Submissions for variant NM_032043.3(BRIP1):c.3444C>A (p.Asp1148Glu)

gnomAD frequency: 0.00011  dbSNP: rs28997573

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131003	SCV000185928	likely benign	Hereditary cancer-predisposing syndrome	2019-01-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000589005	SCV000210829	uncertain significance	not provided	2023-07-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with BRIP1-related and other cancers but also in healthy controls (Seal et al., 2006; Ramus et al., 2015; Tung et al., 2015; Yurgelun et al., 2015; Easton et al., 2016; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 24728327, 26689913, 25186627, 26315354, 26921362, 17033622, 25980754, 23555315, 33471991, 20159562, 21127055)
Invitae	RCV000204453	SCV000260424	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1148 of the BRIP1 protein (p.Asp1148Glu). This variant is present in population databases (rs28997573, gnomAD 0.02%). This missense change has been observed in individual(s) with Lynch syndrome, ovarian cancer, breast cancer, and renal clear cell carcinoma (PMID: 25186627, 25980754, 26315354, 26689913). ClinVar contains an entry for this variant (Variation ID: 133758). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	RCV000411479	SCV000490063	uncertain significance	Fanconi anemia complementation group J	2016-11-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000409042	SCV000490064	uncertain significance	Ovarian neoplasm	2016-11-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589005	SCV000699724	uncertain significance	not provided	2017-01-26	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 c.3444C>A (p.Asp1148Glu) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant . This variant was found in 15/131898 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000165 (11/66494). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The varaint was reported in the literature in BrC/OvC patients, without strong evidence for causality, as well as in a Lynch syndrome patient who carried a potentially pathogenic MLH1 variant (c.1989+3dupC; Yurgelun_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS, while one classified it as likely benign. Due to the relatively high frequency of the variant in the general population, multiple in silico tools predict benign outcome, as well as the co-occurrence in a patient with a potentially pathogenic variant, this variant has been classified as possibly benign variant until additional evidence becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000131003	SCV000902753	likely benign	Hereditary cancer-predisposing syndrome	2016-06-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000989978	SCV001140740	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589005	SCV002010906	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120402	SCV002068447	uncertain significance	not specified	2018-03-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131003	SCV002533693	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-24	criteria provided, single submitter	curation
Genetics and Molecular Pathology, SA Pathology	RCV000989978	SCV002556673	uncertain significance	Familial cancer of breast	2022-05-25	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000989978	SCV002581745	uncertain significance	Familial cancer of breast	2022-08-09	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120402	SCV002760974	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149828	SCV003838373	uncertain significance	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000989978	SCV004019476	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589005	SCV004220722	likely benign	not provided	2021-10-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589005	SCV004564612	uncertain significance	not provided	2023-11-30	criteria provided, single submitter	clinical testing	The BRIP1 c.3444C>A; p.Asp1148Glu variant (rs28997573) is reported in the literature in individuals with hereditary cancer syndromes but is also reported in healthy controls (Bhai 2021, Ramus 2015, Seal 2006, Tung 2015, Yurgelun 2015). This variant is also reported in ClinVar (Variation ID: 133758). It is observed in the general population with an overall allele frequency of 0.01% (29/281212 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is neutral (REVEL: 0.072). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bhai P et al. Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. Front Genet. 2021 Jul 13;12:698595. PMID: 34326862. Ramus SJ et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst. 2015 Aug 27;107(11):djv214. PMID: 26315354. Seal S et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006 Nov;38(11):1239-41. PMID: 17033622. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. PMID: 25980754.
ITMI	RCV000120402	SCV000084554	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000131003	SCV000787968	likely benign	Hereditary cancer-predisposing syndrome	2017-10-30	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535623	SCV001749649	not provided	Fanconi anemia complementation group J; Familial ovarian cancer		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-15-2017 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000589005	SCV001906078	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589005	SCV001953534	likely benign	not provided		no assertion criteria provided	clinical testing