Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing
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BACKGROUND: The growing number of Next Generation Sequencing (NGS) tests is transforming the routine clinical diagnosis of hereditary cancers. Identifying whether a cancer is the result of an underlying disease-causing mutation in a cancer predisposition gene is not only diagnostic for a cancer predisposition syndrome, but also has significant clinical implications in the clinical management of patients and their families. METHODS: Here, we evaluated the performance of MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) in detecting genetic alterations in 76 genes implicated in cancer predisposition syndromes. Output from hybridization-based capture was sequenced on an Illumina HiSeq 2500. A custom analysis pipeline was used to detect single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variants (CNVs). RESULTS: MSK-IMPACT detected all germline variants in a set of 233 unique patient DNA samples, previously confirmed by previous single gene testing. Reproducibility of variant calls was demonstrated using inter- and intra- run replicates. Moreover, in 16 samples, we identified additional pathogenic mutations other than those previously identified through a traditional gene-by-gene approach, including founder mutations in BRCA1, BRCA2, CHEK2 and APC, and truncating mutations in TP53, TSC2, ATM and VHL. CONCLUSIONS: This study highlights the importance of the NGS-based gene panel testing approach in comprehensively identifying germline variants contributing to cancer predisposition and simultaneous detection of somatic and germline alterations.
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MSK-IMPACT is an NGS assay that can detect variants in up to 505 unique cancer genes, including EGFR, TP53, KRAS, STK11, and ALK.
“MSK-IMPACT is an NGS assay that can detect variants in up to 505 unique cancer genes, including EGFR, TP53, KRAS, STK11, and ALK.”
From A clinical benchmark of public self-supervised pathology foundation models (2025) · cites this paper as [44]
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- Authors
- Cheng, D. T., Prasad, M., Chekaluk, Y., Benayed, R., Sadowska, J., Zehir, A., Syed, A., Wang, Y. E., Somar, J., Li, Y., Yelskaya, Z., Wong, D., Robson, M. E., