scholarly journals A scalable EHR-based approach for phenotype discovery and variant interpretation for hereditary cancer genes

2021 ◽  
Author(s):  
Chenjie Zeng ◽  
Lisa A Bastarache ◽  
Ran Tao ◽  
Eric Venner ◽  
Scott Hebbring ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Meta Analysis ◽  
Genetic Disorders ◽  
Genomic Medicine ◽  
Risk Scores ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Emerge Network ◽  
Uncertain Significance ◽  
Potential Pathogenicity

Knowledge of the clinical spectrum of rare genetic disorders helps in disease management and variant pathogenicity interpretation. Leveraging electronic health record (EHR)-linked genetic testing data from the eMERGE network, we determined the associations between a set of 23 hereditary cancer genes and 3017 phenotypes in 23544 individuals. This phenome-wide association study replicated 45% (184/406) of known gene-phenotype associations (P = 5.1 ×10-125). Meta-analysis with an independent EHR-derived cohort of 3242 patients confirmed 14 novel associations with phenotypes in the neoplastic, genitourinary, digestive, congenital, metabolic, mental and neurologic categories. Phenotype risk scores (PheRS) based on weighted aggregations of EHR phenotypes accurately predicted variant pathogenicity for at least 50% of pathogenic variants for 8/23 genes. We generated a catalog of PheRS for 7800 variants, including 5217 variants of uncertain significance, to provide empirical evidence of potential pathogenicity. This study highlights the potential of EHR data in genomic medicine.

Comparison of Somatic and Germline Variant Interpretation in Hereditary Cancer Genes

2019 ◽  
pp. 1-8
Author(s):  
Emily W. Moody ◽  
Jennie Vagher ◽  
Whitney Espinel ◽  
David Goldgar ◽  
Kelsi J. Hagerty ◽  
...  
Keyword(s):  
Health Care Providers ◽  
Hereditary Cancer ◽  
Clinical Test ◽  
Variant Interpretation ◽  
Test Results ◽  
Cancer Genes ◽  
Care Providers ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Brca1 Brca2

PURPOSE To compare the classification of genetic variants reported on tumor genomic profiling (TGP) reports with germline classifications on clinical test results and ClinVar. Results will help to inform germline testing discussions and decisions in patients with tumor variants in genes that are relevant to hereditary cancer risk. PATIENTS AND METHODS This study compared somatic and germline classifications of small nucleotide variants in the following genes: BRCA1, BRCA2, CHEK2, PALB2, ATM, MLH1, MSH2, MSH6, and PMS2. Somatic classifications were taken from reports from a single commercial TGP laboratory of tests ordered by providers at Huntsman Cancer Institute between March 2014 and June 2018. Somatic variant interpretations were compared with classifications from germline test results as well as with ClinVar interpretations. RESULTS Of the 623 variants identified on TGP, 353 had a definitive classification in ClinVar, and 103 were assayed with a germline test, with 66 of the variants tested observed in germline. Analysis of somatic variants of uncertain significance listed on TGP reports determined that 22% had a different interpretation compared with ClinVar and that 32% differed from the interpretation on a germline test result. Pathogenic variants on TGP test results were found to differ 13% and 5% of the time compared with ClinVar interpretations and germline test results, respectively. CONCLUSION These results suggest that TGP variants are often classified differently in a germline context. Differences may be due to different processes in variant interpretation between somatic and germline laboratories. These results are important for health care providers to consider when making decisions about additional testing for hereditary cancer risks.

GeneBreaker - Variant simulation to improve the diagnosis of Mendelian rare genetic diseases

2020 ◽  
Author(s):  
Phillip A. Richmond ◽  
Tamar V. Av-Shalom ◽  
Oriol Fornes ◽  
Bhavi Modi ◽  
Alison M. Elliott ◽  
...  
Keyword(s):  
Rare Disease ◽  
Genetic Diseases ◽  
Genomic Medicine ◽  
Real Life ◽  
Variant Calling ◽  
Pathogenic Variants ◽  
Rare Genetic Diseases ◽  
Diagnosis Rate ◽  
Effective Use ◽  
Potential Pathogenicity

AbstractMendelian rare genetic diseases affect 5-10% of the population, and with over 5,300 genes responsible for ~7,000 different diseases, they are challenging to diagnose. The use of whole genome sequencing (WGS) has bolstered the diagnosis rate significantly. Effective use of WGS relies upon the ability to identify the disrupted gene responsible for disease phenotypes. This process involves genomic variant calling and prioritization, and is the beneficiary of improvements to sequencing technology, variant calling approaches, and increased capacity to prioritize genomic variants with potential pathogenicity. As analysis pipelines continue to improve, careful testing of their efficacy is paramount. However, real-life cases typically emerge anecdotally, and utilization of clinically sensitive and identifiable data for testing pipeline improvements is regulated and limiting. We identified the need for a gene-based variant simulation framework which can create mock rare disease scenarios, utilizing known pathogenic variants or through the creation of novel gene-disrupting variants. To fill this need, we present GeneBreaker, a tool which creates synthetic rare disease cases with utility for benchmarking variant calling approaches, testing the efficacy of variant prioritization, and as an educational mechanism for training diagnostic practitioners in the expanding field of genomic medicine. GeneBreaker is freely available at http://GeneBreaker.cmmt.ubc.ca.

scholarly journals Selective pressures on human cancer genes along the evolution of mammals

2018 ◽  
Author(s):  
Alberto Vicens ◽  
David Posada
Keyword(s):  
Positive Selection ◽  
Hereditary Cancer ◽  
Clonal Selection ◽  
Human Cancer ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Potential Association ◽  
Show Evidence ◽  
Mammalian Genomes ◽  
Evolution Of Mammals

AbstractCancer is a disease of the genome caused by somatic mutation and subsequent clonal selection. Several genes associated to cancer in humans, hereafter cancer genes, also show evidence of (germline) positive selection among species. Taking advantage of a large collection of mammalian genomes, we systematically looked for statistically significant signatures of positive selection using dN/dS models in a list of 430 cancer genes. Among these, we identified 63 genes under putative positive selection in mammals, which are significantly enriched in processes like crosslinking DNA repair. We also found evidence of a higher incidence of positive selection in cancer genes bearing germline mutations, like BRCA2, where positively selected residues are physically linked with known pathogenic variants, suggesting a potential association between germline positive selection and risk of hereditary cancer. Overall, our results suggest that genes associated with hereditary cancer have less selective constraints than genes related to sporadic cancer. Also, that the adaptive evolution of human cancer genes in mammals has been most likely driven by adaptive changes in important traits not directly related to cancer.

Suspected and confirmed germline variants from tumor-only somatic sequencing of 864 gastrointestinal malignancies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13131-e13131
Author(s):  
Shivani Khanna ◽  
Steven Brad Maron ◽  
Leah Chase ◽  
Samantha Lomnicki ◽  
Sonia Kupfer ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Allele Frequency ◽  
Hereditary Cancer ◽  
Univariate Analysis ◽  
Genetic Evaluation ◽  
Pathogenic Variant ◽  
Cancer Genes ◽  
Gastrointestinal Malignancies ◽  
Germline Variants ◽  
Pathogenic Variants

e13131 Background: Targeted tumor-only somatic sequencing informs therapies and is becoming a routine part of cancer care. It also identifies patients with possible germline variants who require confirmatory genetic testing. The aim was to identify patients with suspected and confirmed germline variants whose GI tumors underwent somatic sequencing. Methods: 864 patients with GI tumors who had Foundation One (FO) somatic sequencing from 4/2003-3/2018 were evaluated. Inclusion criteria for suspected germline variants were: a) allele frequency ≥ 35% in hereditary cancer genes and b) pathogenic variants by FO and/or ClinVar. Variants in commonly mutated somatic genes ( TP53, KRAS, CDKN2A) were excluded in patients over age 40. Recommendation of genetic evaluation and germline test results were recorded. Patient, family, and tumor characteristics were compared using univariate analysis. Results: 199 of 864 patients had suspected germline pathogenic variants. 50 patients were recommended genetic evaluation, and 26 patients underwent genetic testing. A germline pathogenic variant was confirmed in 15 patients. Among all patients suspected to have germline variants, 8% were confirmed by genetic testing. Patients under age 40 and those with family cancer history were more often referred for testing (Table). Patients with variants in BRCA1, MLH1, MSH2, PMS2, POLE and TP53 were more often referred for testing. Conclusions: A quarter of patients carried a somatic pathogenic variant with allele frequency ≥35% in a hereditary cancer gene. 25% of these patients were recommended for genetic evaluation. Younger patients and those with family history were more often referred. 8% of patients with suspected germline variants were confirmed by genetic testing. These results provide “real world” experience in using somatic only tumor testing to identify patients with germline pathogenic variants who then might benefit from future cancer screening and genetic testing in family members. Comparison of characteristics by recommendation to undergo genetic testing based on somatic tumor sequencing results. [Table: see text]

scholarly journals The First Korean Case of SLC12A3 Aberrant Skipping of Two Exons Detected by RNA Splicing Analysis

2021 ◽  
Vol 11 (2) ◽  
pp. 210-213
Author(s):  
Kiwoong Ko ◽  
Jong-Won Kim
Keyword(s):  
Rna Splicing ◽  
Autosomal Recessive ◽  
Gitelman Syndrome ◽  
Recessive Trait ◽  
Aberrant Splicing ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Exonic Variant ◽  
Uncertain Significance ◽  
Potential Pathogenicity

Gitelman syndrome is a salt-losing tubular disorder that is transmitted as an autosomal recessive trait. Variants in the <i>SLC12A3</i> gene are found in the majority of Gitelman syndrome patients. A 26-year-old woman visited the genetic counseling clinic. Her fiancé was a known Gitelman syndrome patient who was previously diagnosed with 2 pathogenic variants in <i>SLC12A3</i>. In advance of marriage and future family planning, she wanted to perform genetic testing of <i>SLC12A3</i>. A silent exonic variant c.1050G&#x3e;A was found, and multiple splice site in silico algorithms predicted this variant to have potential alteration of splicing. This variant was classified as “variant of uncertain significance,” and RNA splicing analysis was additionally performed. RNA splicing analysis showed aberrant splicing of exon 7–8 skipping. The result points out the potential pathogenicity of this variant, which should be considered a candidate of variant reclassification in the future. We highly recommend the performance of additional RNA splicing analysis, especially for silent variants predicted to have potential alteration of splicing.

scholarly journals Identification of pathogenic variants in cancer genes using base editing screens with editing efficiency correction

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Changcai Huang ◽  
Guangyu Li ◽  
Jiayu Wu ◽  
Junbo Liang ◽  
Xiaoyue Wang
Keyword(s):  
Cancer Genes ◽  
Loss Of Function ◽  
Genomic Context ◽  
Editing Efficiency ◽  
Base Editing ◽  
Guide Rna ◽  
Pathogenic Variants ◽  
Cancer Genome Sequencing ◽  
Assessment And Treatment ◽  
Uncertain Significance

AbstractBackgroundMillions of nucleotide variants are identified through cancer genome sequencing and it is clinically important to identify the pathogenic variants among them. By introducing base substitutions at guide RNA target regions in the genome, CRISPR-Cas9-based base editors provide the possibility for evaluating a large number of variants in their genomic context. However, the variability in editing efficiency and the complexity of outcome mapping are two existing problems for assigning guide RNA effects to variants in base editing screens.ResultsTo improve the identification of pathogenic variants, we develop a framework to combine base editing screens with sgRNA efficiency and outcome mapping. We apply the method to evaluate more than 9000 variants across all the exons ofBRCA1andBRCA2genes. Our efficiency-corrected scoring model identifies 910 loss-of-function variants forBRCA1/2, including 151 variants in the noncoding part of the genes such as the 5′ untranslated regions. Many of them are identified in cancer patients and are reported as “benign/likely benign” or “variants of uncertain significance” by clinicians. Our data suggest a need to re-evaluate their clinical significance, which may be helpful for risk assessment and treatment of breast and ovarian cancer.ConclusionsOur results suggest that base editing screens with efficiency correction is a powerful strategy to identify pathogenic variants in a high-throughput manner. Applying this strategy to assess variants in both coding and noncoding regions of the genome could have a direct impact on the interpretation of cancer variants.

scholarly journals The Inherited and Familial Component of Early-Onset Colorectal Cancer

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 710
Author(s):  
Maria Daca Alvarez ◽  
Isabel Quintana ◽  
Mariona Terradas ◽  
Pilar Mur ◽  
Francesc Balaguer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Hereditary Cancer ◽  
Early Onset ◽  
Epidemiological Data ◽  
Current Evidence ◽  
Common Disease ◽  
Cancer Genes ◽  
Pathogenic Variants ◽  
Therapeutic Decisions ◽  
Early Onset Colorectal Cancer

