BRIP1

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: ClinGen

*BRIP1* (BRCA1 interacting protein) is a DNA repair gene that contributes to the DNA repair function of BRCA1. *BRIP1* has been linked to familial ovarian cancer (autosomal dominant) and Fanconi anemia complementation group J (autosomal recessive), which were curated separately, Per criteria outlined by the ClinGen Lumping and Splitting Working Group, curations to refute or dispute can be split when needed. This curation focuses on refuting the association with hereditary breast cancer. Evidence curated in this gene-disease relationship includes case-control data and experimental data. **Summary of Case-Control Data: 0 point** This gene-disease relationship has been studied in at least 6 case-control studies at the aggregate and single variant levels. In 2021, two large case-control studies [CARRIERS (PMID: 33471974) and BCAC (PMID: 33471991); both with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in *BRIP1* and breast cancer. Likewise, another large case-control study published in 2017 screened breast cancer cases from commercial laboratories and did not find significant association of pathogenic mutations in *BRIP1* with breast cancer (PMID: 28418444). In addition, three other case-control studies (PMIDs: 17504528, 26921362, 34672684), with case populations ranging from 571 to 13078 did not show an association of LOF variants with breast cancer. **Summary of Experimental Data: 1 point** While case-control studies did not support the gene-disease association, there is experimental evidence showing that BRIP1 physically interacts with BRCA1 (PMID: 14576433). Another study showed that two missense *BRIP1* variants altered the protein functions (PMID: 14983014). Daino et al. (PMID: 24040146) also showed that *BRIP1*-knockout cells had a 3-fold higher rate of proliferation than the controls. However, the Daino et al. paper reported no tumor formation in the knockout mouse model. **Overall Summary:** In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between *BRIP1* and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as refuted by the Breast/Ovarian Cancer GCEP on 5/10/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 6/9/2023 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0005484

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0012187

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012187

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012187

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Illumina

Inheritance Pattern: AD

Disease ID:MONDO:0016248

Submitter: ClinGen

*BRIP1* (BRCA1 interacting protein) is a DNA repair gene that contributes to the DNA repair function of BRCA1. *BRIP1* has been linked to familial ovarian cancer and hereditary breast cancer (autosomal dominant), and Fanconi anemia complementation group J (autosomal recessive). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split the autosomal recessive Fanconi anemia complementation group J into separate curation due to phenotypic variability and different inheritance patterns. We also curated separately the autosomal dominant hereditary breast cancer to refute the gene-disease relationship. Therefore, this curation solely focuses on autosomal dominant familial ovarian cancer. This gene-disease relationship has been studied in at least six case-control or cohort studies at the aggregate variant level (12 points). Five case-control studies suggested significant increased risk for ovarian cancer in monoallelic *BRIP1* variant carriers compared to controls (PMIDs: 26315354, 26720728, 29368626, 32359370, 35172496). Another case-control study (PMID: 31341520) showed conflicting results, in which the authors found a significant association of pathogenic variants in *BRIP1* and ovarian cancer by analyzing crude data; whereas age-adjusted data showed no ovarian cancer association, which may reflect that *BRIP1* variant carriers are more likely to be diagnosed with late-onset ovarian cancer than non-carriers. This gene-disease relationship is also supported by experimental evidence of protein interaction assay and cell culture models (1.5 Points; PMIDs: 11301010, 14576433, 16153896). Pull-down and co-immunoprecipitation assays revealed that the BRCT domain of BRCA1 protein directly interacts with phosphorylated BRIP1, which is further required for DNA damage-induced checkpoint control during the transition from G2 to M phase of the cell cycle. Cells deficient of *BRIP1* also failed to elicit homologous recombination after DNA double stranded breaks. In summary, *BRIP1* is definitively associated with autosomal dominant familial ovarian cancer. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated as definitive by the Breast/Ovarian Cancer GCEP on 10/12/2016. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 07/28/2023 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0012187

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0012187

Submitter: ClinGen

BRIP1 gene, the BRCA1-interacting helicase, has been associated with Fanconi anemia of complementation group J (FANCJ) (#609054). At least 27 variants have reported in unrelated families/groups. Here we record 5 individuals in 4 families (3 Innuit individuals and 2 Hispanic individuals) and 6 individuals in a group of 18 FA cases of unassigned FA complementation group from IFAR [Livran O et al., PubMed: 16116424]; 6 individuals from various backgrounds, many with reported consanguinity (Iran, Canada, UK and Kuwait) from EUFA [Levitus M et al., PMID: 16116423]. Most of these FA individuals either have homozygous or compound heterozygous mutations in BRIP1 gene. The most common one, 2533C>T (R798X), may be a hot spot or an ancient mutation. Immunoblotting showed no BRIP1 protein in lymphoblastoid cells line from individuals who were homozygous or heterozygous with respect to 2533C-T/R798X (R798X/8003A>T and R798X/Y800X) (Levran O et al., 2005.). Western blot using antibody against BRIP1 showed the absence of a full-length BRIP1 protein band in nuclear extracts from cell lines carrying truncating mutations, whereas an attenuated band was observed in the cell line from individual EUFA776 with two missense mutations (1941G>C/W647C and 2119C>T/R707C) (Levitus M et al,. 2005.). Purified recombinant A349P allele protein had reduced iron and was defective in coupling adenosine triphosphate (ATP) hydrolysis and translocase activity to unwinding forked duplex or G-quadruplex DNA substrates or disrupting protein-DNA complexes. The FANCJ-A349P allele failed to rescue cisplatin or telomestatin sensitivity of a FA-J null cell line. Experimental evidences are replicably showed its DNA repair function. Mutations in this gene abolish its DNA helicase activity in cellular levels and animal models.

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: Ambry Genetics