) and both in affected and unaffected individuals in a prostate cancer risk case-control study (PMID: 31214711). This variant has been identified in 1/31392 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.
Ambry Genetics	RCV000775746	SCV001189375	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	The p.L263F variant (also known as c.787C>T), located in coding exon 6 of the BRIP1 gene, results from a C to T substitution at nucleotide position 787. The leucine at codon 263 is replaced by phenylalanine, an amino acid with highly similar properties. In a study of Korean patients with breast cancer and previous negative genetic testing of BRCA1/2, this variant was reported in 2/235 patients and 0/50 controls (Kim H et al. Cancer Res Treat. 2016 Jul;48:955-61). 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.
GeneDx	RCV001813780	SCV002061058	uncertain significance	not provided	2022-01-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast cancer (Kim 2016); This variant is associated with the following publications: (PMID: 26709662, 31214711, 21279724, 34585473, 26790966)
Sema4, Sema4	RCV000775746	SCV002529233	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003316566	SCV004019320	uncertain significance	Familial cancer of breast	2023-02-27	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.
Leiden Open Variation Database	RCV001194717	SCV001364484	benign	not specified	2019-08-13	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.