Submissions for variant NM_032043.3(BRIP1):c.2038_2039dup (p.Leu680fs)

dbSNP: rs587778134

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213084	SCV000150043	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25452441, 26921362, 26315354, 26681312, 28152038, 24728327, 26845104, 21964575, 17033622, 32427313, 16116423, 32295079, 33471991, 30254378, 25807282, 33858029, 28888541)
Ambry Genetics	RCV000116134	SCV000185786	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	clinical testing	The c.2038_2039dupTT pathogenic mutation, located in coding exon 13 of the BRIP1 gene, results from a duplication of TT at nucleotide position 2038, causing a translational frameshift with a predicted alternate stop codon (p.L680Ffs*9). This mutation has been reported in multiple breast and/or ovarian cancer patients (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Shirts BH et al. Genet Med, 2016 10;18:974-81; Easton DF et al. J Med Genet, 2016 05;53:298-309; Susswein LR et al. Genet Med, 2016 08;18:823-32; Dorling et al. N Engl J Med. 2021 02;384:428-439), and has also been detected in healthy individuals undergoing multigene panel testing (Sulem P et al. Nat Genet, 2015 May;47:448-52; Rowley SM et al. Genet Med, 2019 04;21:913-922; Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000116134	SCV000266057	pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000409330	SCV000489855	likely pathogenic	Fanconi anemia complementation group J	2016-08-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000409984	SCV000489856	likely pathogenic	Ovarian neoplasm	2016-08-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469530	SCV000547370	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu680Phefs*9) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 21964575, 25452441, 26315354, 26681312, 26845104). This variant is also known as c.2040_ 2041insTT. ClinVar contains an entry for this variant (Variation ID: 128166). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000213084	SCV000889204	pathogenic	not provided	2017-09-29	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRIP1 protein synthesis. In addition, it has been reported in individuals with breast and/or ovarian cancer in the published literature (PMID: 25452441 (2015), 26681312 (2015), 26315354 (2015), and 26845104 (2016)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000116134	SCV000911176	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides in exon 14 of the BRIP1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 25452441, 26315354, 26681312, 26845104, 26921362, 33471991) as well as in unaffected individuals (PMID: 30254378, 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000213084	SCV001248140	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315650	SCV004019464	pathogenic	Familial cancer of breast	2023-03-02	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003315650	SCV004217110	pathogenic	Familial cancer of breast	2024-02-15	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000213084	SCV005199045	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing
ITMI	RCV000120393	SCV000084545	not provided	not specified	2013-09-19	no assertion provided	reference population
CZECANCA consortium	RCV001271072	SCV001451898	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000213084	SCV001809635	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000213084	SCV001930784	pathogenic	not provided		no assertion criteria provided	clinical testing
CZECANCA consortium	RCV003128146	SCV003804357	pathogenic	Uterine corpus cancer	2023-02-21	no assertion criteria provided	clinical testing