The importance of variants of unknown significance (VUS) in BRCA mutation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e22507-e22507
Author(s):  
N Mullai
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Brca Mutation ◽  
Brca1 And Brca2 ◽  
Management Options ◽  
Brca Mutations ◽  
Variants Of Unknown Significance ◽  
Family Histories ◽  
Unknown Significance ◽  
Brca2 Mutations

e22507 Background: Genetic testing of patients for BRCA mutation may report variants of unknown significance (VUS). The use of multi-gene panels in clinical care has been increasing. Consequently, the reporting of variants of unknown significance has also increased. More than two decades of research and testing have elevated the status of BRCA1 and BRCA2 genes as the most well characterized genes. However, VUS are found even in BRCA1/2 testing. This raises many ethical and policy issues including communicating the significance of the results and possible clinical management options to patients. The practicing physicians would face the ethical and potential legal burden of contacting and explaining to patients, when any role of VUS changes and gets reclassified as potentially harmful. Methods: Data were collected retrospectively from medical records of patients tested for BRCA mutations. The results of fifty-two patients were analyzed. Eight patients had BRCA1 and BRCA2 mutations and twelve patients had variants of unknown significance. Results: When the results of thirteen patients with BRCA mutations with VUS were analyzed further, the variants included POLE, CHEK2, PALB2, MUTHYH, BR1P1, MSH3, ATM, RAD51C, GALNT12, etc. The age of these patients ranged from 39 years to 69 years. Four patients had ovarian cancer and eight patients had breast cancer, and one patient had both breast and ovarian cancers. The number of patients with stage IV, III, II, and I diseases were six, one, two, and two respectively. One patient had bilateral breast cancer and one patient had carcinoma in-situ. Eight patients had family histories of various cancers, including cancers of the breast, uterine, and prostate cancer. All patients were treated appropriately and three patients died due to their disease. Conclusions: Based on patients’ age, family histories, and disease characteristics BRCA mutation analyses were done. All patients tested positive for BRCA mutations and VUS were informed about their results. Variants of BRCA1 and BRCA2 occur in 2%-4% of tests depending on the laboratories, where the tests were performed. There is no concordance as to how VUS results were reported. There is conflicting evidence regarding the pathogenicity of VUS. These make clinical recommendations very complex. Based on existing guidelines, physicians can explain the details of the significance of BRCA! And BRCA2 mutations to patients with clarity. However, it is difficult and unclear to give recommendations regarding prophylactic measures, specific treatment options for BRCA mutation positive breast and ovarian cancer, follow-ups, and family testing in patients with VUS. Therefore, during BRCA testing, when VUS are reported routinely along with mutations of known significance, the treating physicians would need a better guidance to advise their patients without unduly increasing their anxiety, fear, and potential for misunderstanding.

scholarly journals Prevalence of BRCA1 and BRCA2 Mutations Among Patients With Ovarian, Primary Peritoneal, and Fallopian Tube Cancer in India: A Multicenter Cross-Sectional Study

2021 ◽  
pp. 849-861
Author(s):  
Sudeep Gupta ◽  
Senthil Rajappa ◽  
Suresh Advani ◽  
Amit Agarwal ◽  
Shyam Aggarwal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Family History ◽  
Newly Diagnosed ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Fallopian Tube Cancer ◽  
Cross Sectional ◽  
Brca2 Mutations ◽  
Brca1 Brca2

