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Genome Med. 2018 Dec 24;10(1):99. doi: 10.1186/s13073-018-0607-5.

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.

Author information

1
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
2
Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA.
3
División de Investigación, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico.
4
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA.
5
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD, 20877, USA.
6
Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
7
Centro de Oncologia, Hospital Sirio-Libanes, Sao Paulo, SP, 013050-050, Brazil.
8
International Research Center, A.C. Camargo Cancer Center, São Paulo, 01508-010, Brazil.
9
Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
10
Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
11
Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
12
Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
13
Department of Dermatology, Maurizio Bufalini Hospital, Cesena, Italy.
14
Department of Internal Medicine and Medical Specialties, University of Genoa and Genetics of Rare Cancers, IRCCS Ospedale Policinico San Martino, Genoa, Italy.
15
Department of Dermatology, University of L'Aquila, L'Aquila, Italy.
16
Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain.
17
Institute of Dermatology, Catholic University - Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy.
18
Dermatology 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.
19
Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
20
Office of the Director, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
21
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA.
22
Division of Cancer Epidemiology and Genetics, Human Genetics Program National Cancer Institute, NIH, Rockville, MD, 20850, USA.
23
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA. goldstea@mail.nih.gov.
24
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20850, USA. drstewart@mail.nih.gov.

Abstract

BACKGROUND:

Prior 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).

METHODS:

We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS).

RESULTS:

In 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.

CONCLUSION:

The 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.

KEYWORDS:

ACMG secondary findings; Familial cancer exome; Population study; Variant classification

PMID:
30583724
PMCID:
PMC6305568
DOI:
10.1186/s13073-018-0607-5
[Indexed for MEDLINE]
Free PMC Article

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