Classification Of Germline Variants Research Articles

Challenges and approaches to calibrating patient phenotype as evidence for cancer gene variant classification under ACMG/AMP guidelines.

Since first publication of the American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) variant classification guidelines, additional recommendations for application of certain criteria have been released (https://clinicalgenome.org/docs/), to improve their application in the diagnostic setting. However, none have addressed use of the PS4 and PP4 criteria, capturing patient presentation as evidence towards pathogenicity. Application of PS4 can be done through traditional case-control studies, or "proband counting" within or across clinical testing cohorts. Review of the existing PS4 and PP4 specifications for Hereditary Cancer Gene Variant Curation Expert Panels revealed substantial differences in the approach to defining specifications. Using BRCA1, BRCA2 and TP53 as exemplar genes, we calibrated different methods proposed for applying the "PS4 proband counting" criterion. For each approach, we considered limitations, non-independence with other ACMG/AMP criteria, broader applicability, and variability in results for different datasets. Our findings highlight inherent overlap of proband-counting methods with ACMG/AMP frequency codes, and the importance of calibration to derive dataset-specific code weights that can account for potential between-dataset differences in ascertainment and other factors. Our work emphasizes the advantages and generalizability of logistic regression analysis over simple proband-counting approaches to empirically determine the relative predictive capacity and weight of various personal clinical features in the context of multigene panel testing, for improved variant interpretation. We also provide a general protocol, including instructions for data formatting and a web-server for analysis of personal history parameters, to facilitate dataset-specific calibration analyses required to use such data for germline variant classification.

Classification of germline variants identified in cancer predisposition genetic testing - consensus of the CZECANCA consortium.

Hereditary cancer syndromes are an important subset of malignant cancers caused by pathogenic variants in one of many known cancer predisposition genes. Diagnosis of cancer predisposition is based on genetic testing using next-generation sequencing. This allows many genes to be analysed at once, increasing the number of variants identified. The correct classification of the variants found is essential for the clinical interpretation of genetic test results. The aim of this study is to summarise the rules for classifying identified variants within individual laboratories and to present the process for creating a common classification. In the Czech Republic, the sharing of identified genetic variants and the development of their consensus classification among national laboratory diagnostic communities is carried out within the Czech Cancer Panel for Clinical Application (CZECANCA) consortium of scientific and diagnostic oncogenetic laboratories. Consensus for variant classification follows a defined protocol. Sharing the results and consensus classification accelerates and refines the release of genetic test results, harmonises results between laboratories and thus contributes to improving the care of individuals at high risk of cancer and their relatives.

The clinical and genomic landscape of patients with DDX41 variants identified during diagnostic sequencing

AbstractDeleterious germ line variants in DDX41 are a common cause of genetic predisposition to hematologic malignancies, particularly myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Targeted next-generation sequencing was performed in a large cohort of sequentially recruited patients with myeloid malignancy, covering DDX41 as well as 30 other genes frequently mutated in myeloid malignancy. Whole genome transcriptome sequencing data was analyzed on a separate cohort of patients with a range of hematologic malignancies to investigate the spectrum of cancer predisposition. Altogether, 5737 patients with myeloid malignancies were studied, with 152 different DDX41 variants detected. Multiple novel variants were detected, including synonymous variants affecting splicing as demonstrated by RNA-sequencing. The presence of a somatic DDX41 variant was highly associated with DDX41 germ line variants in patients with MDS and AML, and we developed a statistical approach to incorporate the co-occurrence of a somatic DDX41 variant into germ line variant classification at a very strong level (as per the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines). Using this approach, the MDS cohort contained 108 of 2865 (3.8%) patients with germ line likely pathogenic/pathogenic (LP/P) variants, and the AML cohort 106 of 2157 (4.9%). DDX41 LP/P variants were markedly enriched in patients with AML and MDS compared with those in patients with myeloproliferative neoplasms, B-cell neoplasm, and T- or B-cell acute lymphoblastic leukemia. In summary, we have developed a framework to enhance DDX41 variant curation as well as highlighted the importance of assessment of all types of genomic variants (including synonymous and multiexon deletions) to fully detect the landscape of possible clinically relevant DDX41 variants.

Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1

BackgroundGermline variants affecting the proofreading activity of polymerases epsilon and delta cause a hereditary cancer and adenomatous polyposis syndrome characterized by tumors with a high mutational burden and a specific mutational spectrum. In addition to the implementation of multiple pieces of evidence for the classification of gene variants, POLE and POLD1 variant classification is particularly challenging given that non-disruptive variants affecting the proofreading activity of the corresponding polymerase are the ones associated with cancer. In response to an evident need in the field, we have developed gene-specific variant classification recommendations, based on the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria, for the assessment of non-disruptive variants located in the sequence coding for the exonuclease domain of the polymerases.MethodsA training set of 23 variants considered pathogenic or benign was used to define the usability and strength of the ACMG/AMP criteria. Population frequencies, computational predictions, co-segregation data, phenotypic and tumor data, and functional results, among other features, were considered.ResultsGene-specific variant classification recommendations for non-disruptive variants located in the exonuclease domain of POLE and POLD1 were defined. The resulting recommendations were applied to 128 exonuclease domain variants reported in the literature and/or public databases. A total of 17 variants were classified as pathogenic or likely pathogenic, and 17 as benign or likely benign.ConclusionsOur recommendations, with room for improvement in the coming years as more information become available on carrier families, tumor molecular characteristics and functional assays, are intended to serve the clinical and scientific communities and help improve diagnostic performance, avoiding variant misclassifications.

VaRHC: an R package for semi-automation of variant classification in hereditary cancer genes according to ACMG/AMP and gene-specific ClinGen guidelines.

Germline variant classification allows accurate genetic diagnosis and risk assessment. However, it is a tedious iterative process integrating information from several sources and types of evidence. It should follow gene-specific (if available) or general updated international guidelines. Thus, it is the main burden of the incorporation of next-generation sequencing into the clinical setting. We created the vaRiants in HC (vaRHC) R package to assist the process of variant classification in hereditary cancer by: (i) collecting information from diverse databases; (ii) assigning or denying different types of evidence according to updated American College of Molecular Genetics and Genomics/Association of Molecular Pathologist gene-specific criteria for ATM, CDH1, CHEK2, MLH1, MSH2, MSH6, PMS2, PTEN, and TP53 and general criteria for other genes; (iii) providing an automated classification of variants using a Bayesian metastructure and considering CanVIG-UK recommendations; and (iv) optionally printing the output to an .xlsx file. A validation using 659 classified variants demonstrated the robustness of vaRHC, presenting a better criteria assignment than Cancer SIGVAR, an available similar tool. The source code can be consulted in the GitHub repository (https://github.com/emunte/vaRHC) Additionally, it will be submitted to CRAN soon.

28. Identification of TP53 germline variants in pediatric patients undergoing tumor testing

Both somatic and germline alterations in TP53 are common in cancers. Identification of potential germline variants through tumor sequencing is important for patient care. We investigated TP53 sequence and copy number variants in 2,810 tumors from 2,197 pediatric patients by targeted NGS panels with germline confirmation when indicated. Somatic and germline variant classification was performed using published guidelines. In total, 228 TP53 sequence variants were detected in 199 tumors from 173 individuals.

Quantification of Discordant Variant Interpretations in a Large Family-Based Study of Li-Fraumeni Syndrome.

The use of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines has improved germline variant classification concordance, but discrepancies persist, sometimes directly affecting medical management. We evaluated variant discordance between and within families with germline TP53 variants in the National Cancer Institute's Li-Fraumeni syndrome longitudinal cohort study. Germline TP53 genetic testing results were obtained from 421 individuals in 140 families. A discordant test result was defined as a report of pathogenicity that differed between two clinical testing laboratories, between a testing laboratory and the ClinVar database, or between either the laboratory or ClinVar database and variant classification by internal study review. There were 141 variants in 140 families (one family had two different TP53 variants). Fifty-four families had discordant interpretations (54 of 140, 39%). Sixteen families had discordant classifications leading to clinically important differences in medical management (16 of 140, 11%). Interfamilial discordance was observed between four families (two different variants). Intrafamilial discordance was observed within six families. One family experienced both intrafamilial and interfamilial discordance. This large single-gene study found discordant germline TP53 variant interpretations in 39% of families studied; 11% had a variant with the potential to significantly affect medical management. This finding is especially concerning in patients with Li-Fraumeni syndrome because of their exceedingly high risks of multiple cancers and intensive cancer screening and risk-reducing recommendations. Centralized data sharing, gene-specific variant curation guidelines, and provider education for consistent variant interpretation are essential for optimal patient care.

An updated quantitative model to classify missense variants in the TP53 gene: A novel multifactorial strategy.

Multigene panel testing has led to an increase in the number of variants of uncertain significance identified in the TP53 gene, associated with Li-Fraumeni syndrome. We previously developed a quantitative model for predicting the pathogenicity of P53 missense variants based on the combination of calibrated bioinformatic information and somatic to germline ratio. Here, we extended this quantitative model for the classification of P53 predicted missense variants by adding new pieces of evidence (personal and family history parameters, loss-of-function results, population allele frequency, healthy individual status by age 60, and breast tumor pathology). We also annotated which missense variants might have an effect on splicing based on bioinformatic predictions. This updated model plus annotation led to the classification of 805 variants into a clinically relevant class, which correlated well with existing ClinVar classifications, and resolved a large number of conflicting and uncertain classifications. We propose this model as a reliable approach to TP53 germline variant classification and emphasize its use in contributing to optimize TP53-specific ACMG/AMP guidelines.

Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants.

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data amongexperts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.

Suggested application of HER2+ breast tumor phenotype for germline TP53 variant classification within ACMG/AMP guidelines.

Early onset breast cancer is the most common malignancy in women with Li-Fraumeni syndrome, caused by germline TP53 pathogenic variants. It has repeatedly been suggested that breast tumors from TP53 carriers are more likely to be HER2+ than those of noncarriers, but this information has not been incorporated into variant interpretation models for TP53. Breast tumor pathology is already being used quantitatively for assessing pathogenicity of germline variants in other genes, and it has been suggested that this type of evidence can be incorporated into current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification. Here, by reviewing published data and using internal datasets separated by different age groups, we investigated if breast tumor HER2+ status has utility as a predictor of TP53 germline variant pathogenicity, considering age at diagnosis. Overall, our results showed that the identification of HER2+ breast tumors diagnosed before the age of 40 can be conservatively incorporated into the current TP53-specific ACMG/AMP PP4 criterion, following a point system detailed in this manuscript. Further larger studies will be needed to reassess the value of HER2+ breast tumors diagnosed at a later age.

Frequency of pathogenic/likely pathogenic germline variants in cancer-related genes among children with acute leukemia in Saudi Arabia.

The frequency of pathogenic/likely pathogenic (P/LP) germline mutations in cancer-related genes among children with cancer in highly consanguineous populations is not well studied. Whole-exome sequencing of germline DNA was performed in 60 children with acute leukemia. We used the St. Jude Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE) data portal for the classification of germline variants by the St. Jude Medal Ceremony pipeline. Fifty-seven patients had acute lymphoblastic leukemia (ALL) and three patients had acute myeloid leukemia. Parental consanguinity was present in 27 (45%) patients. All patients were of Arab ancestry. Three patients (5%) had a history of cancer in their siblings. Five patients (8.3%) had P/LP germline mutations in cancer-related genes. Three patients with B-ALL had heterozygous pathogenic mutations in TP53, BRCA1, and BRCA2; one patient with B-ALL had homozygous pathogenic mutation in PMS2; and one patient with T-ALL had LP homozygous mutation in AK2 that was associated with reticular dysgenesis. Among patients who had history of parental consanguinity, three (11%) had P/LP germline mutations compared with two (8%) in the absence of parental consanguinity. Fourteen (23%) patients had gold medal variants in cancer-related genes, 13 were heterozygous, and one was homozygous. Silver medal variants were present in 35 (58%) patients; all were heterozygous except one homozygous. Children with acute leukemia in Saudi Arabia had low frequency of P/LP mutations in cancer-related genes despite the high rate of consanguinity. Larger studies using whole-genome sequencing are needed to further explore the heritability of childhood leukemia.