PURPOSE There are deficient data on prevalence of germline mutations in breast cancer susceptibility genes 1 and 2 ( BRCA1/ BRCA2) in Indian patients with ovarian cancer who are not selected by clinical features. METHODS This prospective, cross-sectional, noninterventional study in nine Indian centers included patients with newly diagnosed or relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer. The primary objective was to assess the prevalence of BRCA1/ BRCA2 mutations, and the secondary objective was to correlate BRCA1/ BRCA2 status with clinicopathologic characteristics. Mutation testing was performed by a standard next-generation sequencing assay. RESULTS Between March 2018 and December 2018, 239 patients with a median age of 53.0 (range, 23.0-86.0 years) years were included, of whom 203 (84.9%) had newly diagnosed disease, 36 (15.1%) had family history of ovarian or breast cancer, and 159 (66.5%) had serous subtype of epithelial ovarian cancer. Germline pathogenic or likely pathogenic mutations in BRCA1 and BRCA2 were detected in 37 (15.5%; 95% CI, 11.1 to 20.7) and 14 (5.9%; 95% CI, 3.2 to 9.6) patients, respectively, whereas variants of uncertain significance in these genes were seen in four (1.7%; 95% CI, 0.5 to 4.2) and six (2.5%; 95% CI, 0.9 to 5.4) patients, respectively. The prevalence of pathogenic or likely pathogenic BRCA mutations in patients with serous versus nonserous tumors, with versus without relevant family history, and ≤ 50 years versus > 50 years, were 40 of 159 (25.2%; 95% CI, 18.6 to 32.6) versus 11 of 80 (13.8%; 95% CI, 7.1 to 23.3; P = .0636), 20 of 36 (55.6%; 95% CI, 38.1 to 72.1) versus 41 of 203 (20.2%; 95% CI, 14.9 to 26.4; P < .0001), and 20 of 90 (22.2%; 95% CI, 14.1 to 32.2) versus 31 of 149 (20.8%; 95% CI, 14.6 to 28.2; P = .7956), respectively. CONCLUSION There is a high prevalence of pathogenic or likely pathogenic germline BRCA mutations in Indian patients with ovarian cancer.

scholarly journals A MOLECULAR-BASED APPROACH TO INVESTIGATE BREAST CANCER 1 AND BREAST CANCER 2 STATUS IN OVARIAN CANCER AMONG IRAQI WOMEN

2018 ◽  
Vol 11 (7) ◽  
pp. 199
Author(s):  
Muhannad Shweash ◽  
Saddam Jumaa Naseer ◽  
Maisam Khider Al-anii ◽  
Thulfiqar Fawwaz Mutar
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Patients ◽  
Gene Mutations ◽  
Healthy Controls ◽  
Brca1 And Brca2 ◽  
First Degree Relatives ◽  
Brca Gene ◽  
Brca2 Mutations ◽  
Brca1 And Brca2 Mutations

Objective: Cancer ovary is one of the fatal gynecologic malignancies worldwide. Since breast cancer (BRCA) genes are considered tumor suppressor genes and play important roles in cancer by repairing of chromosomal damage with the error repair of DNA breaks. Therefore, breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations strongly enhance the development of ovarian cancer risk among women. Here, we report that both genes are an essential mediator of progress ovarian cancer, to determine the influence of BRCA1 and BRCA2 mutations in the improvement of ovarian cancer.Methods: A total of 25 subjects were chosen for the genetic studies, and three groups were recruited: fifteen ovarian cancer patients group, five healthy controls, and five first-degree relatives to a known case of ovarian cancer patients.Results: A genetic analysis revealed that a strong correlation exists between both gene mutations’ status in ovarian cancer, and BRCA gene mutations (185delAG, 5382insC, and 4153delA in BRCA1 and 6174delT in BRCA2) remained to establish to have a relatively high frequency among people in this study among ovarian cancer patients. Furthermore, seven patients with ovarian cancer carried all of the four investigated mutations, and five had three mutations.Conclusion: Otherwise, BRCA gene frequency showed low prevalence among first-degree relatives, and to a lesser extent among healthy controls, with only a few had all of the mutations combined. These data demonstrate for the first time a molecular link between BRCA1 and BRCA2 mutations in ovarian cancer progression in Iraq.

scholarly journals Factors influencing women’s decisions to getting tested for BRCA mutation

2018 ◽  
Vol 9 (3) ◽  
pp. 33 ◽  
Author(s):  
Suha Al-Oballi Kridli ◽  
Holly Austin
Keyword(s):  
Ovarian Cancer ◽  
Brca Mutation ◽  
Genetic Mutations ◽  
Inclusion Criteria ◽  
Breast And Ovarian Cancer ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Factors Influencing ◽  
Brca1 And Brca2 Mutations ◽  
Internal And External Factors

Ovarian cancer is the leading cause of death among gynecological cancers. There are many risk factors that can increase a woman’s susceptibility to breast and ovarian cancers, some of which are modifiable.  However, non-modifiable risks for breast and ovarian cancer include the presence of genetic mutations (BRCA) increase the risk of these diseases. The purpose of this review was to identify factors, reported in the literature, known to affect women’s decision to get genetic testing for BRCA1 and BRCA2 mutations for hereditary breast and ovarian cancer. A total of 31 studies that met the inclusion criteria were included in this review. Several internal and external factors, influencing women’s decision to getting tested for BRCA mutations, were identified and explained. Implications for clinical practice were provided.

scholarly journals Prevalence of BRCA1 and BRCA2 Mutations Among High-Risk Saudi Patients With Breast Cancer

2018 ◽  
pp. JGO.18.00066 ◽  
Author(s):  
Omalkhair Abulkhair ◽  
Mohammed Al Balwi ◽  
Ola Makram ◽  
Lamia Alsubaie ◽  
Medhat Faris ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Novel Mutation ◽  
Brca Mutation ◽  
Brca1 Gene ◽  
Brca1 And Brca2 ◽  
Brca1 Mutations ◽  
Brca2 Mutations ◽  
Brca1 And Brca2 Mutations ◽  
Saudi Patients

Purpose Over the past three decades, the incidence rate of breast cancer (BC) among Arab women has continually increased. However, data on the prevalence of BRCA1/2 mutations are scarce. Although the population in Saudi Arabia is at large homogeneous and consanguinity is common, especially in the central, eastern, and southern regions of the country, the prevalence of BRCA1 and BRCA2 mutations and the characteristics of BC are not well studied in the country. Methods This prospective observational study intended to determine the prevalence of BRCA1 and BRCA2 mutations and sought to examine the clinicopathologic features of BC associated with these mutations. Results Of 310 patients, 270 (87%) had no mutation. BRCA mutations were identified in 40 patients; BRCA1 mutations were found in 11% of patients, and BRCA2 mutations were found in 2% of patients. Variants of unknown significance were found in 15% of patients (45 patients). Triple-negative BC (TNBC) accounted for 86% of all patients with BC and mutations. The following three recurrent deleterious founder BRCA1 mutations were observed: c.4136_4137delCT was observed in five unrelated patients, c.5530delC was observed in three unrelated patients, and c.4524G>A mutations were observed in five unrelated patients. One novel mutation was identified in the BRCA1 gene (c.5512 dup [p.Glu1838Glyfs*42]). Conclusion Among high-risk Saudi patients with BC, BRCA1 mutations are prevalent (11%). TNBC is the most common BC subtype. Furthermore, age alone does not have a significant association with mutation, but a combination of risk factors such as age, familial history, and TNBC has a significant association with BRCA mutation.

scholarly journals Tailoring Ovarian Cancer Treatment: Implications of BRCA1/2 Mutations

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 416 ◽  
Author(s):  
Ainhoa Madariaga ◽  
Stephanie Lheureux ◽  
Amit Oza
Keyword(s):  
Ovarian Cancer ◽  
Brca Mutation ◽  
Repair Process ◽  
Resistance Mechanisms ◽  
Tumour Suppressor Genes ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Damage Repair ◽  
Brca Mutation Carriers ◽  
Drug Efflux Pumps

High grade serous ovarian cancer (HGSOC) is the most common epithelial ovarian cancer, harbouring more than 20% germline or somatic mutations in the tumour suppressor genes BRCA1 and BRCA2. These genes are involved in both DNA damage repair process via homologous recombination (HR) and transcriptional regulation. BRCA mutation confers distinct characteristics, including an increased response to DNA-damaging agents, such us platinum chemotherapy and poly-ADP ribose polymerase inhibitors (PARPi). However, several mechanisms of resistance to these agents have been described, including increased HR capacity through reverse BRCA mutations, non-homologous end-joint (NHEJ) repair alterations and drug efflux pumps. Current treatments of ovarian cancer including surgery, chemotherapy, targeted treatment and maintenance strategies, as well as resistance mechanisms will be reviewed, focusing on future trends with respect to BRCA mutation carriers.

