scholarly journals Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant

2022 ◽  
Vol 11 ◽  
Author(s):  
Jun Li ◽  
Ping Wang ◽  
Cuiyun Zhang ◽  
Sile Han ◽  
Han Xiao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Pathogenic Variant ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Preventative Measures ◽  
History Of ◽  
Synonymous Variant ◽  
Intron Region ◽  
Minigene Assay

Breast cancer gene 1 (BRCA1) and BRCA2 are tumor suppressors involved in DNA damage response and repair. Carriers of germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2 have significantly increased lifetime risks of breast cancer, ovarian cancer, and other cancer types; this phenomenon is known as hereditary breast and ovarian cancer (HBOC) syndrome. Accurate interpretation of BRCA1 and BRCA2 variants is important not only for disease management in patients, but also for determining preventative measures for their families. BRCA1:c.132C>T (p.Cys44=) is a synonymous variant recorded in the ClinVar database with “conflicting interpretations of its pathogenicity”. Here, we report our clinical tests in which we identified this variant in two unrelated patients, both of whom developed breast cancer at an early age with ovarian presentation a few years later and had a family history of relevant cancers. Minigene assay showed that this change caused a four-nucleotide loss at the end of exon 3, resulting in a truncated p.Cys44Tyrfs*5 protein. Reverse transcription-polymerase chain reaction identified two fragments (123 and 119 bp) using RNA isolated from patient blood samples, in consistency with the results of the minigene assay. Collectively, we classified BRCA1:c.132C>T (p.Cys44=) as a pathogenic variant, as evidenced by functional studies, RNA analysis, and the patients’ family histories. By analyzing variants recorded in the BRCA Exchange database, we found synonymous changes at the ends of exons could potentially influence splicing; meanwhile, current in silico tools could not predict splicing changes efficiently if the variants were in the middle of an exon, or in the deep intron region. Future studies should attempt to identify variants that influence gene expression and post-transcription modifications to improve our understanding of BRCA1 and BRCA2, as well as their related cancers.

Prevalence of BRCA1 and BRCA 2 and other mutations in Chilean population.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13553-e13553
Author(s):  
Carolina Selman ◽  
Mabel Hurtado ◽  
Badir Chahuan ◽  
Fabiola Mella ◽  
Hugo Marsiglia
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Genetic Counseling ◽  
Triple Negative ◽  
Genetic Test ◽  
Pathogenic Variants ◽  
Brca 2 ◽  
Post Test ◽  
History Of ◽  
Chilean Population

e13553 Background: Arturo López Pérez Foundation (FALP) is a Chilean Institution aimed to treatment of cancer patients. Since 2016 it has an Unit for Oncological Genetic Counseling (AGO) for patients with warning flags of potential cases of cancer of genetic origin AGO Unit is aimed to capture patients with warning flags and deliver information through pre-test counseling, offer possibility of a genetic test and post-test counseling. The purpose of this review is to provide relevant results of four years of this Unit. Methods: A descriptive study was carried out from patient care in the Oncological Genetic Counseling Unit of FALP between 2016 and 2019. It was considered those cases in which the process of pretest/post-test counseling was performed. Six "warningflags" were established: cancer in patients under 50 years of age, triple negative breast cancer, breast cancer in men, ovarian cancer, history of 2 or more primary cancers and a family history of cancer The number of test performed was analyzed. The results were expressed in positive pathogenic variants, uncertain variants and negative results. Results: 365 genetic counseling processes were carried out during the period. The average consultation age was 43.2 years (20.8 and 75.5) and 90.1% (329 attentions ) were female. Of the patients, 79.7% (294) perform the genetic test. 18.5% tested positive for a pathogenic variant, 6.5% for a pathogenic variant plus an uncertain variable, and 2.8% for two pathogenic variants. The mutations found were BRCA2 32.6% BRCA1 29.1%, ATM 10.1% RAD51C 6.7% CDKN2 A 5.6%, MUTYH 3.4% TP53 3.4%, MSH2 3.4% RAD51D 2.4%), NF1 1.1%, NTHL1 1.1%, RET 1.1% A 64.9% (237 patients) had cancer diagnosed at the time of the consultation, versus 33.1% of healthy care. 2% had no information. The type of cancer present was 79.7% breast cancer (189), 8.0% ovarian cancer, 2.1% thyroid cancer, 1.7% breast and ovarian cancer, 0.9% colon and/or endometrial cancer and 7.6% other cancers. The warning flags present were 41.2% age below 50 years, 26.2% family history, 15.4% relatives of people with positive results, 8.5% patients with triple-negative breast cancer, 5.3% patients with ovarian cancer, 2.8% patients with 2 or more primary cancers, and 0.6% male breast cancer patients. Conclusions: The highest percentage of patient care was for women with breast cancer, under 50 years of age. The overall test positivity rate is a cumulative 29%. Mutations in BRCA 1 and BRCA 2 were the most detected mutations, as reported in the literature. The slight predominance of BRCA 2 may be due to a familiar component. This is the largest report made in the Chilean population.