Legacy Genetic Testing Results for Cancer Susceptibility: How Common are Conflicting Classifications in a Large Variant Dataset from Multiple Practices?

The classification of germline variants may differ between labs and change over time. We apply a variant harmonization tool, Ask2Me VarHarmonizer, to map variants to ClinVar and identify discordant variant classifications in a large multipractice variant dataset. A total of 7496 variants sequenced between 1996 and 2019 were collected from 11 clinical practices. Variants were mapped to ClinVar, and lab-reported and ClinVar variant classifications were analyzed and compared. Of the 4798 unique variants identified, 3699 (77%) were mappable to ClinVar. Among mappable variants, variants of unknown significance (VUS) accounted for 74% of lab-reported classifications and 60% of ClinVar classifications. Lab-reported and ClinVar discordances were present in 783 unique variants (21.2% of all mappable variants); 121 variants (2.5% of all unique variants) had within-practice lab-reported discordances; and 56 variants (1.2% of all unique variants) had lab-reported discordances across practices. The unmappable variants were associated with a higher proportion of lab-reported pathogenic classifications (50% vs. 21%, p < 0.0001) and a lower proportion of lab-reported VUS classifications (46% vs. 74%, p < 0.0001). Our study shows that discordant variant classification occurs frequently, which may lead to inappropriate recommendations for prophylactic treatments or clinical management.

Prevalence of Inherited Cancer Predisposition Mutations in a Cohort of Older AML Patients Enrolled on the Beat AML Master Trial

Prevalence of Inherited Cancer Predisposition Mutations in a Cohort of Older AML Patients Enrolled on the Beat AML Master Trial

Abstract P4-03-03: Germline potentially pathogenic variants in breast cancer intrinsic molecular subtypes are not associated with somatic TMB

Abstract Background: Breast cancer (BC) is a heterogeneous disease. It is estimated that 5 to 10% of all BC to have a germline genetic predisposition. A 50-gene assay (PAM50) identifies 5 intrinsic molecular subtypes (IMS): Luminal A, Luminal B, HER2-enriched, Basal-like, and Normal-like. Basal-like breast cancers are enriched for BRCA1/2 germline mutations. Deleterious mutations in BRCA1/2 or other DNA-damage repair (DDR) genes may increase tumor mutational burden (TMB), a biomarker for response to checkpoint inhibition therapy. We sought to determine the spectrum of germline mutations in molecular BC subtypes (IMS), and their relation to somatic TMB. Methods: We performed a retrospective analysis of data from NantHealth database. RNAseq was used to classify breast tumors into IMS. Germline variants within putative driver genes (COSMIC v.76) were detected in analysis of 181 whole-genomes and 89 whole-exomes sequenced using Illumina chemistry. Classification of germline variants into potentially pathogenic variants (pPv) was determined using ClinVar database annotation. Patients were categorized as TMB-high by thresholding on &amp;gt;200 non-synonymous exonic somatic mutations as was previously reported. Results: A total of 270 BC patients with comprehensive omics profiling (germline DNAseq, somatic DNAseq, and somatic RNAseq) were available for this analysis. The mean age (±SD) was 56.4 (± 12.5) years (range 20.8-86.5). Forty-six patients (17.0%) were classified TMB-high. The IMS distribution was 40.7% Luminal A, 31.5% Luminal B, 5.9% HER2-enriched, 21.5% Basal-like, and 0.37% Normal-like. Over 200 unique germline variants were detected of which 98 were pPv according to ClinVar annotation. These pPv spanned 21 genes, 7 of which are directly related to DDR. One hundred and four patients had ≥1 pPv (78 had only 1 pPv, and 26 had &amp;gt;1 pPv). The most common pPv were APC (5.9%), BRCA2 (5.2%), TSC2 (4.4%), BRCA1 (3.7%), SDHB (3.3%), SDHD (3.3%), TSC1 (3.0%), PMS2 (3.0%), MUTYH (2.6%), MSH2 (1.5%) and MSH6 (1.5%). BRCA1 and especially BRCA2 pPv were mostly seen in the basal-like patients. Luminal B had distinctly more germline pPv in PMS2, BRCA1 &amp; BRCA2 than Luminal A. TMB-high patients were not significantly enriched for germline pPv (OR 0.73, p=0.41), even when limited to pPv in DDR genes (OR 0.69, p=0.52). TMB-high patients were present in all 4 major IMS types; Her2-enriched 37.5%, Luminal B 23.5%, Basal-like 17.2%, and Luminal A 9.1%. Conclusion: We identified differential distribution of germline pPv in BC IMS. Of the pPv found, APC was the most commonly detected pPv across subtypes, while BRCA1/2 pPv were clustered in Basal-like subtype, and PMS2 in Luminal B subtype. 17% of all patients had a pPv within at least one DDR gene, that potentially may benefit from targeted therapy. Despite IMS types having distinct germline pPv profiles especially in DDR genes, there was no association with subsequent somatic TMB. This suggests that either 1. somatic events are the primary drivers of TMB, or 2. that germline variants with either unknown or benign significance need to be revisited. Future analysis in a larger demographically well-annotated dataset (commercial data, ExAC, other) or via functional studies should be considered. Citation Format: Obeid E, Reddy SB, Goldstein LJ, Daly MB, Benz SC, Hall MJ, Szeto C. Germline potentially pathogenic variants in breast cancer intrinsic molecular subtypes are not associated with somatic TMB [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-03-03.

Abstract 3289: Implementing evolving clinical standards in a variant interpretation knowledgebase

Abstract The rapid expansion of clinical sequencing and targeted therapies has driven the accelerated evolution of clinical guidelines and regulatory standards surrounding sequence variants. Organizations such as the NCCN, FDA, ACMG, etc., continue to incorporate sequence variants into a variety of clinical contexts. The pace of these changes has led to several disparities between guidelines and resources used for the interpretation of clinically identified variants. 1) Despite the inherent lag in creating such standards through expert consensus, this evolution outpaces their incorporation into many resources used for clinical sequencing analysis. 2) Guidelines are often not readily accessible in programmatic, structured ways to promote rapid updates, including many guidelines only available in human-readable text formats. 3) These guidelines apply to various clinical contexts (drug response, prognosis, etc.), each requiring their own schema changes for their proper incorporation. 4) Levels of specificity provided by these guidelines are not conducive to matching specific genomic coordinates (e.g., FGFR2 fusion) or maintaining evidence provenance. We recently developed the Clinical Interpretations for Variants in Cancer (CIViC; civicdb.org) crowd-sourced, open-access knowledgebase, providing a structured framework for evaluating genomic variants of various types (e.g., fusions, SNVs) for their therapeutic, prognostic, predisposing or diagnostic utility. Since then, the CIViC resource has continued to evolve and has tackled the challenges above. This crowd-sourced model of both data entry and application development leverages a wide network of users with various expertise to adapt the resource at a pace beyond what a single organization could achieve. We have introduced a new entity to CIViC that aggregates individual evidence items into a single clinical assertion, allowing guideline incorporation at varying levels of specificity. For example, classification of germline variants by ACMG guidelines assigns individual evidence to specific codes (e.g., PVS1, PP1) that are aggregated to classify a variant as benign or pathogenic. The CIViC assertion provides the variant classification and supporting evidence that can be readily re-evaluated by any user, not just the initial submitter, and reviews and tracks any changes. An assertion can be created for highly specific variants (e.g., EGFR T790M), which can be submitted to ClinVar or more generic variants (ALK fusions) unsupported by many resources. Assertions support searchable, structured, and versioned annotations including FDA companion tests and drug approvals, germline ACMG categories, somatic AMP/ASCO variant levels, NCCN and WHO guidelines. The CIViC knowledgebase provides rapid integration of the latest guidelines and regulatory standards in a freely accessible resource that is flexible enough to evolve with this rapidly changing field. Citation Format: Kilannin Krysiak, Arpad M. Danos, Alex H. Wagner, Susanna Kiwala, Joshua F. McMichael, Adam C. Coffman, Erica K. Barnell, Yan-Yang Feng, Benjamin J. Ainscough, Cody A. Ramirez, Malachi Griffith, Obi L. Griffith. Implementing evolving clinical standards in a variant interpretation knowledgebase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3289.

