scholarly journals Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes in a 3,552 Japanese whole-genome sequence dataset (3.5KJPNv2)

2020 ◽  
Author(s):  
Hideki Tokunaga ◽  
Keita Iida ◽  
Atsushi Hozawa ◽  
Soichi Ogishima ◽  
Yoh Watanabe ◽  
...  
Keyword(s):  
Prospective Cohort ◽  
Clinical Evidence ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Cancer Syndrome ◽  
Brca1 And Brca2 ◽  
Cancer History ◽  
Pathogenic Variants ◽  
Uncertain Significance

AbstractIdentification of pathogenic germline variants yet no clinical evidence in BRCA genes has become important in patient care of hereditary breast and ovarian cancer syndrome (HBOC). Computational scoring and prospective cohort studies may help to identify such pathogenic variants. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of the genome cohorts by Tohoku Medical Megabank Project (TMM) with the InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAF) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar are used for filtration criteria. Familial predispositions in cancers among the 35,000 TMM genome cohort participants are analyzed to verify the pathogenicity. Seven potentially pathogenic variants were newly identified. Carriers of these potential pathogenic variants and definite P and LP variants among participants of the TMM prospective cohort show a statistically significant preponderance in cancer onset in sisters in the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potential pathogenic variants in BRCA genes for Japanese population. These results will be helpful to follow up the carriers of variants of uncertain significance in the HBOC genes.

scholarly journals Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2)

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0236907
Author(s):  
Hideki Tokunaga ◽  
Keita Iida ◽  
Atsushi Hozawa ◽  
Soichi Ogishima ◽  
Yoh Watanabe ◽  
...  
Keyword(s):  
Prospective Cohort ◽  
Cancer Syndrome ◽  
Brca1 And Brca2 ◽  
Cancer History ◽  
Genome Data ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Prospective Cohorts ◽  
Personalized Health ◽  
Personalized Health Care

Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study.

scholarly journals Pathogenic and uncertain genetic variants have clinical cardiac correlates in diverse biobank participants

2019 ◽  
Author(s):  
Tess D. Pottinger ◽  
Megan J. Puckelwartz ◽  
Lorenzo L. Pesce ◽  
Avery Robinson ◽  
Samuel Kearns ◽  
...  
Keyword(s):  
Genetic Variation ◽  
African Ancestry ◽  
Left Ventricular ◽  
Whole Genome Sequence ◽  
Internal Diameter ◽  
Variants Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Rare Genetic Variation ◽  
Uncertain Significance ◽  
Ventricle Size

AbstractBackgroundGenome sequencing coupled with electronic heath record data can uncover medically important genetic variation. Interpretation of rare genetic variation and its role in mediating cardiovascular phenotypes is confounded by variants of uncertain significance.Methods and ResultsWe analyzed the whole genome sequence of 900 racially and ethnically diverse biobank participants selected from a single US center. Participants were equally divided among European, African, Hispanic, and mixed race/ethnicities. We evaluated the American College of Medical Genetics and Genomics medically actionable list of 59 genes focusing on the cardiac genes. Variation was interpreted using the most recent reports in ClinVar, a database of medically relevant human variation. We identified 19 individuals with pathogenic/likely pathogenic variants in cardiac actionable genes (2%) and found evidence for clinical correlates in the electronic health record. African ancestry participants had more variants of uncertain significance in the medically actionable genes including the 30 cardiac actionable genes, even when normalized to total variant count per person. Longitudinal measures of left ventricle size, corrected for body surface area, from approximately 400 biobank participants (1,723 patient years) correlated with genetic findings. The presence of one or more uncertain variants in the actionable cardiac genes and a cardiomyopathy diagnosis correlated with increased left ventricular internal diameter in diastole and in systole. In particular, MYBPC3 was identified as a gene with excess variants of uncertain significance.ConclusionsThese data indicate a subset of uncertain variants may confer risk and should not be considered benign.

scholarly journals Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

2020 ◽  
Vol 9 (9) ◽  
pp. 3003
Author(s):  
Aldo Germani ◽  
Simona Petrucci ◽  
Laura De Marchis ◽  
Fabio Libi ◽  
Camilla Savio ◽  
...  
Keyword(s):  
Therapeutic Approaches ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants ◽  
Pancreatic Cancers ◽  
Damage Repair ◽  
High Incidence ◽  
Uncertain Significance ◽  
Generation Sequencing ◽  
Index Cases ◽  
Multigene Panel

The 5–10% of breast/ovarian cancers (BC and OC) are inherited, and germline pathogenic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10–20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 113 non-BRCA patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC, and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the CHEK2 gene, and a new pathogenic variant was detected in the RECQL gene. These results supported the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches.