scholarly journals Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Mike M. Moradian ◽  
Davit T. Babikyan ◽  
Sione Markarian ◽  
Jonny G. Petrosyan ◽  
Nare Avanesian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Genes ◽  
Breast Cancer Patients ◽  
Breast And Ovarian Cancer ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
History Of ◽  
History Of Cancer ◽  
Cancer Panel

AbstractHereditary breast and ovarian cancer (HBOC) can be identified by genetic testing of cancer-causing genes. In this study, we identified a spectrum of genetic variations among 76 individuals of Armenian descent either with a family history of cancer or breast cancer before the age of 40. We screened 76 suspected HBOC patients and family members as well as four healthy controls using a targeted and hereditary comprehensive cancer panel (127 genes). We found 26 pathogenic (path) and 6 likely pathogenic (LPath)variants in 6 genes in 44 patients (58%); these variants were found in BRCA1 (17), BRCA2 (19), CHEK2 (4), PALB2 (2), and NBN (1). A few different variants were found in unrelated individuals; most notably, variant p.Trp1815Ter in the BRCA1 gene occurred in four unrelated patients. We did not find any known significant variants in five patients. Comprehensive cancer panel testing revealed pathogenic variants in cancer genes other than BRCA1 and BRCA2, suggesting that testing only BRCA1 and BRCA2 would have missed 8 out of 44 suspected HBOC patients (18%). These data also confirm that a comprehensive cancer panel testing approach could be an appropriate way to identify most of the variants associated with hereditary breast cancer.

scholarly journals A Case Report of Germline Compound Heterozygous Mutations in the BRCA1 Gene of an Ovarian and Breast Cancer Patient

2021 ◽  
Vol 22 (2) ◽  
pp. 889
Author(s):  
Ava Kwong ◽  
Cecilia Y. S. Ho ◽  
Vivian Y. Shin ◽  
Chun Hang Au ◽  
Tsun Leung Chan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Brca1 Gene ◽  
Pathogenic Mutation ◽  
Compound Heterozygous ◽  
Strong Family History ◽  
Breast And Ovarian Cancer ◽  
Pathogenic Mutations ◽  
Increased Risk ◽  
History Of

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.

scholarly journals Expanding the search for germline pathogenic variants for breast cancer. How far should we go and how high should we jump? The missed opportunity!

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Hikmat Abdel-Razeq
Keyword(s):  
Breast Cancer ◽  
Brca1 And Brca2 ◽  
Healthy Women ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
History Of ◽  
Risk Reducing ◽  
Current Guidelines ◽  
Missed Opportunity

Since the identification of BRCA1 and BRCA2 genes 3 decades ago, genetic testing and genetic counseling have become an integral part of routine clinical practice. The risk of breast cancer among carriers of germline pathogenic variants, like BRCA1 and BRCA2, is well established. Risk-reducing interventions, including bilateral mastectomies and salpingo-oophorectomies are both effective and have become more acceptable. Many researchers and professional societies view current guidelines as restrictive and may miss many at-risk women, and are calling to expand testing to include all patients with breast cancer, regardless of their personal or family history of cancer, while others are calling for wider adoption to even include all healthy women at age 30 or older. This review will address expanding testing in two directions; horizontally to include more patients, and even healthy women, and vertically to include more genes using next-generation sequencing-based multi-gene panel testing.