Abstract 3169: The benefits and burdens of assaying matched normal tissue when sequencing cancer genomes

Abstract Targeted sequencing assays are increasingly used to identify tumor mutations that guide therapeutic decisions. Interpretation of a cancer variant's origin and therapeutic impact poses analytical challenges. Recent studies have indicated that jointly analyzing a tumor with its matched normal can accurately discriminate between tumor-specific (somatic) and inherited (germline) mutations. Moreover, a NHGRI/NCI Clinical Sequencing Exploratory Research Consortium Tumor Working Group just released a set of guidelines recommending that laboratories performing cancer sequencing tests should include germline variants. However, procurement of a matched sample is often logistically impractical. In the absence of a matched normal, large databases and analytical techniques are currently used to identify cancer variants in tumor sequencing data. Whether the benefits outweigh the additional burden of sequencing the matched normal for accurate detection of cancer-relevant mutations remains an open question. To compare tumor-only and tumor/normal analysis of cancer samples, we collected a set of &amp;gt;100 formalin-fixed (FFPE) and fresh frozen cancer samples of various tumor types, where matched normal blood or adjacent tissue was available. We performed augmented target enrichment sequencing (exome and large cancer gene panel) of both DNA and RNA. The data was analyzed using cancer bioinformatics pipelines that detect base substitutions, small insertions/deletions, copy number alterations, and gene fusions in both tumor-only and tumor/normal modes. Variants were annotated using described clinical actionability filtering strategies. Analysis of germline variants for secondary findings was performed. We find that 67% of mutations detected in tumor-only mode are reclassified as germline variants when analyzed together with the matched normal sample. These include mutations in hereditary cancer predisposition genes, such as BRCA1, VHL, and other genes with ACMG guidelines that warrant germline variant classification and appropriate management. Clinically actionable mutations may be miscalled as somatic when a matched normal is not available; however, we find the definition of ‘actionable’ can greatly impact the results of this analysis. Finally, the use of newly available large datasets, such as ExAC, substantially decreases the number of miscalled somatic variants in the absence of a matched normal. The effects of administering targeted therapies to patients with germline mutations in the relevant gene are largely unknown. Mutations of putative germline origin may be important for hereditary cancer knowledge and tumor treatment, and should be reported as such. For NGS-based cancer interpretation to guide clinical decisions in a practical and cost-effective manner, highly optimized tumor-only and tumor/normal analyses must be available with proper attention to germline consent, classification and education. Citation Format: Elena Helman, Michael J. Clark, Ravi Alla, Sean M. Boyle, Shujun Luo, Selene Virk, Deanna Church, Parin Sripakdeevong, Jason Harris, Mirian karbelashvili, Christian Haudenschild, John West, Richard Chen. The benefits and burdens of assaying matched normal tissue when sequencing cancer genomes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3169.