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 Non-BRCA1/2 Variants Detected in a High-Risk Chilean Cohort With a History of Breast and/or Ovarian Cancer

2019 ◽  
pp. 1-14 ◽  
Author(s):  
Christina Adaniel ◽  
Francisca Salinas ◽  
Juan Manuel Donaire ◽  
Maria Eugenia Bravo ◽  
Octavio Peralta ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Genetic Testing ◽  
High Risk ◽  
Genetic Predisposition ◽  
Cancer Syndrome ◽  
Breast And Ovarian Cancer ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants ◽  
Cancer Program ◽  
Genetic Test Results

PURPOSE Little is known about the genetic predisposition to breast and ovarian cancer among the Chilean population, in particular genetic predisposition beyond BRCA1 and BRCA2 mutations. In the current study, we aim to describe the germline variants detected in individuals who were referred to a hereditary cancer program in Santiago, Chile. METHODS Data were retrospectively collected from the registry of the High-Risk Breast and Ovarian Cancer Program at Clínica Las Condes, Santiago, Chile. Data captured included index case diagnosis, ancestry, family history, and genetic test results. RESULTS Three hundred fifteen individuals underwent genetic testing during the study period. The frequency of germline pathogenic and likely pathogenic variants in a breast or ovarian cancer predisposition gene was 20.3%. Of those patients who underwent testing with a panel of both high- and moderate-penetrance genes, 10.5% were found to have pathogenic or likely pathogenic variants in non- BRCA1/2 genes. CONCLUSION Testing for non- BRCA1 and -2 mutations may be clinically relevant for individuals who are suspected to have a hereditary breast or ovarian cancer syndrome in Chile. Comprehensive genetic testing of individuals who are at high risk is necessary to further characterize the genetic susceptibility to cancer in Chile.

scholarly journals Interpretation of BRCA2 Splicing Variants: A Case Series of Challenging Variant Interpretations and the Importance of Functional RNA Analysis

2021 ◽  
Author(s):  
Paola Nix ◽  
Erin Mundt ◽  
Bradford Coffee ◽  
Elizabeth Goossen ◽  
Bryan M. Warf ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Case Series ◽  
Cancer History ◽  
Rna Analysis ◽  
Pathogenic Variants ◽  
Conflicting Evidence ◽  
Increased Risk ◽  
Splicing Variants ◽  
Uncertain Significance ◽  
In Silico Models

AbstractA substantial proportion of pathogenic variants associated with an increased risk of hereditary cancer are sequence variants affecting RNA splicing. The classification of these variants can be complex when both non-functional and functional transcripts are produced from the variant allele. We present four BRCA2 splice site variants with complex variant interpretations (BRCA2 c.68-3T>G, c.68-2A>G, c.425G>T, c.8331+2T>C). Evidence supporting a pathogenic classification is available for each variant, including in silico models, absence in population databases, and published functional data. However, comprehensive RNA analysis showed that some functional transcript may be produced by each variant. BRCA2 c.68-3T>G results in a partial splice defect. For BRCA2 c.68-2A>G and c.425G>T, aberrant splicing was shown to produce a potentially functional, in-frame transcript. BRCA2 c.8331+2T>C may utilize a functional GC donor in place of the wild-type GT donor. The severity of cancer history for carriers of these variants was also assessed using a history weighting algorithm and was not consistent with pathogenic controls (carriers of known pathogenic variants in BRCA2). Due to the conflicting evidence, our laboratory classifies these BRCA2 variants as variants of uncertain significance. This highlights the importance of evaluating new and existing evidence to ensure accurate variant classification and appropriate patient care.

Outbreak of Burkholderia contaminans endophthalmitis traced to a clinic ventilation system

2021 ◽  
pp. 1-3
Author(s):  
Theodore Spilker ◽  
Jens Kratholm ◽  
Eliza Depoorter ◽  
Peter Vandamme ◽  
John J. LiPuma
Keyword(s):  
Sequence Analysis ◽  
Cataract Surgery ◽  
Genome Sequence ◽  
Ventilation System ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Genome Sequence Analysis ◽  
Source Of Infection ◽  
Burkholderia Contaminans

Abstract We describe the follow-up investigation of an outbreak of endophthalmitis due to Burkholderia contaminans following cataract surgery in a single clinic. Whole-genome sequence analysis of bacteria recovered from affected patients and the clinic identified the clinic’s ventilation system as the source of infection.

scholarly journals Annotating high-impact 5’untranslated region variants with the UTRannotator

2020 ◽  
Author(s):  
Xiaolei Zhang ◽  
Matthew Wakeling ◽  
James Ware ◽  
Nicola Whiffin
Keyword(s):  
Open Reading Frames ◽  
Supplementary Information ◽  
Untranslated Regions ◽  
Protein Coding ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Upstream Open Reading Frames ◽  
The Impact ◽  
Reading Frames

AbstractSummaryCurrent tools to annotate the predicted effect of genetic variants are heavily biased towards protein-coding sequence. Variants outside of these regions may have a large impact on protein expression and/or structure and can lead to disease, but this effect can be challenging to predict. Consequently, these variants are poorly annotated using standard tools. We have developed a plugin to the Ensembl Variant Effect Predictor, the UTRannotator, that annotates variants in 5’untranslated regions (5’UTR) that create or disrupt upstream open reading frames (uORFs). We investigate the utility of this tool using the ClinVar database, providing an annotation for 30.8% of all 5’UTR (likely) pathogenic variants, and highlighting 31 variants of uncertain significance as candidates for further follow-up. We will continue to update the UTR annotator as we gain new knowledge on the impact of variants in UTRs.Availability and implementationUTRannotator is freely available on Github: https://github.com/ImperialCardioGenetics/UTRannotatorSupplementary informationSupplementary data are available at bioRxiv.

Uptake of pre-symptomatic testing for BRCA1 and BRCA2 is age, gender, offspring and time-dependent

2020 ◽  
pp. jmedgenet-2019-106544
Author(s):  
Claire Forde ◽  
Kate Brunstrom ◽  
Emma Woodward ◽  
Naomi Bowers ◽  
Marta Pereira ◽  
...  
Keyword(s):  
Time Dependent ◽  
Age Group ◽  
Brca1 And Brca2 ◽  
North West ◽  
Pathogenic Variants ◽  
Kaplan Meier ◽  
Index Family ◽  
Initial Uptake ◽  
Variant Identification

BackgroundGenetic testing for BRCA1 and BRCA2 pathogenic variants (PVs) has been available in North West England since 1995. We assessed uptake of pre-symptomatic testing in 1564 families with PVs over a 24.5year follow-up (FU) period.MethodsFirst-degree relatives (FDRs) in families with BRCA1 or BRCA2 PVs were eligible from date of index family report if unaffected by a relevant cancer and alive at report date. FDRs were censored as not having undergone a pre-symptomatic test at diagnosis of a relevant cancer, date of death, age 93 or 30/03/2019. Time to uptake of pre-symptomatic testing was assessed by Kaplan–Meier curves, by gender and children.Results2554 male and 3115 female FDRs were eligible. Overall uptake was 775 (30.3%) in men and 1935 (62.1%) in women. This increased at 15 years to 33.6% and 67.9%, and continued to rise until 24 years (p<0.001). For women, the 29-year to 39-year age group had the highest uptake at 10 years FU (72.5%; p<0.01), whereas the 50-year to 59-year age group was highest in men (37.2%; p<0.01). Women <18 years at the time of familial variant identification had lower initial uptake, but this rose to >80% by 15 years. Uptake was higher in parous women (p<0.001) and in men with daughters (p<0.0001).ConclusionUptake of BRCA1/2 pre-symptomatic testing is age, gender and time-dependent, and higher in women with children and men with daughters.

scholarly journals The Genetic Analyses of French Canadians of Quebec Facilitate the Characterization of New Cancer Predisposing Genes Implicated in Hereditary Breast and/or Ovarian Cancer Syndrome Families

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3406
Author(s):  
Caitlin T. Fierheller ◽  
Wejdan M. Alenezi ◽  
Patricia N. Tonin
Keyword(s):  
Ovarian Cancer ◽  
Genetic Architecture ◽  
French Canadian ◽  
Cancer Syndrome ◽  
French Canadians ◽  
Brca1 And Brca2 ◽  
Genetic Analyses ◽  
Pathogenic Variants ◽  
Predisposing Genes

The French Canadian population of the province of Quebec has been recognized for its contribution to research in medical genetics, especially in defining the role of heritable pathogenic variants in cancer predisposing genes. Multiple carriers of a limited number of pathogenic variants in BRCA1 and BRCA2, the major risk genes for hereditary breast and/or ovarian cancer syndrome families, have been identified in French Canadians, which is in stark contrast to the array of over 2000 different pathogenic variants reported in each of these genes in other populations. As not all such cancer syndrome families are explained by BRCA1 and BRCA2, newly proposed gene candidates identified in other populations have been investigated for their role in conferring risk in French Canadian cancer families. For example, multiple carriers of distinct variants were identified in PALB2 and RAD51D. The unique genetic architecture of French Canadians has been attributed to shared ancestry due to common ancestors of early settlers of this population with origins mainly from France. In this review, we discuss the merits of genetically characterizing cancer predisposing genes in French Canadians of Quebec. We focused on genes that have been implicated in hereditary breast and/or ovarian cancer syndrome families as they have been the most thoroughly characterized cancer syndromes in this population. We describe how genetic analyses of French Canadians have facilitated: (i) the classification of variants in BRCA1 and BRCA2; (ii) the identification and classification of variants in newly proposed breast and/or ovarian cancer predisposing genes; and (iii) the identification of a new breast cancer predisposing gene candidate, RECQL. The genetic architecture of French Canadians provides a unique opportunity to evaluate new candidate cancer predisposing genes regardless of the population in which they were identified.

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