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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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