Dutch and Belgian working group on variant interpretation in hereditary breast and ovarian cancer predisposition genes (LOB)
Since more than 20 years representatives from all clinical genetic diagnostic laboratories from the Netherlands and Flanders (Belgium) are collaborating in the Dutch and Belgian working group LOB (Dutch abbreviation for National Consultation for hereditary Breast cancer diagnostics) to share new developments and insights in the field of germline breast- and ovarian cancer DNA diagnostics. This group meets regularly (~ 3-4 times per year). During the meetings, clinical laboratory geneticists make definitive calls on the pathogenicity of VUS, based on available data and ENIGMA variant interpretation guidelines, to allow uniform interpretation of these variants in the different centers.
The collaborative group Hereditary Breast and Ovarian cancer Research in the Netherlands (HEBON) serves as a resource for conducting various Dutch multi-disciplinary studies with their centralized collection of clinical and genetic data for research purposes. In the past years, the collaborative effort of LOB and HEBON facilitated the collection and analysis of data for several ENIGMA-related studies (REF).
In 2020, a national consortium has been established (CRAFT; Cancer Risk Assessment through Functional Testing) in which researchers performing functional gene tests work closely together with clinical genetics laboratory specialists and clinical geneticists involved in counseling and diagnosis of hereditary breast and ovarian cancer. The CRAFT database includes detailed information necessary for classification of variants in BRCA1, BRCA2 and PALB2 and provides up-to-date variant classifications. The CRAFT consortium facilitates (national and international) collaborative research projects.
For more information please contact:
Dr. Arjen Mensenkamp, Radboud University Nijmegen, the Netherlands, email: email@example.com
Dr. Maaike Vreeswijk, Leiden University Medical Center, the Netherlands, email: firstname.lastname@example.org
Dr Kathleen Claes, Ghent University hospital, Belgium, e-mail: Kathleen.email@example.com
The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC)
The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) is an association of 24 specialized centers located at university hospitals and cooperating gynecological cancer centers and breast centers in Germany coordinated by Prof. Rita Schmutzler. The aim of our consortium is to provide the optimal care and advice for patients and those seeking advice with familial breast and/or ovarian cancer. A central concern is the best possible risk assessment by means of fully comprehensive genetic testing and recording of all risk factors. To enable this, one of our most important tasks in research and diagnostics is therefore the classification of sequence variants found by genetic testing. With our Central National Patient Database and the contained data of meanwhile more than 60,000 risk families, we will continue our ongoing contributions to numerous projects of the ENIGMA consortium in order to meet this challenge in an international network.
Further information can be found at: https://www.konsortium-familiaerer-brustkrebs.de
Contact: Dr. Jan Hauke, University Hospital Cologne, E-mail: firstname.lastname@example.org
The CZECANCA (CZEch CAncer paNel for Clinical Application) consortium
The CZECANCA consortium brings together laboratories involved in cancer predisposition diagnostics and clinical research in the Czech Republic. The consortium manages the genotype-to-phenotype database (currently including 17,654 Czech high-risk cancer patients and 2,453 population-matched controls analyzed by identical 226 gene panel), develops consensual variant classification, updates national guidelines for cancer predisposition germline genetic testing, and participates in updating national guidelines for clinical care of carriers of pathogenic variants in cancer predisposition genes. Other activities of the consortium and contacts are available on its website: http://www.czecanca.cz
The French consortium (French UGG = UNICANCER Genetics group)
The French consortium (French UGG = UNICANCER Genetics group) is a National Cancer Genetics Network which gathers expert clinicians, biologists, and researchers. The consortium was established in 1991 to contribute to the identification of cancer predisposing genes and estimation of cancer risks based on national (GENEPSO, GEMO, GENESIS) and international (IBCCS, CIMBA) genetic epidemiological studies and to define recommendations for genetic testing and management of individuals at risk (1–4). In 2022, the UGG consists of a network of 148 public/private cancer genetics clinics throughout France and 26 academic molecular genetics laboratories, 17 of which routinely perform breast-ovarian cancer genetic testing.
Between 1994 and 2020, about 300,000 index cases (ICs) were sequenced for BRCA1/BRCA2 (and other genes) in the UGG cancer genetics clinic and laboratory network. The sequencing was performed by specific gene analyzes until 2017 and by multigene panel thereafter (5,6). All identified variants (except for common polymorphisms) are reported in a dedicated BRCA1/BRCA2 database initially called UMD-BRCA1/ BRCA2 (BRCAShare7) and now called FrOG (French OncoGenetics) database: https://frog-db.fr/. The FrOG database now includes variants of 13 genes whose alterations are associated with an increased risk of cancer. This database is a helpful everyday tool for molecular geneticists and an essential resource for the variant classification.
A working group composed of the UGG molecular geneticists is in charge of the classification of variants. The curation of breast-ovarian cancer associated genes is under the responsibility of S. Caputo. The HBOC UGG group has designed the COVAR (COsegregation VARiants) study. The objective of the study is to organize co-segregation studies of the VUS of the French database (8).
With our UGG network, we have contributed and will continue our ongoing contributions to numerous projects of the ENIGMA consortium in order to meet this challenge in an international network.
For further information: https://recherche.unicancer.fr/fr/les-groupes-d-experts/groupe-genetique-et-cancer/
- Lesueur, F. et al. GEMO, a National Resource to Study Genetic Modifiers of Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Pathogenic Variant Carriers. Front. Oncol. 8, 490 (2018).
- Caputo, S. et al. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res. 40, D992–D1002 (2012).
- Girard, E. et al. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. Int. J. Cancer 144, 1962–1974 (2019).
- Jiao, Y. et al. A new hybrid record linkage process to make epidemiological databases interoperable: application to the GEMO and GENEPSO studies involving BRCA1 and BRCA2 mutation carriers. BMC Med. Res. Methodol. 21, 155 (2021).
- Moretta, J. et al. [The French Genetic and Cancer Consortium guidelines for multigene panel analysis in hereditary breast and ovarian cancer predisposition]. Bull. Cancer (Paris) (2018) doi:10.1016/j.bulcan.2018.08.003.
- Dhooge, M. et al. National recommendations of the French Genetics and Cancer Group – Unicancer on the modalities of multi-genes panel analyses in hereditary predispositions to tumors of the digestive tract. Eur. J. Med. Genet. 63, 104080 (2020).
- Béroud, C. et al. BRCA Share: A Collection of Clinical BRCA Gene Variants. Hum. Mutat. (2016) doi:10.1002/humu.23113.
- Caputo, S. M. et al. Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach. Am. J. Hum. Genet. 108, 1907–1923 (2021).
The UK Cancer Variant Interpretation Group (CanVIG-UK)
The UK Cancer Variant Interpretation Group (CanVIG-UK) consists of >350 clinical scientists, geneticists, oncologists, and genetic counsellors from across the UK and Republic of Ireland (ROI). Via a regular monthly meeting, CanVIG-UK provides an active forum for information sharing and discussion between diagnostic labs across the UK and Ireland. These meetings serve as an opportunity to review as a community new variant interpretation guidance from gene-specific VCEPs, as well as new data and recommendations from UK-ACGS (Association of Clinical Genomic Science) and ClinGen. In partnership with UK-ACGS, to ensure national consistency in reporting and classification across the full NHS lab community, we have developed a very detailed specification of the ACMG variant interpretation framework, including specific delineation of where ACMG evidence codes that can or can’t be combined. We share ahead of each meeting a problematic “variant-of-the-month” which labs classify ahead of the meeting and we review for the purposes of education and consensus classification.
Through CanVIG-UK we have evolved the Cancer Predisposition Gene Variant Database, CanVar-UK (https://canvaruk.org/). CanVar-UK presents for each variant in >100 cancer susceptibility genes, data arranged by tab, from curated publicly available resources (eg in silico tools, gnomAD), selected functional assays, gen epi analyses, live ClinVar classifications, as well as our national NHS Digital numerator/denominator counts for NHS testing for MMR/BRCA variants in highly enriched probands.
CanVIG-UK members have access to the CanVar-UK diagnostic user forum, through which they can generate from CAnVar-UK an email about a tricky variant to be sent out to the full diagnostic user community (>400 members). This off-line discussion between diagnostic teams across hospitals and laboratory hubs facilitates a remote multicentre ‘classification MDT’, with all email dialogue captured in CanVar-UK for future reference. CanVar-UK also provides an urgent alert system to notify all members in the event of variant re-classification. We are now welcoming those working in genomic diagnostics from outside of the UK to join our CanVar-UK “diagnostic users forum” (register at https://canvaruk.org/). Consensus classifications from CanVIG-UK and CanVar-UK are submitted to ClinVar for international consideration.
CanVIG-UK is supported by funding from Cancer Research UK and is led by Clare Turnbull, Alice Garrett, Sophie Allen and the team at the Institute of Cancer Research. CanVIG-UK is supported by the CanVIG-UK Steering and Advisory Group (CStAG), which comprises a lab lead from each UK Genomic Laboratory Hubs and meets monthly to plan in detail CanVIG-UK activities. CanVIG-UK also works closely with NHS England and NHS Digital to coordinate national laboratory data submissions..
For more information, please see https://www.cangene-canvaruk.org/canvig-uk
or email CanVIG@icr.ac.uk
Danish Breast Cancer Classification group (DBKG)
Danish Breast Cancer Classification group (DBKG) is a national collaboration group including the major genetic and genomic hospital departments in Denmark performing genetic testing and interpretation of germline variants in breast and ovarian cancer associated genes. DBKG is part of Danish Breast Cancer Collaborative Group (DBCG). The major aim for the group is classification of genetic variants in a concerted action to ensure state of the art and uniform interpretation of variants according to ENIGMA guidelines. The group has regular meetings every second month and sub working groups are focusing on specific genes and variants. The DBKG database currently contains more than 2000 variants curated by the members.
DBKG is also coordinating research projects aiming classification of variants on a national level and within the framework of ENIGMA.
Publication describing Danish Breast Cancer Classification group (Pedersen et al., 2018)
Contact: Prof. Mads Thomassen, Odense University Hospital, e-mail: Mads.Thomassen@rsyd.dk