Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation

Correspondence to Dr Alvaro N Monteiro, Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Alvaro.Monteiro@Moffitt.org ; Dr Maaike P G Vreeswijk, Human Genetics, Leiden University Medical Center, Leiden, 2300RC, The Netherlands; M.P.G.Vreeswijk@lumc.nl In...

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Published in:Journal of medical genetics Vol. 57; no. 8; pp. 509 - 518
Main Authors: Monteiro, Alvaro N, Bouwman, Peter, Kousholt, Arne N, Eccles, Diana M, Millot, Gael A, Masson, Jean-Yves, Schmidt, Marjanka K, Sharan, Shyam K, Scully, Ralph, Wiesmüller, Lisa, Couch, Fergus, Vreeswijk, Maaike P G
Format: Journal Article
Language:English
Published: England BMJ Publishing Group LTD 01.08.2020
BMJ Publishing Group
Series:Online ahead of print
Subjects:
BRCA1 protein
BRCA2 protein
Breast cancer
Classification
Clinical significance
Deoxyribonucleic acid
DNA
Epidemiology
Genes
Genetic screening
Genetics
Genomes
Genomics
Human genetics
Life Sciences
Ovarian cancer
Pathogenicity
Phenotypes
Phenotypic variations
Proteins
Netherlands
molecular genetics
genetic screening/counselling
cancer: breast
getting research into practice
clinical genetics
ISSN:0022-2593, 1468-6244, 1468-6244
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Abstract Correspondence to Dr Alvaro N Monteiro, Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Alvaro.Monteiro@Moffitt.org ; Dr Maaike P G Vreeswijk, Human Genetics, Leiden University Medical Center, Leiden, 2300RC, The Netherlands; M.P.G.Vreeswijk@lumc.nl Introduction Since the identification and cloning of BRCA1 in 1994,1 and shortly thereafter of BRCA2,2 genetic tests of germline DNA to identify pathogenic variants in genes linked to hereditary breast and ovarian cancer (HBOC) have become mainstream.3 These tests are critical to identify women at increased risk relative to the general population. In ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), a clinically oriented database, currently ~37% of BRCA1 and ~45% of BRCA2 unique variants recorded are VUS. [...]there is a critical need to classify variants according to their pathogenicity.Table 1 Fraction of VUS in BRCA1 and BRCA2 Databases BIC* ClinVar† BRCA Exchange‡ gnomAD§ N % (%VUS) N % (%VUS) N % (%VUS) N % BRCA1 unique variants 1781 100 5821 100 7898 100 2936 100 BRCA1 VUS 891 50.0 (100) 2146 36.9 (100) 5186 65.7 (100) n/a n/a BRCA1 missense 607 34.1 (68.1) 1715 29.5 (79.9) 1892 24.0 (36.5) 938 31.9 BRCA1 missense VUS 569 31.9 (63.9) 1633 28.1 (76.1) 1714 21.7 (33.1) n/a n/a BRCA2 unique variants 2000 100 8119 100 10 422 100 4262 100 BRCA2 VUS 1065 53.3 (100) 3615 44.5 (100) 6980 67.0 (100) n/a n/a BRCA2 missense 891 44.6 (83.7) 3111 38.3 (86.1) 3484 33.4 (49.9) 1909 44.8 BRCA2 missense VUS 838 41.9 (78.7) 3011 37.1 (83.3) 3190 30.6 (45.7) n/a n/a *BIC (https://research.nhgri.nih.gov/bic/) is a locus-specific database established in 1995 for BRCA1 and BRCA2 variants, including loci primarily found in clinical or research testing. †ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) is a public archive of reports of the relationships among human variations and phenotypes and includes submissions reporting variants found in patient samples from clinical or research testing, and from the literature (note: [...]developers of functional assays should consider that clinical recommendations are unlikely to be made based on variants in genes for which the association has not been robustly established. [...]a detailed understanding of the strength of evidence for association between each gene (and its variant alleles) and HBOC risk should be sought to evaluate the clinical utility of a proposed functional assay. Missense variation is unlikely to significantly affect the overall protein function when located in disordered regions or in repeat motifs. [...]functional assays for these regions (or for a protein with a large portion of its coding sequence composed by these regions) may not be a priority.
