ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.2992_2995del (p.Lys998fs) (rs786203717)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167141 SCV000217971 pathogenic Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing The c.2992_2995delAAGA pathogenic mutation, located in coding exon 19 of the BRIP1 gene, results from a deletion of 4 nucleotides between positions 2992 and 2995, causing a translational frameshift with a predicted alternate stop codon. This mutation has been described in two women with early onset breast cancer (De Nicolo A et al. Clin. Cancer Res. 2008 Jul; 14(14):4672-80; Tedaldi G et al. Oncotarget 2017 Jul;8(29):47064-47075). Functional analysis indicates that the premature truncation resulting from this alteration interferes with the stability of the protein and with its ability to interact with BRCA1 (De Nicolo A et al. Clin. Cancer Res. 2008 Jul; 14(14):4672-80). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000458808 SCV000547323 pathogenic Familial cancer of breast; Fanconi anemia, complementation group J 2020-09-17 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BRIP1 gene (p.Lys998Glufs*60). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 252 amino acids of the BRIP1 protein. This variant is not present in population databases (rs786203717, ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 18628483, 26921362, 28423363). ClinVar contains an entry for this variant (Variation ID: 187416). This variant disrupts the C-terminal 252 amino acid residues of the BRIP1 protein, partially disrupting the BRCA1-interacting domain that is essential for proper BRIP1 function (PMID: 21345144). It is also expected to disrupt the TopBP1-BRIP1 interaction that plays a critical role in RPA chromatin loading in response to DNA damage (PMID: 20159562, 21127055). Experimental studies have shown that this variant leads to the expression of a truncated, unstable protein that has impaired ability to bind to BRCA1 (PMID: 18628483). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000478533 SCV000564817 pathogenic not provided 2020-04-08 criteria provided, single submitter clinical testing Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 252 amino acids are lost and replaced with 59 incorrect amino acids; Published functional studies demonstrate a damaging effect: impaired protein stability and interaction with BRCA1 (De Nicolo 2008); Observed in individuals with breast cancer (De Nicolo 2008, Easton 2016); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 21345144, 26921362, 20159562, 30322717, 18628483, 20346647, 28423363, 29368626, 31325073)
Color Health, Inc RCV000167141 SCV000684241 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-03 criteria provided, single submitter clinical testing
Counsyl RCV000663176 SCV000786341 pathogenic Fanconi anemia, complementation group J; Neoplasm of ovary 2018-04-13 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000167141 SCV001448750 pathogenic Hereditary cancer-predisposing syndrome 2019-03-20 criteria provided, single submitter clinical testing
Department of Pediatric Oncology, Hematology and Clinical Immunology,University Clinics Duesseldorf RCV000167141 SCV001482294 uncertain significance Hereditary cancer-predisposing syndrome criteria provided, single submitter research
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001554295 SCV001774870 pathogenic Breast carcinoma 2021-08-09 no assertion criteria provided clinical testing

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