Submissions for variant NM_032043.3(BRIP1):c.2593C>T (p.Arg865Trp)

gnomAD frequency: 0.00004  dbSNP: rs578022079

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217245	SCV000273828	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-03	criteria provided, single submitter	clinical testing	The p.R865W variant (also known as c.2593C>T), located in coding exon 18 of the BRIP1 gene, results from a C to T substitution at nucleotide position 2593. The arginine at codon 865 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). This alteration has also been identified in 1/976 alleles from a cohort of Dutch melanomaprone families (Potjer TP et al. Int. J. Cancer, 2019 05;144:2453-2464). In one study, the p.R865W alteration was detected in 6/101,759 breast cancer cases and 2/15,587 ovarian cancer cases (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). In an inter-strand cross link damage survival assay, the p.R865W alteration was found to be functionally abnormal (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). 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.
Invitae	RCV000228828	SCV000291018	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-10-21	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 865 of the BRIP1 protein (p.Arg865Trp). This variant is present in population databases (rs578022079, gnomAD 0.005%). This missense change has been observed in individual(s) with breast or ovarian cancer and a personal or family history of melanoma (PMID: 29368626, 30414346, 31822495). ClinVar contains an entry for this variant (Variation ID: 230320). 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. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 31822495). 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.
GeneDx	RCV000586310	SCV000329159	uncertain significance	not provided	2019-11-05	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30414346, 29368626, 29641532, 31822495)
Color Diagnostics, LLC DBA Color Health	RCV000217245	SCV000684226	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 865 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study has reported the mutant protein to be defective for repair of interstrand crosslink damage in a BRIP1-/- HeLa cell growth rescue assay (PMID: 31822495). This variant has been reported in an individual with breast cancer (PMID: 29368626) and in an individual with melanoma (PMID: 30414346), as well as in a few individuals unaffected with cancer (PMID: 29368626, 29641532). In one study, this variant was observed in 6/101,759 individuals with breast cancer, in 2/15,587 individuals with ovarian cancer, and in 2/9,884 FLOSSIES individuals (women over age 70 lacking personal history of cancer; PMID: 31822495). In an international breast cancer case-control meta-analysis, this variant was detected in 5/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 8/281722 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267955	SCV000699699	uncertain significance	not specified	2022-08-01	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2593C>T (p.Arg865Trp) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250326 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2593C>T has been reported in the literature in individuals affected with breast or ovarian cancer (e.g. Weber-Lassalle_2018, Moyer_2020). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 5/60466 cases, but was also found in 2/53461 controls (Dorling_2021 through LOVD). The variant has also been found in 2/7,325 women of European American ancestry who were over 70 years of age, and never had cancer (FLOSSIES database). In addition, the variant was reported in one individual with melanoma from a melanoma-affected family, but the variant did not co-segregate with disease (Potjer_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had a reduced half-life in vitro compared to the wild-type protein and was unable to rescue a BRIP1 null phenotype in an inter-strand cross link damage survival assay (Moyer_2020). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000662563	SCV000785165	uncertain significance	Fanconi anemia complementation group J; Neoplasm of ovary	2017-05-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000709537	SCV000839364	uncertain significance	Fanconi anemia complementation group J	2018-07-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000217245	SCV002533637	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267955	SCV002551161	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003316204	SCV004019295	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.
Baylor Genetics	RCV003316204	SCV004214685	uncertain significance	Familial cancer of breast	2023-10-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586310	SCV004220708	uncertain significance	not provided	2023-05-12	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000047 (6/128716 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been reported in individuals with breast/ovarian cancer as well as in controls (PMIDs: 29368626 (2018), 29641532 (2018), 31822495 (2019), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRIP1)). It has also been observed in an individual with melanoma (PMID: 30414346 (2019)). A functional study indicated this variant causes reduced protein stability and impaired DNA interstrand cross-link repair in a cell survival assay (PMID: 31822495 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.