A new bioinformatics tool to help assess the significance of BRCA1 variants

Abstract

Background: Germline pathogenic variants in the breast cancer type 1 susceptibility gene BRCA1 are associated with a 60% lifetime risk for breast and ovarian cancer. This overall risk estimate is for all BRCA1 variants; obviously, not all variants confer the same risk of developing a disease. In cancer patients, loss of BRCA1 function in tumor tissue has been associated with an increased sensitivity to platinum agents and to poly-(ADP-ribose) polymerase (PARP) inhibitors. For clinical management of both at-risk individuals and cancer patients, it would be important that each identified genetic variant be associated with clinical significance. Unfortunately for the vast majority of variants, the clinical impact is unknown. The availability of results from studies assessing the impact of variants on protein function may provide insight of crucial importance.

Results and conclusion: We have collected, curated, and structured the molecular and cellular phenotypic impact of 3654 distinct BRCA1 variants. The data was modeled in triple format, using the variant as a subject, the studied function as the object, and a predicate describing the relation between the two. Each annotation is supported by a fully traceable evidence. The data was captured using standard ontologies to ensure consistency, and enhance searchability and interoperability. We have assessed the extent to which functional defects at the molecular and cellular levels correlate with the clinical interpretation of variants by ClinVar submitters. Approximately 30% of the ClinVar BRCA1 missense variants have some molecular or cellular assay available in the literature. Pathogenic variants (as assigned by ClinVar) have at least some significant functional defect in 94% of testable cases. For benign variants, 77% of ClinVar benign variants, for which neXtProt Cancer variant portal has data, shows either no or mild experimental functional defects. While this does not provide evidence for clinical interpretation of variants, it may provide some guidance for variants of unknown significance, in the absence of more reliable data. The neXtProt Cancer variant portal ( https://www.nextprot.org/portals/breast-cancer ) contains over 6300 observations at the molecular and/or cellular level for BRCA1 variants.

Keywords: BRCA1; Biological database; Cancer; Functional defect assessment; Genetic variants; Molecular phenotypes.

Fig. 1

Schematic representation of the BRCA1 primary structure. Major domains are highlighted, and the position of the binding of important interaction partners in shown on top

Fig. 2

Overview of the BRCA1 phenotypes captured at the molecular and biological process levels in the neXtProt Cancer variant portal. The number of unique variants with the most representative phenotypic observations is shown. Numbers in orange background represent variants with some deleterious effect, and numbers in blue background represent variants with no impact for the assayed function

Fig. 3

Position of the variants with defects in ubiquitin transferase activity, BARD1 binding, and UBE2D1 binding for the first 300 BRCA1 residues. Positions where variations have no or mild impact are shown in green, those with moderate effects in yellow, and those with severe defects in red. The positions with no data are in white. The RING domain is indicated (positions 24 to 65)

Fig. 4

Screenshot of the neXtProt Cancer variant portal. Evidence for the triplet “Ser1715Asn decreases transcription, DNA-templated”. There are three evidences supporting this statement based on two papers, annotated as “Severe” because of the amplitude of the activity reduction in each study. One of the evidences is tagged as “Silver” because the human BRCA1 variant was analyzed in a yeast system, which the curator judged less reliable since yeast does not have a BRCA1 ortholog