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Updated: Mar 30, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA
Kasmintan A Schrader1, Donavan T Cheng2, Vijai Joseph3
1Department 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.
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.
Insights
Routine tumor sequencing frequently identifies germline variants, with 15.7% of patients harboring presumed pathogenic germline variants (PPGVs). These findings can reveal unexpected genetic conditions beyond cancer susceptibility.
Area of Science:
- Genomics
- Oncology
- Clinical Genetics
Background:
- Tumor genetic sequencing aids in identifying targetable alterations for cancer therapy.
- Focus has been on tumor-specific variants, but germline variants also hold clinical significance.
Purpose of the Study:
- To determine the prevalence of germline variants detected during routine clinical tumor sequencing.
- To assess the clinical implications of these germline findings.
Main Methods:
- Utilized MSK-IMPACT, a 341-gene panel, for tumor-normal sequencing in 1566 patients with advanced cancer.
- Analyzed germline variants in 187 genes associated with Mendelian diseases.
Main Results:
- Identified presumed pathogenic germline variants (PPGVs) in 15.7% of patients, with 198 cases involving cancer susceptibility genes.
- Germline findings in cancer genes were concordant with cancer type in 40.9% of cases.
- Found mutations in non-cancer Mendelian disease genes in 3.5% of patients.
Conclusions:
- Germline variants are frequently detected in patients undergoing tumor-normal sequencing.
- These variants can uncover unsuspected syndromic associations, impacting patient care beyond cancer treatment.
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