AbstractList Correspondence to Dr Alvaro N Monteiro, Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Alvaro.Monteiro@Moffitt.org ; Dr Maaike P G Vreeswijk, Human Genetics, Leiden University Medical Center, Leiden, 2300RC, The Netherlands; M.P.G.Vreeswijk@lumc.nl Introduction Since the identification and cloning of BRCA1 in 1994,1 and shortly thereafter of BRCA2,2 genetic tests of germline DNA to identify pathogenic variants in genes linked to hereditary breast and ovarian cancer (HBOC) have become mainstream.3 These tests are critical to identify women at increased risk relative to the general population. In ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), a clinically oriented database, currently ~37% of BRCA1 and ~45% of BRCA2 unique variants recorded are VUS. [...]there is a critical need to classify variants according to their pathogenicity.Table 1 Fraction of VUS in BRCA1 and BRCA2 Databases BIC* ClinVar† BRCA Exchange‡ gnomAD§ N % (%VUS) N % (%VUS) N % (%VUS) N % BRCA1 unique variants 1781 100 5821 100 7898 100 2936 100 BRCA1 VUS 891 50.0 (100) 2146 36.9 (100) 5186 65.7 (100) n/a n/a BRCA1 missense 607 34.1 (68.1) 1715 29.5 (79.9) 1892 24.0 (36.5) 938 31.9 BRCA1 missense VUS 569 31.9 (63.9) 1633 28.1 (76.1) 1714 21.7 (33.1) n/a n/a BRCA2 unique variants 2000 100 8119 100 10 422 100 4262 100 BRCA2 VUS 1065 53.3 (100) 3615 44.5 (100) 6980 67.0 (100) n/a n/a BRCA2 missense 891 44.6 (83.7) 3111 38.3 (86.1) 3484 33.4 (49.9) 1909 44.8 BRCA2 missense VUS 838 41.9 (78.7) 3011 37.1 (83.3) 3190 30.6 (45.7) n/a n/a *BIC (https://research.nhgri.nih.gov/bic/) is a locus-specific database established in 1995 for BRCA1 and BRCA2 variants, including loci primarily found in clinical or research testing. †ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) is a public archive of reports of the relationships among human variations and phenotypes and includes submissions reporting variants found in patient samples from clinical or research testing, and from the literature (note: [...]developers of functional assays should consider that clinical recommendations are unlikely to be made based on variants in genes for which the association has not been robustly established. [...]a detailed understanding of the strength of evidence for association between each gene (and its variant alleles) and HBOC risk should be sought to evaluate the clinical utility of a proposed functional assay. Missense variation is unlikely to significantly affect the overall protein function when located in disordered regions or in repeat motifs. [...]functional assays for these regions (or for a protein with a large portion of its coding sequence composed by these regions) may not be a priority.
Germline DNA tests to identify pathogenic variants in genes linked to hereditary breast and ovarian cancer susceptibility have become widely available. However, the clinical utility of genetic testing depends on reliable evidence-based classification of sequence variants. Determination of pathogenicity traditionally relies on painstaking pedigree-based segregation analyses. However, the rapid increase in usage of germline DNA tests has led to the discovery of a large number of variants of uncertain clinical significance (VUS). For most VUS there is insufficient information for segregation analysis and therefore assessment of functional consequences is increasingly being used to support clinical annotation. Functional assays need to be accurate, robust, and reproducible to be used for clinical purposes. Here we use the lessons learned from BRCA1 and BRCA2 to identify best practices for the use of functional assays for clinical annotation of germline VUS in breast and ovarian cancer genes. We provide recommendations for the interpretation and use of established functional assays as well as for the development of new assays.
Author Kousholt, Arne N
Vreeswijk, Maaike P G
Millot, Gael A
Sharan, Shyam K
Monteiro, Alvaro N
Eccles, Diana M
Scully, Ralph
Schmidt, Marjanka K
Couch, Fergus
Bouwman, Peter
Masson, Jean-Yves
Wiesmüller, Lisa
AuthorAffiliation 6 Department of Molecular Biology, Medical Biochemistry and Pathology; Laval University Cancer Research Center, Québec City, QC, G1V 0A6, Canada
1 Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
4 Hub de Bioinformatique et Biostatistique – Département Biologie Computationnelle, Institut Pasteur, USR 3756 CNRS, Paris, France
10 Department of Obstetrics and Gynecology, Ulm University, Germany
7 Division of Molecular Pathology; Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
11 Mayo Clinic, Rochester, MN, USA
5 Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC, G1R 2J6, Canada
9 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
3 Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YA
12 Department of Human Genetics, Leiden University Med
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  fullname: Couch, Fergus
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  organization: Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
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ISSN 0022-2593
1468-6244
IngestDate Tue Nov 04 01:54:25 EST 2025
Thu Nov 13 06:20:27 EST 2025
Thu Sep 04 18:29:25 EDT 2025
Tue Oct 07 07:23:13 EDT 2025
Wed Feb 19 02:27:47 EST 2025
Tue Nov 18 21:45:33 EST 2025
Sat Nov 29 07:21:00 EST 2025
Thu Apr 24 22:51:40 EDT 2025
IsDoiOpenAccess true
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Issue 8
Keywords molecular genetics
genetic screening/counselling
cancer: breast
getting research into practice
clinical genetics
Language English
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AUTHOR CONTRIBUTIONS
This manuscript emerged from discussions held at a Netherlands Cancer Institute (NKI) workshop on Functional Analysis of Sequence Variants in Hereditary Breast and Ovarian Cancer Genes (Amsterdam, Netherlands). A.M. and M.V. planned the study and coordinated the discussions and are responsible for the overall content as guarantors. All authors contributed to the discussions, to the preparation and editing of the manuscript; reviewed and approved the final manuscript.
ORCID 0000-0003-0920-8433
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Snippet Correspondence to Dr Alvaro N Monteiro, Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA;...
Germline DNA tests to identify pathogenic variants in genes linked to hereditary breast and ovarian cancer susceptibility have become widely available....
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SubjectTerms BRCA1 protein
BRCA2 protein
Breast cancer
Classification
Clinical significance
Deoxyribonucleic acid
DNA
Epidemiology
Genes
Genetic screening
Genetics
Genomes
Genomics
Human genetics
Life Sciences
Ovarian cancer
Pathogenicity
Phenotypes
Phenotypic variations
Proteins
Title Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation
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Volume 57
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