Submissions for variant NM_032043.3(BRIP1):c.2765T>G (p.Leu922Ter)

gnomAD frequency: 0.00001  dbSNP: rs587782410

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131449	SCV000186433	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-25	criteria provided, single submitter	clinical testing	The p.L922* pathogenic mutation (also known as c.2765T>G), located in coding exon 18 of the BRIP1 gene, results from a T to G substitution at nucleotide position 2765. This changes the amino acid from a leucine to a stop codon within coding exon 18. This mutation has been identified in a cohort of unselected patients with triple negative breast cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11), in 0/3236 cases with invasive epithelial ovarian cancer and in 1/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107), and in 1/13213 breast cancer cases and 0/5242 controls from the UK (Easton DF et al. J Med Genet, 2016 05;53:298-309). 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.
GeneDx	RCV000216847	SCV000279375	pathogenic	not provided	2024-02-11	criteria provided, single submitter	clinical testing	Nonsense 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (PMID: 25452441, 26921362, 29368626); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26315354, 25452441, 26921362, 28152038, 29368626, 29308099, 31980526, 29922827, 33804961, 35022142, 34887416)
Counsyl	RCV000410978	SCV000489911	pathogenic	Fanconi anemia complementation group J	2016-08-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000412207	SCV000489912	pathogenic	Ovarian neoplasm	2016-08-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468535	SCV000547327	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu922*) 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 present in population databases (rs587782410, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 25452441, 26921362). ClinVar contains an entry for this variant (Variation ID: 142366). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588116	SCV000699703	likely pathogenic	Hereditary breast ovarian cancer syndrome	2016-11-25	criteria provided, single submitter	clinical testing	Variant summary: The BRIP1 c.2765T>G (p.Leu922X) variant results in a premature termination codon, predicted to cause a truncated or absent BRIP1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121394, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRIP1 variant of 1/16000. The variant has been reported in one triple negative breast cancer case as well as a high-risk unaffected control (Couch_2015, Ramus_2015) via publications. In addition, multiple clinical diagnostic laboratories cite the variant as "pathogenic." However, it does need to be noted, a recent publication by Easton_2016 (PMID: 26921362) indicates that the prevalence of truncating variants in BRIP1 have comparable occurrences in controls and cases, for example, p.Arg798Ter was observed in 23 cases and 18 controls, suggesting that truncating variants may not be associated with a substantial increase in breast cancer risk, although the authors do state "BRIP1 screening might have utility for ovarian cancer risk prediction, in combination with other risk factors." Therefore, the variant of interest has been classified as "Likely Pathogenic."
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131449	SCV000803167	pathogenic	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216847	SCV000887991	pathogenic	not provided	2023-09-05	criteria provided, single submitter	clinical testing	The BRIP1 c.2765T>G (p.Leu922*) variant causes the premature termination of BRIP1 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 25452441 (2015), 26921362 (2016), 29368626 (2018), and 33471991 (2021)), in an individual with testicular, prostate, and bladder cancer (PMDI: 35022142 (2022)), and in unaffected controls (PMIDs: 26315354 (2015), 34887416 (2021), 33804961 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ BRIP1)). The frequency of this variant in the general population, 0.000026 (3/113686 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131449	SCV000903752	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-25	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 19 of the BRIP1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been reported in an individual affected with triple negative breast cancer (PMID: 25452441) and an unaffected control in an ovarian cancer case-control study (PMID: 26315354). This variant has been identified in 3/251392 chromosomes 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.
Sema4, Sema4	RCV000131449	SCV002533645	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288648	SCV002579049	likely pathogenic	Familial cancer of breast	2022-03-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288648	SCV004019420	pathogenic	Familial cancer of breast	2023-03-01	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000216847	SCV004026116	pathogenic	not provided	2022-07-29	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2_SUP
Baylor Genetics	RCV002288648	SCV004211325	pathogenic	Familial cancer of breast	2024-02-21	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000216847	SCV005089806	likely pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing