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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2018-07-01
|
| Series: | Human Genomics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40246-018-0168-0 |
| _version_ | 1811187877620482048 |
|---|---|
| author | Isabelle Cusin Daniel Teixeira Monique Zahn-Zabal Valentine Rech de Laval Anne Gleizes Valeria Viassolo Pierre O. Chappuis Pierre Hutter Amos Bairoch Pascale Gaudet |
| author_facet | Isabelle Cusin Daniel Teixeira Monique Zahn-Zabal Valentine Rech de Laval Anne Gleizes Valeria Viassolo Pierre O. Chappuis Pierre Hutter Amos Bairoch Pascale Gaudet |
| author_sort | Isabelle Cusin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T14:11:04Z |
| format | Article |
| id | doaj.art-3490c6acaf0b4b4d82f6cfe2451da075 |
| institution | Directory Open Access Journal |
| issn | 1479-7364 |
| language | English |
| last_indexed | 2024-04-11T14:11:04Z |
| publishDate | 2018-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Human Genomics |
| spelling | doaj.art-3490c6acaf0b4b4d82f6cfe2451da0752022-12-22T04:19:42ZengBMCHuman Genomics1479-73642018-07-0112111110.1186/s40246-018-0168-0A new bioinformatics tool to help assess the significance of BRCA1 variantsIsabelle Cusin0Daniel Teixeira1Monique Zahn-Zabal2Valentine Rech de Laval3Anne Gleizes4Valeria Viassolo5Pierre O. Chappuis6Pierre Hutter7Amos Bairoch8Pascale Gaudet9CALIPHO group, SIB Swiss Institute of BioinformaticsCALIPHO group, SIB Swiss Institute of BioinformaticsCALIPHO group, SIB Swiss Institute of BioinformaticsCALIPHO group, SIB Swiss Institute of BioinformaticsCALIPHO group, SIB Swiss Institute of BioinformaticsOncogenetics and Cancer Prevention Unit, Division of Oncology, University Hospitals of GenevaOncogenetics and Cancer Prevention Unit, Division of Oncology, University Hospitals of GenevaSophia GeneticsCALIPHO group, SIB Swiss Institute of BioinformaticsCALIPHO group, SIB Swiss Institute of BioinformaticsAbstract 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.http://link.springer.com/article/10.1186/s40246-018-0168-0BRCA1Genetic variantsMolecular phenotypesFunctional defect assessmentBiological databaseCancer |
| spellingShingle | Isabelle Cusin Daniel Teixeira Monique Zahn-Zabal Valentine Rech de Laval Anne Gleizes Valeria Viassolo Pierre O. Chappuis Pierre Hutter Amos Bairoch Pascale Gaudet A new bioinformatics tool to help assess the significance of BRCA1 variants Human Genomics BRCA1 Genetic variants Molecular phenotypes Functional defect assessment Biological database Cancer |
| title | A new bioinformatics tool to help assess the significance of BRCA1 variants |
| title_full | A new bioinformatics tool to help assess the significance of BRCA1 variants |
| title_fullStr | A new bioinformatics tool to help assess the significance of BRCA1 variants |
| title_full_unstemmed | A new bioinformatics tool to help assess the significance of BRCA1 variants |
| title_short | A new bioinformatics tool to help assess the significance of BRCA1 variants |
| title_sort | new bioinformatics tool to help assess the significance of brca1 variants |
| topic | BRCA1 Genetic variants Molecular phenotypes Functional defect assessment Biological database Cancer |
| url | http://link.springer.com/article/10.1186/s40246-018-0168-0 |
| work_keys_str_mv | AT isabellecusin anewbioinformaticstooltohelpassessthesignificanceofbrca1variants AT danielteixeira anewbioinformaticstooltohelpassessthesignificanceofbrca1variants AT moniquezahnzabal anewbioinformaticstooltohelpassessthesignificanceofbrca1variants AT valentinerechdelaval anewbioinformaticstooltohelpassessthesignificanceofbrca1variants AT annegleizes anewbioinformaticstooltohelpassessthesignificanceofbrca1variants AT valeriaviassolo anewbioinformaticstooltohelpassessthesignificanceofbrca1variants AT pierreochappuis anewbioinformaticstooltohelpassessthesignificanceofbrca1variants AT pierrehutter anewbioinformaticstooltohelpassessthesignificanceofbrca1variants AT amosbairoch anewbioinformaticstooltohelpassessthesignificanceofbrca1variants AT pascalegaudet anewbioinformaticstooltohelpassessthesignificanceofbrca1variants AT isabellecusin newbioinformaticstooltohelpassessthesignificanceofbrca1variants AT danielteixeira newbioinformaticstooltohelpassessthesignificanceofbrca1variants AT moniquezahnzabal newbioinformaticstooltohelpassessthesignificanceofbrca1variants AT valentinerechdelaval newbioinformaticstooltohelpassessthesignificanceofbrca1variants AT annegleizes newbioinformaticstooltohelpassessthesignificanceofbrca1variants AT valeriaviassolo newbioinformaticstooltohelpassessthesignificanceofbrca1variants AT pierreochappuis newbioinformaticstooltohelpassessthesignificanceofbrca1variants AT pierrehutter newbioinformaticstooltohelpassessthesignificanceofbrca1variants AT amosbairoch newbioinformaticstooltohelpassessthesignificanceofbrca1variants AT pascalegaudet newbioinformaticstooltohelpassessthesignificanceofbrca1variants |