scholarly journals Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Kodai Abe ◽  
Arisa Ueki ◽  
Yusaku Urakawa ◽  
Minoru Kitago ◽  
Tomoko Yoshihama ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Family History ◽  
Genetic Analysis ◽  
Pathogenic Variant ◽  
Familial Pancreatic Cancer ◽  
Case Presentation ◽  
Pathogenic Variants ◽  
Pancreatic Cancers ◽  
Epidemiological Surveys ◽  
History Of

Abstract Background Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

scholarly journals Prevalence of germline BRCA mutations in HER2-negative metastatic breast cancer: global results from the real-world, observational BREAKOUT study

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Joyce O’Shaughnessy ◽  
Christine Brezden-Masley ◽  
Marina Cazzaniga ◽  
Tapashi Dalvi ◽  
Graham Walker ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Ovarian Cancer ◽  
Risk Factor ◽  
Metastatic Breast Cancer ◽  
Family History ◽  
Metastatic Breast ◽  
Cytotoxic Chemotherapy ◽  
First Line ◽  
History Of

Abstract Background The global observational BREAKOUT study investigated germline BRCA mutation (gBRCAm) prevalence in a population of patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Methods Eligible patients had initiated first-line cytotoxic chemotherapy for HER2-negative MBC within 90 days prior to enrollment. Hormone receptor (HR)-positive patients had experienced disease progression on or after prior endocrine therapy, or endocrine therapy was considered unsuitable. gBRCAm status was determined using baseline blood samples or prior germline test results. For patients with a negative gBRCAm test, archival tissue was tested for somatic BRCAm and homologous recombination repair mutations (HRRm). Details of first-line cytotoxic chemotherapy were also collected. Results Between March 2017 and April 2018, 384 patients from 14 countries were screened and consented to study enrollment; 341 patients were included in the full analysis set (median [range] age at enrollment: 56 [25–89] years; 256 (75.3%) postmenopausal). Overall, 33 patients (9.7%) had a gBRCAm (16 [4.7%] in gBRCA1 only, 12 [3.5%] in gBRCA2 only, and 5 [1.5%] in both gBRCA1 and gBRCA2). gBRCAm prevalence was similar in HR-positive and HR-negative patients. gBRCAm prevalence was 9.0% in European patients and 10.6% in Asian patients and was higher in patients aged ≤ 50 years at initial breast cancer (BC) diagnosis (12.9%) than patients aged > 50 years (5.4%). In patients with any risk factor for having a gBRCAm (family history of BC and/or ovarian cancer, aged ≤ 50 years at initial BC diagnosis, or triple-negative BC), prevalence was 10.4%, versus 5.8% in patients without these risk factors. HRRm prevalence was 14.1% (n = 9/64) in patients with germline BRCA wildtype. Conclusions Patient demographic and disease characteristics supported the association of a gBRCAm with younger age at initial BC diagnosis and family history of BC and/or ovarian cancer. gBRCAm prevalence in this cohort, not selected on the basis of risk factors for gBRCAm, was slightly higher than previous results suggested. gBRCAm prevalence among patients without a traditional risk factor for harboring a gBRCAm (5.8%) supports current guideline recommendations of routine gBRCAm testing in HER2-negative MBC, as these patients may benefit from poly(ADP-ribose) polymerase (PARP) inhibitor therapy. Trial registration NCT03078036.

Genetic counseling and testing for breast-ovarian cancer susceptibility: what do women want?

