A comprehensive laboratory‐based program for classification of variants of uncertain significance in hereditary cancer genes

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.

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Comparison of Somatic and Germline Variant Interpretation in Hereditary Cancer Genes

JCO Precision Oncology ◽

10.1200/po.19.00144 ◽

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.

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Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

Biomedicines ◽

10.3390/biomedicines10010106 ◽

2022 ◽

Vol 10 (1) ◽

pp. 106

Author(s):

Estefanía Martínez-Barrios ◽

Sergi Cesar ◽

José Cruzalegui ◽

Clara Hernandez ◽

Elena Arbelo ◽

...

Keyword(s):

Pediatric Population ◽

Genetic Diagnosis ◽

Rare Event ◽

Clinical Genetics ◽

Healthy Children ◽

Unexpected Death ◽

Variants Of Uncertain Significance ◽

Arrhythmic Death ◽

Uncertain Significance

Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40–50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype–phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype–phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

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Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2021.09.003 ◽

2021 ◽

Vol 108 (10) ◽

pp. 1907-1923

Author(s):

Sandrine M. Caputo ◽

Lisa Golmard ◽

Mélanie Léone ◽

Francesca Damiola ◽

Marine Guillaud-Bataille ◽

...

Keyword(s):

Brca1 And Brca2 ◽

Variants Of Uncertain Significance ◽

Powerful Approach ◽

Uncertain Significance

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A review of a multifactorial probability based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS)

Human Mutation ◽

10.1002/humu.22064 ◽

2012 ◽

Vol 33 (5) ◽

pp. 900-903 ◽

Cited By ~ 1

Author(s):

Noralane M. Lindor ◽

Lucia Guidugli ◽

Xianshu Wang ◽

Maxime P. Vallée ◽

Alvaro N. A. Monteiro ◽

...

Keyword(s):

Brca1 And Brca2 ◽

Variants Of Uncertain Significance ◽

Uncertain Significance

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A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS)

Human Mutation ◽

10.1002/humu.21627 ◽

2011 ◽

Vol 33 (1) ◽

pp. 8-21 ◽

Cited By ~ 124

Author(s):

Noralane M. Lindor ◽

Lucia Guidugli ◽

Xianshu Wang ◽

Maxime P. Vallée ◽

Alvaro N. A. Monteiro ◽

...

Keyword(s):

Brca1 And Brca2 ◽

Variants Of Uncertain Significance ◽

Uncertain Significance

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Functional Assays for Classification of BRCA2 Variants of Uncertain Significance

Cancer Research ◽

10.1158/0008-5472.can-07-1587 ◽

2008 ◽

Vol 68 (9) ◽

pp. 3523-3531 ◽

Cited By ~ 85

Author(s):

Daniel J. Farrugia ◽

Mukesh K. Agarwal ◽

Vernon S. Pankratz ◽

Amie M. Deffenbaugh ◽

Dmitry Pruss ◽

...

Keyword(s):

Variants Of Uncertain Significance ◽

Functional Assays ◽

Uncertain Significance

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A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients

Clinical Chemistry ◽

10.1093/clinchem/hvaa250 ◽

2020 ◽

Author(s):

Lidia Feliubadaló ◽

Alejandro Moles-Fernández ◽

Marta Santamariña-Pena ◽

Alysson T Sánchez ◽

Anael López-Novo ◽

...

Keyword(s):

Hereditary Cancer ◽

Diagnostic Yield ◽

Clinical Information ◽

Variant Classification ◽

Collaborative Effort ◽

Variants Of Uncertain Significance ◽

Large Gene ◽

Gene Panel Testing ◽

Uncertain Significance ◽

Risk Of Cancer

Abstract Background Gene panel testing by massive parallel sequencing has increased the diagnostic yield but also the number of variants of uncertain significance. Clinical interpretation of genomic data requires expertise for each gene and disease. Heterozygous ATM pathogenic variants increase the risk of cancer, particularly breast cancer. For this reason, ATM is included in most hereditary cancer panels. It is a large gene, showing a high number of variants, most of them of uncertain significance. Hence, we initiated a collaborative effort to improve and standardize variant classification for the ATM gene. Methods Six independent laboratories collected information from 766 ATM variant carriers harboring 283 different variants. Data were submitted in a consensus template form, variant nomenclature and clinical information were curated, and monthly team conferences were established to review and adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria to ATM, which were used to classify 50 representative variants. Results Amid 283 different variants, 99 appeared more than once, 35 had differences in classification among laboratories. Refinement of ACMG/AMP criteria to ATM involved specification for twenty-one criteria and adjustment of strength for fourteen others. Afterwards, 50 variants carried by 254 index cases were classified with the established framework resulting in a consensus classification for all of them and a reduction in the number of variants of uncertain significance from 58% to 42%. Conclusions Our results highlight the relevance of data sharing and data curation by multidisciplinary experts to achieve improved variant classification that will eventually improve clinical management.

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Classification of genetic variants in hereditary cancer genes

Clinical DNA Variant Interpretation ◽

10.1016/b978-0-12-820519-8.00003-x ◽

2021 ◽

pp. 349-387

Author(s):

Lidia Feliubadaló ◽

Michael T. Parsons ◽

Marta Pineda ◽

Emma Tudini

Keyword(s):

Hereditary Cancer ◽

Genetic Variants ◽

Cancer Genes

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