scholarly journals Analysis of BRCA1/2 variants of unknown significance in the prospective Korean Hereditary Breast Cancer study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joo Heung Kim ◽  
Sunggyun Park ◽  
Hyung Seok Park ◽  
Ji Soo Park ◽  
Seung-Tae Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hereditary Breast Cancer ◽  
Breast Cancer Patients ◽  
Odds Ratios ◽  
Genome Database ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Management Plans ◽  
Uncertain Significance ◽  
Single Nucleotide Polymorphism Database

AbstractGenetic testing for BRCA1 and BRCA2 is crucial in diagnosing hereditary breast and ovarian cancer syndromes and has increased with the development of multigene panel tests. However, results classified as variants of uncertain significance (VUS) present challenges to clinicians in attempting to choose an appropriate management plans. We reviewed a total of 676 breast cancer patients included in the Korean Hereditary Breast Cancer (KOHBRA) study with a VUS on BRCA mutation tests between November 2007 and April 2013. These results were compared to the ClinVar database. We calculated the incidence and odds ratios for these variants using the Korean Reference Genome Database. A total of 58 and 91 distinct VUS in BRCA1 and BRCA2 were identified in the KOHBRA study (comprising 278 and 453 patients, respectively). A total of 27 variants in the KOHBRA study were not registered in the Single Nucleotide Polymorphism database. Among BRCA1 VUSs, 20 were reclassified as benign or likely benign, four were reclassified as pathogenic or likely pathogenic, and eight remained as VUSs according to the ClinVar database. Of the BRCA2 VUSs, 25 were reclassified as benign or likely benign, two were reclassified as pathogenic or likely pathogenic, and 33 remained as VUS according to the ClinVar database. There were 12 variants with conflicting interpretations of pathogenicity for BRCA1 and 18 for BRCA2. Among them, p.Leu1780Pro showed a particularly high odds ratio. Six pathogenic variants and one conflicting variant identified using ClinVar could be reclassified as pathogenic variants in this study. Using updated ClinVar information and calculating odds ratios can be helpful when reclassifying VUSs in BRCA1/2.

scholarly journals Analysis of BRCA1/2 variants of unknown significance in patients with breast cancer from a prospective KOHBRA study

2020 ◽  
Author(s):  
Joo Heung Kim ◽  
Sunggyun Park ◽  
Hyung Seok Park ◽  
Ji Soo Park ◽  
Seung-Tae Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brca Mutation ◽  
Breast Cancer Patients ◽  
Odds Ratios ◽  
Brca1 And Brca2 ◽  
Genome Database ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Management Plans ◽  
Uncertain Significance

Abstract Background Genetic testing for BRCA1 and BRCA2 genes is crucial for diagnosing hereditary breast and ovarian cancer syndromes (HBOC). Testing for such genes has been on the rise due to the development of multigene panel tests. However, results classified as variants of uncertain significance (VUS) present challenges to clinicians trying to interpret their functions and choose appropriate management plans.Methods We reviewed a total of 676 breast cancer patients who had VUS on BRCA mutation tests between November 2007 and April 2013 in the KOHBRA study. These results were compared to the ClinVar database. We calculated the incidence and odds ratios for these variants using the Korean Reference Genome Database (KRGDB).Results A total of 58 and 91 distinct VUS in BRCA1 and 2 were identified in the KOHBRA study (comprising 258 and 453 patients, respectively). A total of 27 variants in the KOHBRA study were not registered in the SNP database. Of the BRCA1 VUS, 20 variants were reclassified as benign or likely benign, 4 variants were reclassified as pathogenic or likely pathogenic, and 8 variants remained as VUS according to the ClinVar database. Of the BRCA2 VUS variants, 25 variants were reclassified as benign or likely benign, two variants were reclassified as pathogenic or likely pathogenic, and 33 variants remained as VUS according to the Clinvar database. There were 12 variants with conflicting interpretations of pathogenicity for BRCA1 and 18 variants for BRCA2. Among them, p.Leu1780Pro showed a particularly high odds ratio.Conclusions Six pathogenic variants and one conflicting variant identified using ClinVar could be reclassified as pathogenic variants in this study. Using updated ClinVar and calculating odds ratios can be helpful when reclassifying VUS in BRCA1/2.