1998 ◽  
Vol 16 (1) ◽  
pp. 133-138 ◽  
Author(s):  
J Audrain ◽  
B Rimer ◽  
D Cella ◽  
J Garber ◽  
B N Peshkin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Genetic Counseling ◽  
Cancer Susceptibility ◽  
Genetic Counselor ◽  
Care Physician ◽  
Counseling And Testing ◽  
History Of ◽  
Optimal Approach ◽  
Medical Recommendations

PURPOSE To assess preferences for the content and process of genetic counseling and testing for breast-ovarian cancer susceptibility among women at high risk for breast cancer. METHODS Ninety-eight healthy women who had a family history of breast cancer in at least two first-degree relatives participated in a structured telephone survey that evaluated preferences for type of provider and the content and process of pretest education and posttest genetic counseling. RESULTS Forty-two percent of women preferred that pretest education be delivered by a genetic counselor, while 22% preferred an oncologist. This preference was positively associated with a desire to discuss psychosocial issues during the session (P = .001). For posttest counseling, 38% of women preferred an oncologist, while 20% preferred a genetic counselor. However, women who desired supportive counseling during this session were significantly more likely to prefer a genetic counselor to an oncologist (P = .02). Fewer women wished to see a primary care physician or gynecologist for pretest education (11%) or posttest counseling (22%). With regard to the counseling process, 82% of women wished to self-refer for genetic counseling, but 63% desired advice and recommendations about whether to be tested. CONCLUSION When feasible, the optimal approach may be for oncologists to work with genetic counselors to provide pretest education and medical recommendations. Elicitation of patients' preferences may be useful to determine the level of counseling services needed.

Evaluating the impact of a history of breast cancer on outcomes in women with high-grade serous ovarian cancer

2018 ◽  
Vol 149 ◽  
pp. 212
Author(s):  
J. Gillen ◽  
M. Rowland ◽  
A.Y. Liu ◽  
S. Vesely ◽  
B. Powell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
History Of ◽  
The Impact

Genetic testing in young women with breast cancer: Results from a web-based survey

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21093-21093
Author(s):  
J. A. Shin ◽  
S. Gelber ◽  
J. Garber ◽  
R. Rosenberg ◽  
M. Przypyszny ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Genetic Testing ◽  
Family History ◽  
High Risk ◽  
Young Women ◽  
College Education ◽  
Web Based ◽  
Increased Risk ◽  
History Of

21093 Background: Young women with breast cancer have an increased risk of harboring a BRCA1/2 mutation. The frequency of genetic testing in this population is not well described. We evaluated the reported frequency and factors associated with genetic testing among young breast cancer survivors identified through the Young Survival Coalition (YSC), an international advocacy group for young women with breast cancer. Methods: Items regarding family history and genetic testing were included in a large web-based survey addressing quality of life and fertility issues for young women with breast cancer. All YSC members were invited by email in March 2003 (N= 1,703 women) to participate in this cross-sectional survey. Results: 657 women completed the on-line survey; 622 were eligible for this analysis (age <40, no metastatic or recurrent disease). Mean age at breast cancer diagnosis was 33 years; mean age when surveyed 35.5 years. Stages included: 0 (10%), I (27%), II (49%), III (12%), missing (3%). 90% of women were white; 64% married; 49% with children; 78% had at least a college education; 42% of women reported a 1st or 2nd degree relative with breast or ovarian cancer, and 13% considered themselves high-risk for harboring a genetic mutation at the time of diagnosis. At the time of the survey, 23% of women had undergone genetic testing, and 26% of those tested reported that a mutation was found. In a multivariate model, women who were younger (age 36–40 vs. age =30, O.R. 2.26, p=0.004), more educated (< college vs. > college education, O.R. 2.62, p=0.0009), had a family history of breast or ovarian cancer (O.R. 3.15, p<0.0001), and had had a mastectomy (O.R. 1.99, p=0.001) were more likely to have undergone genetic testing. Non-significant covariates included: age at survey, stage, time since diagnosis, race, marital status, employment, finances, insurance, number of children, comorbidities, baseline anxiety and depression, and fear of recurrence. Conclusion: The majority of women diagnosed with breast cancer age 40 and younger do not undergo genetic testing. Younger, more educated women with a family history of breast or ovarian cancer are more likely to get tested. Further research to define the appropriateness of genetic testing in this relatively high-risk population is warranted. No significant financial relationships to disclose.

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