Submissions for variant NM_032043.3(BRIP1):c.2469G>T (p.Arg823Ser)

gnomAD frequency: 0.00003  dbSNP: rs587780239

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590497	SCV000150051	uncertain significance	not provided	2023-05-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of pancreatic or breast cancer (Shindo et al., 2017; Hu et al., 2020; Lerner-Ellis et al., 2021); This variant is associated with the following publications: (PMID: 17033622, 28767289, 29368626, 32659497, 11301010, 32885271)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123356	SCV000166679	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 serine, which is neutral and polar, at codon 823 of the BRIP1 protein (p.Arg823Ser). This variant is present in population databases (rs587780239, gnomAD 0.1%). This missense change has been observed in individual(s) with breast cancer or pancreatic cancer (PMID: 17033622, 28767289). ClinVar contains an entry for this variant (Variation ID: 128173). 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. 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.
Ambry Genetics	RCV000116142	SCV000186708	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-04	criteria provided, single submitter	clinical testing	The p.R823S variant (also known as c.2469G>T), located in coding exon 16 of the BRIP1 gene, results from a G to T substitution at nucleotide position 2469. The arginine at codon 823 is replaced by serine, an amino acid with dissimilar properties. This variant was reported in 1/1212 breast cancer patients with a family history of breast or ovarian cancer, but was not seen in 2081 controls (Seal S et al. Nat. Genet. 2006 Nov;38:1239-41). It was also reported in 1/1142 pancreatic cancer patients (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). This variant was also observed in 2/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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	RCV000116142	SCV000537542	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 823 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 17033622), pancreatic cancer (PMID: 28767289, 32659497) and ovarian cancer (Collet 2015, DOI: 10.3934/genet.2015.4.263), but also in control individuals (PMID: 29368626). This variant has been identified in 12/249930 chromosomes (10/10054 Ashkenazi Jewish 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	RCV000590497	SCV000699696	uncertain significance	not provided	2016-01-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000662607	SCV000785251	uncertain significance	Fanconi anemia complementation group J; Ovarian neoplasm	2017-06-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590497	SCV001469732	uncertain significance	not provided	2023-08-04	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 17033622 (2006), 32885271 (2021) 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRIP1)), and pancreatic cancer (PMID: 28767289 (2017), 32659497 (2020)). This variant has also been reported in unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRIP1)). The frequency of this variant in the general population, 0.00099 (10/10054 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.
Sema4, Sema4	RCV000116142	SCV002533628	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000123356	SCV002789893	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2022-05-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315651	SCV004019508	uncertain significance	Familial cancer of breast	2023-03-02	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	RCV003315651	SCV004214628	uncertain significance	Familial cancer of breast	2024-03-04	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000116142	SCV000787966	likely benign	Hereditary cancer-predisposing syndrome	2017-06-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356515	SCV001551712	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRIP1 p.Arg823Ser variant was identified in 2 of 4132 proband chromosomes (frequency: 0.0005) from individuals or families with breast or pancreatic cancer and was not identified in 4162 control chromosomes from healthy individuals (Seal 2006, Shindo 2017). The variant was also identified in dbSNP (ID: rs587780239) as "With Likely benign, Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics and three other submitters; and as likely benign by True Health Diagnostics). The variant was identified in control databases in 12 of 244892 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 111146 chromosomes (freq: 0.00002) and Ashkenazi Jewish in 10 of 9830 chromosomes (freq: 0.001), while the variant was not observed in the African, Other, Latino, East Asian, Finnish, or South Asian populations. The p.Arg823 residue is conserved in mammals but not in more distantly related organisms, although 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
GenomeConnect - Invitae Patient Insights Network	RCV001356515	SCV001749658	not provided	Malignant tumor of breast		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-09-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.