title: Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA.
abstract: OBJECTIVE
  Tumor genetic sequencing identifies potentially targetable genetic alterations with therapeutic implications. Analysis has concentrated on detecting tumor-specific variants, but recognition of germline variants may prove valuable as well.
  
  
  OBJECTIVE
  To estimate the burden of germline variants identified through routine clinical tumor sequencing.
  
  
  METHODS
  Patients with advanced cancer diagnoses eligible for studies of targeted agents at Memorial Sloan Kettering Cancer Center are offered tumor-normal sequencing with MSK-IMPACT, a 341-gene panel. We surveyed the germline variants seen in 187 overlapping genes with Mendelian disease associations in 1566 patients who had undergone tumor profiling between March and October 2014.
  
  
  METHODS
  The number of presumed pathogenic germline variants (PPGVs) and variants of uncertain significance per person in 187 genes associated with single-gene disorders and the proportions of individuals with PPGVs in clinically relevant gene subsets, in genes consistent with known tumor phenotypes, and in genes with evidence of second somatic hits in their tumors.
  
  
  RESULTS
  The mean age of the 1566 patients was 58 years, and 54% were women. Presumed pathogenic germline variants in known Mendelian disease-associated genes were identified in 246 of 1566 patients (15.7%; 95% CI, 14.0%-17.6%), including 198 individuals with mutations in genes associated with cancer susceptibility. Germline findings in cancer susceptibility genes were concordant with the individual's cancer type in only 81 of 198 cases (40.9%; 95% CI, 34.3%-47.9%). In individuals with PPGVs retained in the tumor, somatic alteration of the other allele was seen in 39 of 182 cases (21.4%; 95% CI, 16.1%-28.0%), of which 13 cases did not show a known correlation of the germline mutation and a known syndrome. Mutations in non-cancer-related Mendelian disease genes were seen in 55 of 1566 cases (3.5%; 95% CI, 27.1%-45.4%). Almost every individual had more than 1 variant of uncertain significance (1565 of 1566 patients; 99.9%; 95% CI, 99.6%-99.9%).
  
  
  CONCLUSIONS
  Germline variants are common in individuals undergoing tumor-normal sequencing and may reveal otherwise unsuspected syndromic associations.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York2Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada3Department of Medical Genetics, University of British Columbia, Vancouver, British C.
authors.forename: Kasmintan A
authors.initials: KA
authors.lastname: Schrader
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Donavan T
authors.initials: DT
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York5Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, New York.
authors.forename: Vijai
authors.initials: V
authors.lastname: Joseph
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Meera
authors.initials: M
authors.lastname: Prasad
authors.affiliation: Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering, New York, New York7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael
authors.initials: M
authors.lastname: Walsh
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Zehir
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ai
authors.initials: A
authors.lastname: Ni
authors.affiliation: Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering, New York, New York.
authors.forename: Tinu
authors.initials: T
authors.lastname: Thomas
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ryma
authors.initials: R
authors.lastname: Benayed
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Asad
authors.initials: A
authors.lastname: Ashraf
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Annie
authors.initials: A
authors.lastname: Lincoln
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Maria
authors.initials: M
authors.lastname: Arcila
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York6Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering, New York, New York.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Stadler
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York9Weill Cornell Medical College, New York, New York10Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York11Center for Molecular.
authors.forename: David
authors.initials: D
authors.lastname: Solit
authors.forename: David M
authors.initials: DM
authors.lastname: Hyman
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Hyman
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Klimstra
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York10Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York5Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, New York6Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering, New York, Ne.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York9Weill Cornell Medical College, New York, New York10Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York11Center for Molecula.
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York6Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering, New York, New York9Weill Cornell Medical College, New York, New York.
authors.forename: Mark
authors.initials: M
authors.lastname: Robson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009519:New York City; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011379:Prognosis; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor