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 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 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.

Differential outcomes in patients treated with endocrine therapy for early or locally advanced breast cancer based on BRCA mutation status

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22065-e22065 ◽  
Author(s):  
R. Wesolowski ◽  
A. G. Shealy ◽  
J. Tao ◽  
H. C. Moore
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Brca Mutation ◽  
Breast Cancer Patients ◽  
Brca1 And Brca2 ◽  
Mutation Status ◽  
Hormone Receptor Positive ◽  
History Of

e22065 Background: Mutations in BRCA1 and BRCA2 genes lead to defects in DNA repair. Estrogen receptor modulates transcription of genes responsible for cell division, which depends on cell's ability to repair DNA for genomic integrity. Differential efficacy of endocrine therapy for breast cancer, therefore, may be possible depending on the tumor's BRCA mutation status. Methods: Through an IRB approved registry, breast cancer patients tested for BRCA1 and BRCA2 mutations and treated with endocrine therapy for hormone-receptor positive non-metastatic disease were identified. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) respectively. Fisher's exact test or Wilcoxon rank sum test were used to assess differences among subgroups with respect to their characteristics. Cox proportional hazard analysis was used to identify univariate and multivariate risk factors for OS and PFS. Results: Of 115 breast cancer patients tested for BRCA mutations, 63 met the inclusion criteria of whom 16 patients were BRCA 1 or 2 mutation positive and 47 were negative. In the BRCA(+) group, 14 patients (87.5%) had stage I-III disease at diagnosis. In the BRCA(-) group, 5 patients (10.6%) had stage 0 disease while 41 patients (87.2%) had stage I-III disease at diagnosis. Stage at diagnosis was unavailable for 2 BRCA(+) and 1 BRCA(-) patients. Both groups were similar with respect to Her-2 expression status, history of ovarian suppression, age of diagnosis, and age of menopause. Median age was 48 yo in BRCA(+) group, 42 yo in BRCA(-), (p=0.12). Median follow up was 76.1 mos in BRCA(+) and 62.9 mos in BRCA(-) group. OS was worse in BRCA(+) group (HR 7.38, 95% [CI] 1.49–36.4 p=0.014). After adjustment for stage and history of ovarian suppression, the difference remained significant (HR 16.6, 95% [CI] 1.95–142, p=0.010). There was no difference in PFS (HR 2.02, 95% [CI] 0.82–4.96, p=0.13). Conclusions: Patients with BRCA mutation, hormone-receptor positive hereditary breast cancer treated with endocrine therapy had inferior survival compared with similar patients who are BRCA mutation negative. Prospective studies to evaluate the differential effects of endocrine therapy in these populations are warranted. No significant financial relationships to disclose.

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

2018 ◽  
Vol 55 (12) ◽  
pp. 794-802 ◽  
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.

scholarly journals Associations of pathogenic mutations responsible for breast cancer risk with histology and immunohistochemistry in Romanian population

2018 ◽  
Vol 26 (2) ◽  
pp. 165-175 ◽  
Author(s):  
Iulian Gabriel Goidescu ◽  
Dan Tudor Eniu ◽  
Gabriela Valentina Caracostea ◽  
Gheorghe Cruciat ◽  
Florin Stamatian
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Ductal Carcinoma ◽  
Breast Cancer Patients ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants ◽  
Romanian Population ◽  
First Time ◽  
Histology And Immunohistochemistry

Abstract Introduction: Breast cancer is the most common cancer in women worldwide, and Romania makes no exception from this trend. Genetic screening for Hereditary Breast and Ovarian Cancer began to be used on a larger scale after the introduction of Next Generation Sequencing. The aim of this study was to assess the association of deleterious mutations responsible for breast cancer with histopathological and immunohistochemical prognostic factors and to identify some genetic variants in the BRCA1 and BRCA2 genes. Method: 80 patients with breast cancer and negative genetic test or pathogenic variants on BRCA1/2, TP53, PALB2, CHEK2, ATM genes were included. All the cases had a prior histological diagnosis and complete immunohistochemical features. The genetic testing was conducted through a multigene panel. Results: 65% of patients had a deleterious mutation on BRCA genes. In 97.5% of cases the histology was invasive ductal carcinoma. Significant differences were identified between BRCA1 group and negative mutation group regarding estrogen receptor (ER) (p=0.0051), progesterone receptor (PR) (p=0.0004) and Ki67 (p=0.001). Seven breast cancer patients had BRCA1 c.3607C>T variant, which was statistically significantly associated with triple- negative breast cancer (p <0.0001). Of the 7 cases diagnosed with BRCA 2 mutations we identified the c.8755-1G>A variant in 3 cases and the c.9371A>T variant in 3 cases. Discussion and conclusion: Our study confirmed the association of BRCA1 mutations with negative ER, PR or triple negative breast cancer (TNBC). Description of BRCA1 c.3607C>T mutation for the first time in Romanian population and its association with TNBC will need further investigation.

