Submissions for variant NM_032043.3(BRIP1):c.2992_2995del (p.Lys998fs)

dbSNP: rs786203717

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167141	SCV000217971	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-22	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 identified in early onset breast cancer and ovarian cancer patients (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; Carter NJ et al. Gynecol Oncol. 2018 Dec;151(3):481-488). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458808	SCV000547323	pathogenic	Familial cancer of breast; Fanconi anemia complementation group J	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys998Glufs*60) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 252 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs786203717, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 18628483, 26921362, 28423363). ClinVar contains an entry for this variant (Variation ID: 187416). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects BRIP1 function (PMID: 18628483, 20159562, 21127055, 21345144). This variant disrupts a region of the BRIP1 protein in which other variant(s) (p.Ser1070Glnfs*8) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000478533	SCV000564817	pathogenic	not provided	2023-05-08	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 et al., 2008); Observed in individuals with breast, ovarian, or renal cancer (De Nicolo et al., 2008; Easton et al., 2016; Tedaldi et al., 2017; Carter et al., 2018; Yngvadottir et al., 2022); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21345144, 26921362, 20159562, 18628483, 20346647, 29368626, 31325073, 34426522, 35441217, 29922827, 33840814, 28423363, 30322717)
Color Diagnostics, LLC DBA Color Health	RCV000167141	SCV000684241	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-06	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last exon. This variant is expected to escape nonsense-mediated decay and be expressed as a truncated protein that lacks the functional domains involved in BRCA1-binding, DNA damage and replication stress responses and attenuation of DNA damage tolerance pathway (PMID: 11301010, 14983014, 20159562, 20173781, 22792074). A functional study has shown that this variant affects protein stability and impairs interaction with BRCA1 (PMID: 18628483). This variant has been reported in multiple individuals affected with breast cancer or from a high risk family (PMID: 18628483, 26921362, 28423363, 29368626, 31325073). One of these individuals also carried a pathogenic variant in the BRCA2 gene (PMID: 28423363). This variant has been observed in multiple individuals affected with breast cancer or having a family history of breast, ovarian or colorectal cancer (Color internal data). This variant has been identified in 5/282468 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 Likely Pathogenic.
Counsyl	RCV000663176	SCV000786341	pathogenic	Fanconi anemia complementation group J; Ovarian neoplasm	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
Revvity Omics, Revvity	RCV001781517	SCV002017944	pathogenic	Fanconi anemia complementation group J	2019-05-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000167141	SCV002533667	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-17	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265649	SCV002547613	pathogenic	Hereditary breast ovarian cancer syndrome	2022-05-04	criteria provided, single submitter	clinical testing	Variant summary: BRIP1 c.2992_2995delAAGA (p.Lys998GlufsX60) results in a premature termination codon causes a truncation of the encoded protein which is a commonly known mechanism for disease (De Nicolo_2008). Truncations downstream of this position have been observed at our laboratory and reported in association with other BRIP1-related cancers in the HGMD database. The variant allele was found at a frequency of 1.6e-05 in 251076 control chromosomes. c.2992_2995delAAGA has been reported in the literature among individuals with a variety of BRIP1-associated cancers such as breast/ovarian and AML (example, De Nicolo_2008, Tedaldi_2017, Carter_2018, Weber-Lassalle_2018, Wagener_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Di Nicolo_2008). The most pronounced variant effect impairs BRIP1 function and its ability to interact with BRCA1. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV002288764	SCV002579452	pathogenic	Familial cancer of breast	2021-08-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288764	SCV004019355	pathogenic	Familial cancer of breast	2023-02-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002288764	SCV004175999	pathogenic	Familial cancer of breast	2024-05-22	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PS4,PM2_SUP
Baylor Genetics	RCV002288764	SCV004214739	pathogenic	Familial cancer of breast	2023-09-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478533	SCV004220715	pathogenic	not provided	2023-04-12	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRIP1 mRNA and causes the premature termination of BRIP1 protein synthesis. The frequency of this variant in the general population, 0.000023 (3/129046 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with breast and/or ovarian cancer (PMID: 18628483 (2008), 26921362 (2016), 28423363 (2017), 29368626 (2018), 30322717 (2018), and 31325073 (2019)), as well as in an individual with acute myeloid leukemia (PMID: 33840814 (2021)). One functional study on transfected cells showed that the truncation interferes with the stability of the protein and with its ability to interact with BRCA1 (PMID: 18628483 (2008)), while another demonstrated reduced protein expression and BRCA1 binding disruption (PMID: 21345144 (2011)). Based on the available information, this variant is classified as pathogenic.
Genomic Medicine Lab, University of California San Francisco	RCV002288764	SCV004847121	pathogenic	Familial cancer of breast	2023-12-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000478533	SCV005075166	pathogenic	not provided	2024-06-01	criteria provided, single submitter	clinical testing	BRIP1: PVS1:Strong, PM2, PS3:Moderate, PS4:Moderate
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf	RCV000167141	SCV001482294	uncertain significance	Hereditary cancer-predisposing syndrome		flagged submission	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