Frequency and spectrum of founder and non-founder BRCA1 and BRCA2 mutations in a large series of Russian breast cancer and ovarian cancer patients

2020 ◽  
Vol 184 (1) ◽  
pp. 229-235
Author(s):  
Anna P. Sokolenko ◽  
Tatiana N. Sokolova ◽  
Valeria I. Ni ◽  
Elena V. Preobrazhenskaya ◽  
Aglaya G. Iyevleva ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Patients ◽  
Large Series ◽  
Brca1 And Brca2 ◽  
Brca2 Mutations ◽  
Brca1 And Brca2 Mutations

The incidence of BRCA1 and BRCA2 variants of unknown significance varies in different ethnic populations

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10002-10002 ◽  
Author(s):  
D. M. Opatt ◽  
M. Morrow ◽  
M. Daly
Keyword(s):  
Breast Cancer ◽  
African American ◽  
Genetic Testing ◽  
African American Women ◽  
White Women ◽  
Personal History ◽  
Brca1 And Brca2 ◽  
Variants Of Unknown Significance ◽  
Unknown Significance ◽  
History Of

10002 Background: BRCA1 and BRCA2 mutations in the general population are rare. Women with these mutations have a significantly increased risk of invasive breast and ovarian cancer (65–85% and 15–65% cumulative lifetime risk, respectively). Variants of unknown significance (VUS), which are of uncertain clinical importance, account for up to 50% of all identified BRCA1 and BRCA2 sequence alterations1. Methods: Pooled data from all patients presenting to Fox Chase Cancer Center for genetic counseling was examined. Patients underwent genetic testing after detailed genetic counseling. Clinical data, including gender, ethnic background, and personal history of cancer, and total number of patients tested were collected. Results: A total of 1,765 women and 236 men underwent genetic testing. The distribution of ethnicity was: <1% Asian, 2.7% African American, <1% Hispanic, 2.4% other or of more than one ethnicity, 83% White, and 11% unknown. Mutations of BRCA1 and BRCA2 were seen in 13% of the women and 2.7% of the men. VUS were seen in 6.2% of the women and .15% of the men. Of the women positive for a VUS, 2.4% were Asian, 18.1% were African American, 5.5% were Hispanic, 4.7% were more than one ethnicity, 66.9% were White, and 2.4% were Unknown ethnicity. Only .15% of the men tested were positive for a VUS, all of whom were White. Of the 51 African American women tested, 45.1% were positive for a VUS while only 5.5% of the 1,503 White women tested were positive (p<0.0001). Of the females testing positive for a VUS, a personal history of breast cancer was seen in 66.7% of Asians, 78.3% of African Americans, 100% of Hispanics, 83.3% of those more than one race, 61% of Whites, and none of the people of unknown ethnic origin. One of three men testing positive for a VUS reported a history of breast cancer. Conclusions: Identification of VUS occurred disproportionately in African Americans, occurring ten times more often in African American women than White women in our study. Studies to improve classification of VUS as deleterious or neutral are needed to enhance the utility of genetic testing for women at risk, particularly those of African American ethnicity. 1Goldman, DE et al. Am. J. Hum. Genet., 2004. No significant financial relationships to disclose.

