title: Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.
abstract: OBJECTIVE
  Multigene panels are commercially available tools for hereditary cancer risk assessment that allow for next-generation sequencing of numerous genes in parallel. However, it is not clear if these panels offer advantages over traditional genetic testing. We investigated the number of cancer predisposition gene mutations identified by parallel sequencing in individuals with suspected Lynch syndrome.
  
  
  METHODS
  We performed germline analysis with a 25-gene, next-generation sequencing panel using DNA from 1260 individuals who underwent clinical genetic testing for Lynch syndrome from 2012 through 2013. All patients had a history of Lynch syndrome-associated cancer and/or polyps. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations and variants of uncertain clinical significance (VUS). We also analyzed data on patients' personal and family history of cancer, including fulfillment of clinical guidelines for genetic testing.
  
  
  RESULTS
  Of the 1260 patients, 1112 met National Comprehensive Cancer Network (NCCN) criteria for Lynch syndrome testing (88%; 95% confidence interval [CI], 86%-90%). Multigene panel testing identified 114 probands with Lynch syndrome mutations (9.0%; 95% CI, 7.6%-10.8%) and 71 with mutations in other cancer predisposition genes (5.6%; 95% CI, 4.4%-7.1%). Fifteen individuals had mutations in BRCA1 or BRCA2; 93% of these met the NCCN criteria for Lynch syndrome testing and 33% met NCCN criteria for BRCA1 and BRCA2 analysis (P = .0017). An additional 9 individuals carried mutations in other genes linked to high lifetime risks of cancer (5 had mutations in APC, 3 had bi-allelic mutations in MUTYH, and 1 had a mutation in STK11); all of these patients met NCCN criteria for Lynch syndrome testing. A total of 479 individuals had 1 or more VUS (38%; 95% CI, 35%-41%).
  
  
  CONCLUSIONS
  In individuals with suspected Lynch syndrome, multigene panel testing identified high-penetrance mutations in cancer predisposition genes, many of which were unexpected based on patients' histories. Parallel sequencing also detected a high number of potentially uninformative germline findings, including VUS.
authors.affiliation: Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: Matthew_Yurgelun@DFCI.Harvard.edu.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Yurgelun
authors.affiliation: Myriad Genetic Laboratories, Salt Lake City, Utah.
authors.forename: Brian
authors.initials: B
authors.lastname: Allen
authors.affiliation: Myriad Genetic Laboratories, Salt Lake City, Utah.
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Kaldate
authors.affiliation: Myriad Genetic Laboratories, Salt Lake City, Utah.
authors.forename: Karla R
authors.initials: KR
authors.lastname: Bowles
authors.affiliation: Myriad Genetic Laboratories, Salt Lake City, Utah.
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Judkins
authors.affiliation: Myriad Genetic Laboratories, Salt Lake City, Utah.
authors.forename: Praveen
authors.initials: P
authors.lastname: Kaushik
authors.affiliation: Myriad Genetic Laboratories, Salt Lake City, Utah.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Roa
authors.affiliation: Myriad Genetic Laboratories, Salt Lake City, Utah.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wenstrup
authors.affiliation: Myriad Genetic Laboratories, Salt Lake City, Utah.
authors.forename: Anne-Renee
authors.initials: AR
authors.lastname: Hartman
authors.affiliation: Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation; D040941:Heredity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor
keywords: Colon Cancer Genetics; HNPCC; Hereditary Nonpolyposis Colorectal Cancer; Inherited Cancer