Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
14 Oct 2024
14 Oct 2024
Historique:
received:
01
05
2024
accepted:
25
09
2024
revised:
09
09
2024
medline:
15
10
2024
pubmed:
15
10
2024
entrez:
14
10
2024
Statut:
aheadofprint
Résumé
Breast cancer remains a significant global health challenge. In Australia, the adoption of publicly-funded multigene panel testing for eligible cancer patients has increased accessibility to personalised care, yet has also highlighted the increasing prevalence of variants of uncertain significance (VUS), complicating clinical decision-making. This project aimed to explore the spectrum and actionability of breast cancer VUS in Australian familial cancer centers (FCCs). Leveraging data from 11 FCCs participating in the Inherited Cancer Connect database, we retrieved VUS results from 1472 patients. Through ClinVar crosschecks and application of gene-specific ACMG/AMP guidelines, we showed the potential for reclassification of 4% of unique VUS as pathogenic or likely pathogenic, and 80% as benign or likely benign. Surveys conducted with FCCs and diagnostic laboratories described current practices and challenges in variant reclassifications, highlighting resource constraints preventing periodic VUS review and notifications from the laboratories to the FCCs. Our study suggests there are benefits to routine VUS review and reclassification, particularly in publicly-funded healthcare systems. Future research should focus on assessing the clinical impact and cost-effectiveness of implementing routine variant review practices, alongside efforts to enhance communication between FCCs and laboratories.
Identifiants
pubmed: 39402389
doi: 10.1038/s41431-024-01705-9
pii: 10.1038/s41431-024-01705-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : APP177524
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : APP177524
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : APP177524
Organisme : National Breast Cancer Foundation (NBCF)
ID : IIRS-21-102
Informations de copyright
© 2024. The Author(s).
Références
Larsen MJ, Thomassen M, Gerdes AM, Kruse TA. Hereditary breast cancer: clinical, pathological and molecular characteristics. Breast Cancer. 2014;8:145–55.
pubmed: 25368521
pmcid: 4213954
Mehrgou A, Akouchekian M. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Iran. 2016;30:369.
pubmed: 27493913
pmcid: 4972064
Adedokun B, Zheng Y, Ndom P, Gakwaya A, Makumbi T, Zhou AY, et al. Prevalence of Inherited Mutations in Breast Cancer Predisposition Genes among Women in Uganda and Cameroon. Cancer Epidemiol Biomark Prev. 2020;29:359–67.
doi: 10.1158/1055-9965.EPI-19-0506
Daly MB, Pal T, Maxwell KN, Churpek J, Kohlmann W, AlHilli Z, et al. NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024. J Natl Compr Canc Netw. 2023;21:1000–10.
doi: 10.6004/jnccn.2023.0051
pubmed: 37856201
Blondeaux E, Arecco L, Punie K, Graffeo R, Toss A, De Angelis C, et al. Germline TP53 pathogenic variants and breast cancer: A narrative review. Cancer Treat Rev. 2023;114:102522.
doi: 10.1016/j.ctrv.2023.102522
pubmed: 36739824
Baretta Z, Mocellin S, Goldin E, Olopade OI, Huo D. Effect of BRCA germline mutations on breast cancer prognosis: A systematic review and meta-analysis. Medicine. 2016;95:e4975.
doi: 10.1097/MD.0000000000004975
pubmed: 27749552
pmcid: 5059054
Amano Y, Raz A, Timmermans S, Shkedi-Rafid S. Cancer patients’ understandings of genetic variants of uncertain significance in clinical care. J Community Genet. 2022;13:381–8.
doi: 10.1007/s12687-022-00594-z
pubmed: 35616809
pmcid: 9134724
Makhnoon S, Shirts BH, Bowen DJ. Patients’ perspectives of variants of uncertain significance and strategies for uncertainty management. J Genet Couns. 2019;28:313–25.
doi: 10.1002/jgc4.1075
pubmed: 30636062
Chang EY, Solomon I, Culver JO, Gorman N, Comeaux JG, Lerman C, et al. Clinical and laboratory genetic counselor attitudes on the reporting of variants of uncertain significance for multigene cancer panels. J Genet Couns. 2023;32:706–16.
doi: 10.1002/jgc4.1680
pubmed: 36747331
Rehm HL, Alaimo JT, Aradhya S, Bayrak-Toydemir P, Best H, Brandon R, et al. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change. Genet Med. 2023;25:100947.
doi: 10.1016/j.gim.2023.100947
pubmed: 37534744
Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42:D980–5.
doi: 10.1093/nar/gkt1113
pubmed: 24234437
Makhnoon S, Levin B, Ensinger M, Mattie K, Volk RJ, Zhao Z, et al. A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian and colorectal cancer susceptibility genes. Cancer Med. 2023;12:2875–84.
doi: 10.1002/cam4.5202
pubmed: 36426404
Tsai GJ, Rañola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, et al. Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. Genet Med. 2019;21:1435–42.
doi: 10.1038/s41436-018-0335-7
pubmed: 30374176
So MK, Jeong TD, Lim W, Moon BI, Paik NS, Kim SC, et al. Reinterpretation of BRCA1 and BRCA2 variants of uncertain significance in patients with hereditary breast/ovarian cancer using the ACMG/AMP 2015 guidelines. Breast Cancer. 2019;26:510–9.
doi: 10.1007/s12282-019-00951-w
pubmed: 30725392
Innella G, Ferrari S, Miccoli S, Luppi E, Fortuno C, Parsons MT, et al. Clinical implications of VUS reclassification in a single-centre series from application of ACMG/AMP classification rules specified for BRCA1/2. J Med Genet. 2024;61:483–9.