Screening for a BRCA2 Rearrangement in High-Risk Breast/Ovarian Cancer Families: Evidence for a Founder Effect and Analysis of the Associated Phenotypes

2007 ◽  
Vol 25 (15) ◽  
pp. 2027-2034 ◽  
Author(s):  
Patrícia M. Machado ◽  
Rita D. Brandão ◽  
Branca M. Cavaco ◽  
Joana Eugénio ◽  
Sandra Bento ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
High Risk ◽  
Male Breast Cancer ◽  
Brca Mutation ◽  
Male Breast ◽  
Rt Pcr ◽  
Brca Mutations ◽  
Cancer Phenotypes ◽  
High Risk Breast

Purpose BRCA2 rearrangements are rare genetic events. A large BRCA2 genomic insertion was recurrently observed in our participants, and we sought to characterize it at the molecular and phenotypic level. Patients and Methods We studied 210 high-risk breast/ovarian cancer families. Fifty-three probands were fully screened for BRCA1/2 mutations, and three of 53 had a large insertion in exon 3 of BRCA2. This finding was analyzed by polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), and sequencing. An additional 157 consecutive families were screened for this mutation by a three-step PCR method. Phenotype and haplotype analysis was also performed. Results Sixteen BRCA mutations were observed in 19 of 53 patients (36% detection rate). A recurrent Alu motif insertion in position c.156_157 was observed after sequencing of an abnormal fragment obtained after the amplification of BRCA2 exon 3. RT-PCR revealed exon 3 skipping. Screening of this rearrangement identified 14 additional families (out of 157). In total, 17 (8%) of 210 high-risk families ascertained in our clinic were positive for this mutation. Segregation of a common haplotype (from D13S260 to D13S1695) confirmed a common origin, estimated to have occurred 2,400 to 2,600 years ago. The following four cancer phenotypes were observed in the 17 positive families: female breast (n = 9), male breast (n = 4), breast/ovarian (n = 2), and heterogeneous (n = 2). Male breast cancer was more frequently observed in c.156_157insAlu–positive families compared with negative families (23% v 12%, respectively), and 33% of all male breast cancer families with an identified BRCA mutation were c.156_157insAlu positive. Conclusion c.156_157insAlu is a founder mutation of Portuguese origin and is the most frequent BRCA2 rearrangement described to date.

BRCA1 and BRCA2 Mutation Frequency in Women Evaluated in a Breast Cancer Risk Evaluation Clinic

2002 ◽  
Vol 20 (4) ◽  
pp. 994-999 ◽  
Author(s):  
Helen A. Shih ◽  
Fergus J. Couch ◽  
Katherine L. Nathanson ◽  
M. Anne Blackwood ◽  
Timothy R. Rebbeck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Risk Evaluation ◽  
Brca2 Mutation ◽  
Brca1 And Brca2 ◽  
Brca1 Mutations ◽  
Brca2 Mutations ◽  
Brca1 And Brca2 Mutations

PURPOSE: To determine the prevalence of BRCA1 and BRCA2 mutations in families identified in a breast cancer risk evaluation clinic. PATIENTS AND METHODS: One hundred sixty-four families seeking breast cancer risk evaluation were screened for coding region mutations in BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis and DNA sequencing. RESULTS: Mutations were identified in 37 families (22.6%); 28 (17.1%) had BRCA1 mutations and nine (5.5%) had BRCA2 mutations. The Ashkenazi Jewish founder mutations 185delAG and 5382insC (BRCA1) were found in 10 families (6.1%). However, 6174delT (BRCA2) was found in only one family (0.6%) despite estimates of equal frequency in the Ashkenazi population. In contrast to other series, the average age of breast cancer diagnosis was earlier in BRCA2 mutation carriers (32.1 years) than in women with BRCA1 mutations (37.6 years, P = .028). BRCA1 mutations were detected in 20 (45.5%) of 44 families with ovarian cancer and 12 (75%) of 16 families with both breast and ovarian cancer in a single individual. Significantly fewer BRCA2 mutations (two [4.5%] of 44) were detected in families with ovarian cancer (P = .01). Eight families had male breast cancer; one had a BRCA1 mutation and three had BRCA2 mutations. CONCLUSION: BRCA1 mutations were three times more prevalent than BRCA2 mutations. Breast cancer diagnosis before 50 years of age, ovarian cancer, breast and ovarian cancer in a single individual, and male breast cancer were all significantly more common in families with BRCA1 and BRCA2 mutations, but none of these factors distinguished between BRCA1 and BRCA2 mutations. Evidence for reduced breast cancer penetrance associated with the BRCA2 mutation 6174delT was noted.

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