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

Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40–50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype–phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype–phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

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

Colombia Medica ◽

10.25100/cm.v50i3.2385 ◽

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.

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

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105565 ◽

2018 ◽

Vol 55 (12) ◽

pp. 794-802 ◽

Cited By ~ 10

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.

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Functional Assays for Classification of BRCA2 Variants of Uncertain Significance

Cancer Research ◽

10.1158/0008-5472.can-07-1587 ◽

2008 ◽

Vol 68 (9) ◽

pp. 3523-3531 ◽

Cited By ~ 85

Author(s):

Daniel J. Farrugia ◽

Mukesh K. Agarwal ◽

Vernon S. Pankratz ◽

Amie M. Deffenbaugh ◽

Dmitry Pruss ◽

...

Keyword(s):

Variants Of Uncertain Significance ◽

Functional Assays ◽

Uncertain Significance

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BRCA1 and BRCA2 Variants of Uncertain Significance. Part Two: Medical Management

Seminars in Oncology ◽

10.1053/j.seminoncol.2011.04.009 ◽

2011 ◽

Vol 38 (5) ◽

pp. 605-611

Author(s):

Susan Miller-Samuel ◽

Anne Rosenberg ◽

Adam Berger ◽

Leonard Gomella ◽

David Loren ◽

...

Keyword(s):

Medical Management ◽

Brca1 And Brca2 ◽

Variants Of Uncertain Significance ◽

Uncertain Significance

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

Frontiers in Oncology ◽

10.3389/fonc.2021.682445 ◽

2021 ◽

Vol 11 ◽

Author(s):

Daniele Fanale ◽

Alessia Fiorino ◽

Lorena Incorvaia ◽

Alessandra Dimino ◽

Clarissa Filorizzo ◽

...

Keyword(s):

High Risk ◽

Clinical Significance ◽

Clinical Management ◽

University Hospital ◽

Sequencing Analysis ◽

Brca1 And Brca2 ◽

Variants Of Uncertain Significance ◽

Pathogenic Variants ◽

Risk Variants ◽

Uncertain Significance

About 10–20% of breast/ovarian (BC/OC) cancer patients undergoing germline BRCA1/2 genetic testing have been shown to harbor Variants of Uncertain Significance (VUSs). Since little is known about the prevalence of germline BRCA1/2 VUS in Southern Italy, our study aimed at describing the spectrum of these variants detected in BC/OC patients in order to improve the identification of potentially high-risk BRCA variants helpful in patient clinical management. Eight hundred and seventy-four BC or OC patients, enrolled from October 2016 to December 2020 at the “Sicilian Regional Center for the Prevention, Diagnosis and Treatment of Rare and Heredo-Familial Tumors” of University Hospital Policlinico “P. Giaccone” of Palermo, were genetically tested for germline BRCA1/2 variants through Next-Generation Sequencing analysis. The mutational screening showed that 639 (73.1%) out of 874 patients were BRCA-w.t., whereas 67 (7.7%) were carriers of germline BRCA1/2 VUSs, and 168 (19.2%) harbored germline BRCA1/2 pathogenic/likely pathogenic variants. Our analysis revealed the presence of 59 different VUSs detected in 67 patients, 46 of which were affected by BC and 21 by OC. Twenty-one (35.6%) out of 59 variants were located on BRCA1 gene, whereas 38 (64.4%) on BRCA2. We detected six alterations in BRCA1 and two in BRCA2 with unclear interpretation of clinical significance. Familial anamnesis of a patient harboring the BRCA1-c.3367G>T suggests for this variant a potential of pathogenicity, therefore it should be carefully investigated. Understanding clinical significance of germline BRCA1/2 VUS could improve, in future, the identification of potentially high-risk variants useful for clinical management of BC or OC patients and family members.

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

Qeios ◽

10.32388/ibod5k ◽

2022 ◽

Author(s):

Antonio Russo

Keyword(s):

Ovarian Cancer ◽

Brca1 And Brca2 ◽

Variants Of Uncertain Significance ◽

Uncertain Significance

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