pubmed: 38160042
Ha HI, Ryu JS, Shim H, Kong SY, Lim MC. Reclassification of BRCA1 and BRCA2 variants found in ovarian epithelial, fallopian tube, and primary peritoneal cancers. J Gynecologic Oncol. 2020;31:e83.
doi: 10.3802/jgo.2020.31.e83
Li D, Shi Y, Li A, Cao D, Su H, Yang H, et al. Retrospective reinterpretation and reclassification of BRCA1/2 variants from Chinese population. Breast Cancer. 2020;27:1158–67.
doi: 10.1007/s12282-020-01119-7
pubmed: 32566972
Liu Y, Wang H, Wang X, Liu J, Li J, Wang X, et al. Prevalence and reclassification of BRCA1 and BRCA2 variants in a large, unselected Chinese Han breast cancer cohort. J Hematol Oncol. 2021;14:18.
doi: 10.1186/s13045-020-01010-0
pubmed: 33461583
pmcid: 7814423
Lefter M, Vis JK, Vermaat M, den Dunnen JT, Taschner PEM, Laros JFJ. Mutalyzer 2: next generation HGVS nomenclature checker. Bioinformatics. 2021;37:2811–7.
doi: 10.1093/bioinformatics/btab051
pubmed: 33538839
pmcid: 8479679
Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, Wang Q, et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature. 2024;625:92–100.
doi: 10.1038/s41586-023-06045-0
pubmed: 38057664
Walker LC, Hoya M, Wiggins GAR, Lindy A, Vincent LM, Parsons MT, et al. Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup. Am J Hum Genet. 2023;110:1046–67.
doi: 10.1016/j.ajhg.2023.06.002
pubmed: 37352859
pmcid: 10357475
Tavtigian SV, Harrison SM, Boucher KM, Biesecker LG. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Hum Mut. 2020;41:1734–7.
Makhnoon S, Davidson E, Shirts B, Arun B, Shete S. Practices and Views of US Oncologists and Genetic Counselors Regarding Patient Recontact After Variant Reclassification: Results of a Nationwide Survey. JCO Precis Oncol. 2023;7:e2300079.
doi: 10.1200/PO.23.00079
pubmed: 37384863
pmcid: 10581618
Tudini E, Andrews J, Lawrence DM, King-Smith SL, Baker N, Baxter L, et al. Shariant platform: Enabling evidence sharing across Australian clinical genetic-testing laboratories to support variant interpretation. Am J Hum Genet. 2022;109:1960–73.
doi: 10.1016/j.ajhg.2022.10.006
pubmed: 36332611
pmcid: 9674965
Li L, Tian X, Woodzell V, Gibbs RA, Yuan B, Venner E. Tracking updates in clinical databases increases efficiency for variant reanalysis. Genet Med Open. 2024;2:101841.
Fortuno C, Lee K, Olivier M, Pesaran T, Mai PL, de, et al. Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. Hum Mutat. 2021;42:223–36.
doi: 10.1002/humu.24152
pubmed: 33300245
Mester JL, Ghosh R, Pesaran T, Huether R, Karam R, Hruska KS, et al. Gene-specific criteria for PTEN variant curation: Recommendations from the ClinGen PTEN Expert Panel. Hum Mutat. 2018;39:1581–92.
doi: 10.1002/humu.23636
pubmed: 30311380
pmcid: 6329583
Luo X, Maciaszek JL, Thompson BA, Leong HS, Dixon K, Sousa S, et al. Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines. J Med Genet. 2023;60:568–75.
doi: 10.1136/jmg-2022-108807
pubmed: 36600593
Tuffaha HW, Mitchell A, Ward RL, Connelly L, Butler JRG, Norris S, et al. Cost-effectiveness analysis of germ-line BRCA testing in women with breast cancer and cascade testing in family members of mutation carriers. Genet Med. 2018;20:985–94.
doi: 10.1038/gim.2017.231
pubmed: 29300376
Koldehoff A, Danner M, Civello D, Rhiem K, Stock S, Müller D. Cost-Effectiveness of Targeted Genetic Testing for Breast and Ovarian Cancer: A Systematic Review. Value Health. 2021;24:303–12.
doi: 10.1016/j.jval.2020.09.016
pubmed: 33518037
Sun L, Brentnall A, Patel S, Buist DSM, Bowles EJA, Evans DGR, et al. A Cost-effectiveness Analysis of Multigene Testing for All Patients With Breast Cancer. JAMA Oncol. 2019;5:1718–30.
doi: 10.1001/jamaoncol.2019.3323
pubmed: 31580391
pmcid: 6777250
Davidson AL, Kondrashova O, Leonard C, Wood S, Tudini E, Hollway GE, et al. Analysis of hereditary cancer gene variant classifications from ClinVar indicates a need for regular reassessment of clinical assertions. Hum Mutat. 2022;43:2054–62.
doi: 10.1002/humu.24468
pubmed: 36095262
Walsh N, Cooper A, Dockery A, O’Byrne JJ. Variant reclassification and clinical implications. J Med Genet. 2024;61:207–11.
doi: 10.1136/jmg-2023-109488
pubmed: 38296635
Loong L, Garrett A, Allen S, Choi S, Durkie M, Callaway A, et al. Reclassification of clinically-detected sequence variants: Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK). Genet Med. 2022;24:1867–77.
doi: 10.1016/j.gim.2022.05.002
pubmed: 35657381