ArticleGenome medicine2018
Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls.
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20 citing papers in PubMed.
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- Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma.JAMA oncology · 2020Article
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Authors and funding
50 authors.
Jung KimClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Wen LuoCancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA.
Mingyi WangCancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA.
Talia Wegman-OstroskyClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Megan N FroneClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Jennifer J JohnstonMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA.
Michael L NickersonLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD, 20877, USA.
Melissa RotunnoEpidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Shengchao A LiCancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA.
Maria I AchatzClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Seth A BrodieCancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA.
Michael DeanLaboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD, 20877, USA.
Kelvin C de AndradeClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Fernanda P FortesClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Matthew GianferanteClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Payal KhinchaClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Mary L McMasterClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Lisa J McReynoldsClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Alexander PemovClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Maisa PinheiroClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Karina M SantiagoClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Blanche P AlterClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Neil E CaporasoOccupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Shahinaz M GadallaClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Lynn R GoldinIntegrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Mark H GreeneClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Jennifer LoudClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Xiaohong R YangIntegrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Neal D FreedmanMetabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Susan M GapsturBehavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
Mia M GaudetBehavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
Donato CalistaDepartment of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy.
Paola GhiorzoDepartment of Internal Medicine and Medical Specialties, University of Genoa and Genetics of Rare Cancers, IRCCS Ospedale Policinico San Martino, Genoa, Italy.
Maria Concetta FargnoliDepartment of Dermatology, University of L'Aquila, L'Aquila, Italy.
Eduardo NagoreDepartment of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
Ketty PerisInstitute of Dermatology, Catholic University - Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
Susana PuigDermatology Department, Melanoma Unit, Hospital Clinic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain & Centro de Investigacion Biomedica en Red en Enfermedades Raras (CIBERER), Valencia, Spain.
Maria Teresa LandiIntegrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Belynda HicksCancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA.
Bin ZhuCancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA.
Jia LiuCancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA.
Joshua N SampsonBiostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Stephen J ChanockOffice of the Director, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Lisa J MirabelloClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Lindsay M MortonRadiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Leslie G BieseckerMedical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA.
Margaret A TuckerDivision of Cancer Epidemiology and Genetics, Human Genetics Program National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Sharon A SavageClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
Alisa M GoldsteinClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA. goldstea@mail.nih.gov.
Douglas R StewartClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA. drstewart@mail.nih.gov.
Funding
Clinical Genetic Studies of Familial and Hereditary Cancer SyndromesZIACP010144 · NCI · DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS · PI SAVAGE, SHARON A. · 2009 to 2025
$111.8MGenomic Ascertainment - Molecular and Genetic AspectsZIAHG200359 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI BIESECKER, LESLIE · 2009 to 2025
$19.7MGenomic Ascertainment - Clinical and Behavioral AspectsZIAHG200387 · NHGRI · NATIONAL HUMAN GENOME RESEARCH INSTITUTE · PI BIESECKER, LESLIE · 2013 to 2025
$15.5MNHGRI NIH HHS HG200359 09NHGRI NIH HHS HG200387 04
Abstract
backgroundPrior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8-5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982).
methodsWe used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS).
resultsIn the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers.
conclusionThe 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls.
Indexed as
Genetic Predisposition to DiseaseMutationPolymorphism, Single NucleotideAgedCohort StudiesDNA Mutational AnalysisEthnicityFemaleGenes, NeoplasmHumansMaleNeoplasmsACMG secondary findingsFamilial cancer exomePopulation studyVariant classification
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