scholarly journals Prevalence and Spectrum of Germline BRCA1 and BRCA2 Variants of Uncertain  Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome

Qeios ◽  
2022 ◽  
Author(s):  
Antonio Russo
Keyword(s):  
Ovarian Cancer ◽  
Brca1 And Brca2 ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance

scholarly journals BRCA1 and BRCA2 mutations in breast and ovarian cancer families from south west Colombia

2020 ◽  
pp. 163-175
Author(s):  
Laura Cifuentes-C ◽  
Ana Lucia Rivera-Herrera ◽  
Guillermo Barreto
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
In Silico ◽  
Novel Mutation ◽  
In Silico Analysis ◽  
Moderate Increase ◽  
Brca1 And Brca2 ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance ◽  
Colombian Pacific

Introduction: Breast cancer is the most common neoplasia of women from all over the world especially women from Colombia. 5%­10% of all cases are caused by hereditary factors, 25% of those cases have mutations in the BRCA1/BRCA2 genes. Objective: The purpose of this study was to identify the mutations associated with the risk of familial breast and/or ovarian cancer in a population of Colombian pacific. Methods: 58 high-risk breast and/or ovarian cancer families and 20 controls were screened for germline mutations in BRCA1 and BRCA2, by Single Strand Conformation Polymorphism (SSCP) and sequencing. Results: Four families (6.9%) were found to carry BRCA1 mutations and eight families (13.8%) had mutations in BRCA2. In BRCA1, we found three Variants of Uncertain Significance (VUS), of which we concluded, using in silico tools, that c.81­12C>G and c.3119G>A (p.Ser1040Asn) are probably deleterious, and c.3083G>A (p.Arg1028His) is probably neutral. In BRCA2, we found three variants of uncertain significance: two were previously described and one novel mutation. Using in silico analysis, we concluded that c.865A>G (p.Asn289Asp) and c.6427T>C (p.Ser2143Pro) are probably deleterious and c.125A>G (p.Tyr42Cys) is probably neutral. Only one of them has previously been reported in Colombia. We also identified 13 polymorphisms (4 in BRCA1 and 9 in BRCA2), two of them are associated with a moderate increase in breast cancer risk (BRCA2 c.1114A>C and c.8755­66T>C). Conclusion: According to our results, the Colombian pacific population presents diverse mutational spectrum for BRCA genes that differs from the findings in other regions in the country.

Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach

2021 ◽  
Vol 108 (10) ◽  
pp. 1907-1923
Author(s):  
Sandrine M. Caputo ◽  
Lisa Golmard ◽  
Mélanie Léone ◽  
Francesca Damiola ◽  
Marine Guillaud-Bataille ◽  
...  
Keyword(s):  
Brca1 And Brca2 ◽  
Variants Of Uncertain Significance ◽  
Powerful Approach ◽  
Uncertain Significance

Reclassification of BRCA1 and BRCA2 variants of uncertain significance: a multifactorial analysis of multicentre prospective cohort

2018 ◽  
Vol 55 (12) ◽  
pp. 794-802 ◽  
Author(s):  
Jee-Soo Lee ◽  
Sohee Oh ◽  
Sue Kyung Park ◽  
Min-Hyuk Lee ◽  
Jong Won Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
External Validation ◽  
Brca1 And Brca2 ◽  
Clinical Genetic ◽  
Validation Data ◽  
Data Set ◽  
Variants Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Highly Correlated

BackgroundBRCA1 and BRCA2 (BRCA1/2) variants classified ambiguously as variants of uncertain significance (VUS) are a major challenge for clinical genetic testing in breast cancer; their relevance to the cancer risk is unclear and the association with the response to specific BRCA1/2-targeted agents is uncertain. To minimise the proportion of VUS in BRCA1/2, we performed the multifactorial likelihood analysis and validated this method using an independent cohort of patients with breast cancer.MethodsWe used a data set of 2115 patients with breast cancer from the nationwide multicentre prospective Korean Hereditary Breast Cancer study. In total, 83 BRCA1/2 VUSs (BRCA1, n=26; BRCA2, n=57) were analysed. The multifactorial probability was estimated by combining the prior probability with the overall likelihood ratio derived from co-occurrence of each VUS with pathogenic variants, personal and family history, and tumour characteristics. The classification was compared with the interpretation according to the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG/AMP) guidelines. An external validation was conducted using independent data set of 810 patients.ResultsWe were able to redefine 38 VUSs (BRCA1, n=10; BRCA2, n=28). The revised classification was highly correlated with the ACMG/AMP guideline-based interpretation (BRCA1, p for trend=0.015; BRCA2, p=0.001). Our approach reduced the proportion of VUS from 19% (154/810) to 8.9% (72/810) in the retrospective validation data set.ConclusionThe classification in this study would minimise the ‘uncertainty’ in clinical interpretation, and this validated multifactorial model can be used for the reliable annotation of BRCA1/2 VUSs.

scholarly journals A review of a multifactorial probability based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS)

2012 ◽  
Vol 33 (5) ◽  
pp. 900-903 ◽  
Author(s):  
Noralane M. Lindor ◽  
Lucia Guidugli ◽  
Xianshu Wang ◽  
Maxime P. Vallée ◽  
Alvaro N. A. Monteiro ◽  
...  
Keyword(s):  
Brca1 And Brca2 ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance

scholarly journals A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS)

2011 ◽  
Vol 33 (1) ◽  
pp. 8-21 ◽  
Author(s):  
Noralane M. Lindor ◽  
Lucia Guidugli ◽  
Xianshu Wang ◽  
Maxime P. Vallée ◽  
Alvaro N. A. Monteiro ◽  
...  
Keyword(s):  
Brca1 And Brca2 ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance

Initial Results of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome

2015 ◽  
Vol 81 (10) ◽  
pp. 941-944 ◽  
Author(s):  
Dt R. Howarth ◽  
Sharon S. Lum ◽  
Pamela Esquivel ◽  
Carlos A. Garberoglio ◽  
Maheswari Senthil ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Genetic Testing ◽  
Breast And Ovarian Cancer ◽  
Variants Of Uncertain Significance ◽  
Panel Testing ◽  
Pathogenic Mutations ◽  
Uncertain Significance ◽  
Multigene Panel Testing ◽  
The Impact ◽  
Multigene Panel

Multigene panel testing for hereditary cancer risk has recently become commercially available; however, the impact of its use on patient care is undefined. We sought to evaluate results from implementation of panel testing in a multidisciplinary cancer center. We performed a retrospective review of consecutive patients undergoing genetic testing after initiating use of multigene panel testing at Loma Linda University Medical Center. From February 13 to August 25, 2014, 92 patients were referred for genetic testing based on National Comprehensive Cancer Network guidelines. Testing was completed in 90 patients. Overall, nine (10%) pathogenic mutations were identified: five BRCA1/2, and four in non-BRCA loci. Single-site testing identified one BRCA1 and one BRCA2 mutation. The remaining mutations were identified by use of panel testing for hereditary breast and ovarian cancer. There were 40 variants of uncertain significance identified in 34 patients. The use of panel testing more than doubled the identification rate of clinically significant pathogenic mutations that would have been missed with BRCA testing alone. The large number of variants of uncertain significance identified will require long-term follow-up for potential reclassification. Multigene panel testing provides additional information that may improve patient outcomes.

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