scholarly journals Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1286 ◽  
Author(s):  
Concetta Santonocito ◽  
Roberta Rizza ◽  
Ida Paris ◽  
Laura De Marchis ◽  
Carmela Paolillo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Patients ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
In Vitro Diagnostic ◽  
Variant Frequency ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Pathogenic variants (PVs) carriers in BRCA1 or BRCA2 are associated with an elevated lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). The prevalence of BRCA1 and BRCA2 germline alterations is extremely variable among different ethnic groups. Particularly, the rate of variants in Italian BC and/or OC families is rather controversial and ranges from 8% to 37%, according to different reports. By In Vitro Diagnostic (IVD) next generation sequencing (NGS)-based pipelines, we routinely screened thousands of patients with either sporadic or cancer family history. By NGS, we identified new PVs and some variants of uncertain significance (VUS) which were also evaluated in silico using dedicated tools. We report in detail data regarding BRCA1/2 variants identified in 517 out of 2351 BC and OC patients. The aim of this study was to report the incidence and spectrum of BRCA1/2 variants observed in BC and/or OC patients, tested in at Policlinico Gemelli Foundation Hospital, the origin of which is mainly from Central and Southern Italy. This study provides an overview of the variant frequency in these geographic areas of Italy and provides data that could be used in the clinical management of patients.

scholarly journals Prevalence of RECQL germline variants in Pakistani early-onset and familial breast cancer patients

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Muhammad Usman Rashid ◽  
Noor Muhammad ◽  
Faiz Ali Khan ◽  
Umara Shehzad ◽  
Humaira Naeemi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Early Onset ◽  
Familial Breast Cancer ◽  
High Performance ◽  
Breast Cancer Patients ◽  
Germline Variants ◽  
Variants Of Unknown Significance ◽  
Breast Cancer Predisposition ◽  
Novel Variants

Abstract Background The RecQ Like Helicase (RECQL) gene has previously been shown to predispose to breast cancer mainly in European populations, in particular to estrogen receptor (ER) and/or progesterone receptor (PR) positive tumor. Here, we investigated the contribution of pathogenic RECQL germline variants to hereditary breast cancer in early-onset and familial breast cancer patients from Pakistan. Methods Comprehensive RECQL variant analysis was performed in 302 BRCA1 and BRCA2 negative patients with ER and/or PR positive breast tumors using denaturing high-performance liquid chromatography followed by DNA sequencing. Novel variants were classified using Sherloc guidelines. Results One novel pathogenic protein-truncating variant (p.W75*) was identified in a 37-year-old familial breast cancer patient. The pathogenic variant frequencies were 0.3% (1/302) in early-onset and familial breast cancer patients and 0.8% (1/133) in familial patients. Further, three novel variants of unknown significance, p.I141F, p.S182S, and p.C475C, were identified in familial breast cancer patients at the age of 47, 68, and 47 respectively. All variants were absent in 250 controls. Conclusions Our data suggest that the RECQL gene plays a negligible role in breast cancer predisposition in Pakistan.

scholarly journals Multi gene panel testing for hereditary breast cancer - is it ready to be used?

2019 ◽  
Author(s):  
Andreea Catana ◽  
Adina Patricia Apostu ◽  
Razvan-Geo Antemie
Keyword(s):  
Breast Cancer ◽  
Hereditary Breast Cancer ◽  
Gene Panel ◽  
Variants Of Uncertain Significance ◽  
Panel Testing ◽  
Brca Genes ◽  
Prophylactic Measures ◽  
Gene Panel Testing ◽  
Uncertain Significance ◽  
High Level

Breast cancer is one of the most common malignancies and the leading cause of death among women worldwide. About 20% of breast cancers are hereditary. Approximately 30% of the mutations have remained negative after testing BRCA1/2 even in families with a Mendelian inheritance pattern for breast cancer. Additional non-BRCA genes have been identified as predisposing for breast cancer. Multi gene panel testing tries to cover and explain the BRCA negative inherited breast cancer, improving efficiency, speed and costs of the breast cancer screening. We identified 23 studies reporting results from individuals who have undergone multi gene panel testing for hereditary breast cancer and noticed a prevalence of 1-12% of non-BRCA genes, but also a high level of variants of uncertain significance. A result with a high level of variants of uncertain significance is likely to be more costly than bring benefits, as well as increase the anxiety for patients. Regarding further development of multi gene panel testing, more research is required to establish both the optimal care of patients with cancer (specific treatments like PARP inhibitors) and the management of unaffected individuals (chemoprevention and/or prophylactic surgeries). Early detection in these patients as well as prophylactic measures will significantly increase the chance of survival. Therefore, multi gene panel testing is not yet ready to be used outside clear guidelines. In conclusion, studies on additional cohorts will be needed to better define the real prevalence, penetrance and the variants of these genes, as well as to describe clear evidence-based guidelines for these patients. 

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