Prevalence Rates of Pathogenic Mutations in theBRCA1andBRCA2Genes in Families with Different Disease Histories: Results from the German Consortium for Hereditary Breast and Ovarian Cancer.

The germline carrier of the BRCA1 pathogenic mutation has been well proven to confer an increased risk of breast and ovarian cancer. Despite BRCA1 biallelic pathogenic mutations being extremely rare, they have been reported to be embryonically lethal or to cause Fanconi anemia (FA). Here we describe a patient who was a 48-year-old female identified with biallelic pathogenic mutations of the BRCA1 gene, with no or very subtle FA-features. She was diagnosed with ovarian cancer and breast cancer at the ages of 43 and 44 and had a strong family history of breast and gynecological cancers.

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Results of NGS panel of hereditary breast and ovarian cancer in Lebanese women.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13045 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13045-e13045

Author(s):

Joseph Al Ajami ◽

Nadine Jalkh ◽

Ghadi Moubarak ◽

Roland Eid ◽

Fady Haddad ◽

...

Keyword(s):

Ovarian Cancer ◽

High Risk ◽

Mutation Rate ◽

Founder Effect ◽

Familial Cancer ◽

Brca1 Gene ◽

Pathogenic Mutation ◽

Genetic Alterations ◽

Breast And Ovarian Cancer ◽

Pathogenic Mutations

e13045 Background: Hereditary breast (BC) and ovarian cancer (OC) genetic alterations are considered the most prevalent among familial cancer. To date, four studies have exposed the mutations related to hereditary BC predisposition in the Lebanese population , with percentage of BRCA-related pathogenic mutations ranging between 5 % and 15 %. Methods: Between 2017 and 2019, 117 patients with high risk hereditary breast and ovarian cancer were referred to undergo the testing at the Unité de Génétique médicale (UGM) of Saint-Joseph University of Beirut, Lebanon. The sequencing was accomplished by using the 21-panel Next-Generation Sequencing (NGS) method for all of our patients, to which we also added the MLPA technique followed by the Sanger sequencing for validation whenever a genetic alteration was found. Results: From 117 Lebanese women with high-risk hereditary breast and ovarian cancer predisposition, 19 pathogenic mutations were identified in this study: 11 BRCA1, 1 BRCA2, 2 PALB2, 1 ATM, 1 CDH1, 1 MSH6, 1 RAD51C, and 1 BRIP1. Among those, 13 patients had BC, one had OC and five were healthy individuals. Five similar mutations were found within the BRCA1 gene, the p.C44F mutation, accounting for 45.4 %, thus suggesting a founder effect. Average age at diagnosis in the BC patients carrying a mutation was 41 years and 38.5% had a triple negative BC. Conclusions: The overall pathogenic mutation rate was equal to 16.2% while the BRCA deleterious mutation rate was 10.3% lower to those reported in the literature. The p.C44F mutation appeared five times suggesting a founder effect. [Table: see text]

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Mutational Landscape for Indian Hereditary Breast and Ovarian Cancer Cohort Suggests Need for Identifying Population Specific Genes and Biomarkers for Screening

Frontiers in Oncology ◽

10.3389/fonc.2020.568786 ◽

2021 ◽

Vol 10 ◽

Author(s):

Mohammed Shaad N. Kadri ◽

Komal M. Patel ◽

Poonam A. Bhargava ◽

Franky D. Shah ◽

Nutan V. Badgujar ◽

...

Keyword(s):

Ovarian Cancer ◽

Early Detection ◽

In Silico ◽

Indian Population ◽

Brca2 Gene ◽

Breast And Ovarian Cancer ◽

Prediction Tools ◽

Ovarian Cancers ◽

Brca Genes ◽

Pathogenic Mutations

BackgroundBreast and ovarian cancers are the most prevalent cancers and one of the leading causes of death in Indian women. The healthcare burden of breast and ovarian cancers and the rise in mortality rate are worrying and stress the need for early detection and treatment.MethodsWe performed amplicon sequencing of 144 cases who had breast/ovarian cancer disease (total 137 cases are patients and seven are tested for BRCA1/2 carrier) Using our custom designed gene panel consisting of 14 genes, that are associated with high to moderate risk of breast and ovarian cancers. Variants were called using Torrent Variant Caller and were annotated using ThermoFisher’s Ion Reporter software. Classification of variants and their clinical significance were identified by searching the variants against ClinVar database.ResultsFrom a total of 144 cases, we were able to detect 42 pathogenic mutations in [40/144] cases. Majority of pathogenic mutations (30/41) were detected in BRCA1 gene, while (7/41) pathogenic mutations were detected in BRCA2 gene, whereas, (2/41) pathogenic mutations were detected in TP53 gene and BRIP1, PALB2, and ATM genes respectively. So, BRCA genes contributed 88.09% of pathogenic mutations, whereas non-BRCA genes contributed 11.91% of pathogenic mutations. We were also able to detect 25 VUS which were predicted to be damaging by in silico prediction tools.ConclusionEarly detection of cancers in the Indian population can be done by genetic screening using customized multi-gene panels. Indications of our findings show that in the Indian population, apart from the common BRCA genes, there are other genes that are also responsible for the disease. High frequency mutations detected in the study and variants of uncertain significance predicted to be damaging by in silico pathogenicity prediction tools can be potential biomarkers of hereditary breast and ovarian cancer in Indian HBOC patients.

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A Recurrent BRCA2 Mutation Explains the Majority of Hereditary Breast and Ovarian Cancer Syndrome Cases in Puerto Rico

Cancers ◽

10.3390/cancers10110419 ◽

2018 ◽

Vol 10 (11) ◽

pp. 419 ◽

Cited By ~ 8

Author(s):

Hector Diaz-Zabala ◽

Ana Ortiz ◽

Lisa Garland ◽

Kristine Jones ◽

Cynthia Perez ◽

...

Keyword(s):

Ovarian Cancer ◽

Puerto Rico ◽

Puerto Rican ◽

Age Of Onset ◽

Brca2 Mutation ◽

Brca2 Gene ◽

Dna Polymorphisms ◽

Common Mutation ◽

Breast And Ovarian Cancer ◽

Pathogenic Mutations

Breast cancer is the most common cause of cancer diagnosis in women and is responsible for considerable mortality among the women of Puerto Rico. However, there are few studies in Puerto Rico on the genetic factors influencing risk. To determine the contribution of pathogenic mutations in BRCA1 and BRCA2, we sequenced these genes in 302 cases from two separate medical centers, who were not selected for age of onset or family history. We identified nine cases that are carriers of pathogenic germline mutation. This represents 2.9% of unselected cases and 5.6% of women meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA testing. All of the identified pathogenic mutations were in the BRCA2 gene and the most common mutation is the p.Glu1308Ter (E1308X) mutation in BRCA2 found in eight out of nine cases, representing 89% of the pathogenic carriers. The E1308X mutation has been identified in breast and ovarian cancer families in Spain, and analysis of flanking DNA polymorphisms shows that all E1308X carriers occur on the same haplotype. This is consistent with BRCA2 E1308X being a founder mutation for the Puerto Rican population. These results will contribute to better inform genetic screening and counseling of breast and ovarian cancer cases in Puerto Rico and Puerto Rican populations in mainland United States.

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

The American Surgeon ◽

10.1177/000313481508101006 ◽

2015 ◽

Vol 81 (10) ◽

pp. 941-944 ◽

Cited By ~ 8

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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