Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA

JAMA Oncol. 2016 Jan;2(1):104-11. doi: 10.1001/jamaoncol.2015.5208.


Importance: 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.

Design, setting, and participants: 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.

Main outcomes and measures: 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 and relevance: Germline variants are common in individuals undergoing tumor-normal sequencing and may reveal otherwise unsuspected syndromic associations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics*
  • DNA Mutational Analysis / methods*
  • Female
  • Gene Expression Profiling / methods*
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Humans
  • Male
  • Middle Aged
  • Models, Genetic
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Neoplasms / therapy
  • New York City
  • Phenotype
  • Precision Medicine
  • Predictive Value of Tests
  • Prognosis
  • Risk Assessment
  • Risk Factors


  • Biomarkers, Tumor