Early-onset colorectal cancer (EOCRC), defined as that diagnosed before the age of 50, accounts for 10–12% of all new colorectal cancer (CRC) diagnoses. Epidemiological data indicate that EOCRC incidence is increasing, despite the observed heterogeneity among countries. Although the cause for such increase remains obscure, ≈13% (range: 9–26%) of EOCRC patients carry pathogenic germline variants in known cancer predisposition genes, including 2.5% of patients with germline pathogenic variants in hereditary cancer genes traditionally not associated with CRC predisposition. Approximately 28% of EOCRC patients have family history of the disease. This article recapitulates current evidence on the inherited syndromes that predispose to EOCRC and its familial component. The evidence gathered support that all patients diagnosed with an EOCRC should be referred to a specialized genetic counseling service and offered somatic and germline pancancer multigene panel testing. The identification of a germline pathogenic variant in a known hereditary cancer gene has relevant implications for the clinical management of the patient and his/her relatives, and it may guide surgical and therapeutic decisions. The relative high prevalence of hereditary cancer syndromes and familial component among EOCRC patients supports further research that helps understand the genetic background, either monogenic or polygenic, behind this increasingly common disease.

scholarly journals Whole Exome Sequencing Analysis in Fetal Skeletal Dysplasia Detected by Ultrasonography: An Analysis of 38 Cases

2021 ◽  
Vol 12 ◽  
Author(s):  
Ying Peng ◽  
Shuting Yang ◽  
Xiaoliang Huang ◽  
Jialun Pang ◽  
Jing Liu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Recurrence Risk ◽  
Snp Analysis ◽  
Sequencing Analysis ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Uncertain Significance

Background: Skeletal dysplasias (SDs) are a heterogeneous group of genetic disorders that primarily affect bone and cartilage. This study aims to identify the genetic causes for fetal SDs, and evaluates the diagnostic yield of prenatal whole-exome sequencing (WES) for this disorder.Methods: WES was performed on 38 fetuses with sonographically identified SDs and normal results of karyotype and single nucleotide polymorphism (SNP) analysis. Candidate variants were selected by bioinformatics analysis, and verified by Sanger sequencing.Results: WES revealed pathogenic or likely pathogenic variants associated with SDs in 65.79% (25/38) of fetuses, variants of uncertain significance (VUS) in SDs-related genes in 10.53% (4/38) cases, and incidental findings in 31.58% (12/38) fetuses. The SDs-associated variants identified in the present study affected 10 genes, and 35.71% (10/28) of the variants were novel.Conclusion: WES has a high diagnostic rate for prenatal SDs, which improves pregnancy management, prenatal counseling and recurrence risk assessment for future pregnancies. The newly identified variants expanded mutation spectrum of this disorder.

scholarly journals Patients with pathogenic variants for breast cancer other than BRCA1 and BRCA2: qualitative interviews about health care experiences

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Kristin E. Clift ◽  
Sarah K. Macklin ◽  
Stephanie L. Hines
Keyword(s):  
Breast Cancer ◽  
Health Care ◽  
Hereditary Cancer ◽  
Qualitative Interviews ◽  
Clinical Effects ◽  
Test Results ◽  
Cancer Genes ◽  
Care Providers ◽  
Pathogenic Variants ◽  
Health Care Experiences

Abstract Background Genetic testing for hereditary cancer syndromes has been revolutionized by next-generation sequencing, which allows for simultaneous review of numerous genes. Multigene panels are regularly offered to patients because of their scope and decreased cost and turnaround time. However, many genes included on larger panels have not been studied as extensively as BRCA1 and BRCA2 (BRCA1/2), and their clinical effects are often not as well established. Methods We identified patients who received positive test results for pathogenic variants of breast cancer genes from January 2012 through May 2018. We mailed a survey and conducted qualitative interviews to explore the personal and health care experiences of patients with pathogenic variants of BRCA1/2 and patients with “other” (ie, non-BRCA1/2 or PALB2; PTEN; ATM; TP53; NBM, RAD51C; MSH6) variants. We compared the experiences of these patients. Results Fifty-nine out of 128 individuals responded to the survey (46%). Thirty-two patients had BRCA1/2 variants, and 27 had other variants. (49 women and 10 men; median [range] age, 63 [34–87] years). We interviewed 21 patients (17 women and 4 men; median [range] age, 59.6 [34–82] years). Of the interview participants, ten patients had BRCA1/2 variants, and 11 had non-BRCA1/2 variants. Patients reported receiving poor information about their genetic test results, and they often educated their physicians about their results. Some patients believed that they had been ignored or “brushed off” by health care professionals because non-BRCA1/2 genes are less understood outside the genetics research community. Patients with BRCA1/2 variants had similar problems with health care providers, despite increased awareness and established guidelines about BRCA1/2. Conclusions Research is required to understand the clinical significance and proper management of diseases attributable to newly characterized hereditary cancer genes. Additional evaluation of patient and provider education should be at the forefront of efforts to improve patient care.

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