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 Analysis of Pathogenic Variants in BRCA1 and BRCA2 Genes using Next-Generation Sequencing in Women with Triple Negative Breast Cancer from South India

2021 ◽  
Author(s):  
Taruna Rajagopal ◽  
Arun Seshachalam ◽  
Arunachalam Jothi ◽  
Krishna Kumar Rathnam ◽  
Srikanth Talluri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Brca Mutation ◽  
Mutation Screening ◽  
Preventive Therapy ◽  
Brca1 And Brca2 ◽  
Indian Women ◽  
Pathogenic Variants ◽  
South Indian

Abstract The frequency of triple-negative breast cancer (TNBC) incidence varies among different populations, suggesting the involvement of genetic component towards TNBC development. Previous studies have reported that BRCA1/2 germline mutations confer a lifetime risk of developing TNBC. However, there is hardly any information regarding the common pathogenic variants (PVs) in BRCA1/2 genes that contribute to TNBC in the Indian population. Hence, we screened for PVs in BRCA1/2 and their association with clinico-pathological features in TNBC patients. Among the 59 TNBC genomic DNA samples sequenced, 8 BRCA mutations were detected in 59 TNBC patients (13.6%). Almost 50% pre-menopausal TNBC patients had a BRCA mutation. Of the 8 BRCA mutations, we observed BRCA1 mutations in 6 TNBC patients, and BRCA2 mutations in 2 TNBC patients. Among the 6 BRCA1 mutations, three were c.68_69delAG (185delAG) mutation. Remarkably, all the TNBC patients with BRCA mutations exhibited higher-grade tumors (grade 2 or 3). However, among the BRCA mutation carriers, only one patient with a BRCA2 mutation (p.Glu1879Lys) developed metastasis in the observed cohort. Our data advocates that South Indian women with higher grade TNBC tumors and without hereditary breast and ovarian cancer should be considered for BRCA mutation screening, thereby enabling enhanced decision-making and preventive therapy.

Therapeutic radiation for breast cancer in BRCA mutation carriers and contralateral breast cancer (CBC) risk

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 611-611
Author(s):  
H. C. Moore ◽  
R. Wesolowski ◽  
T. K. Choueiri ◽  
L. Rybicki ◽  
A. G. Shealy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Radiation Treatment ◽  
Brca Mutation ◽  
Negative Group ◽  
Breast Cancer Patients ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Mutation Carriers ◽  
Brca Mutation Carriers

611 Background: BRCA mutation carriers diagnosed with breast cancer are at high risk for contralateral second primary breast cancers. Mutations in BRCA1 and BRCA2 lead to defects in DNA repair. Radiation treatment for breast cancer is felt to increase risk of CBC, but the interaction between BRCA status and local radiation therapy with respect to their effects on CBC is unclear. Methods: Through an IRB approved database registry at the Cleveland Clinic, breast cancer patients tested for BRCA1 and BRCA2 mutations were identified and evaluated for CBC events and radiation treatment history. Patients with inadequate clinical follow-up, those with bilateral synchronous breast cancer and those undergoing bilateral mastectomy within one year of the original breast cancer diagnosis were excluded from the analysis. Chi-square test was used to compare CBC rates with or without prior radiation separately in patients testing positive and those testing negative for BRCA mutations. Results: Of 115 identified breast cancer patients tested for BRCA mutations, 57 met the inclusion criteria. Twenty-one carried BRCA1 or BRCA2 mutations and 36 tested negative for these mutations. Median follow-up for the two groups was 69.5 months (92 months in BRCA positive group and 51.5 months in BRCA negative group). Median age at diagnosis was 45 years (41 years in BRCA positive group and 48.5 in BRCA negative group). Among the 21 carriers, 9 patients (43%) developed CBC while only 3 of 36 patients (8%) testing negative for BRCA mutations developed CBC. Thirteen of 21 mutation carriers (62%) had received radiation treatment for the original cancer: CBC occurred in 3 of 13 (23%) radiated patients and 6 of 8 (75%) patients who had not received radiation (p= 0.02). Among 36 patients with negative BRCA testing, 30 (83%) had received radiation: CBC occurred in 3 of 30 (10%) mutation negative patients who had received prior radiation and in 0 of the 6 patients who had not received radiation (p = 0.42). Conclusions: CBC incidence was higher among BRCA mutation carriers than a control group suspected of having hereditary breast cancer but testing negative for these mutations. The use of radiation in the presence of a BRCA mutation, however, does not appear to further increase the risk for CBC. No significant financial relationships to disclose.

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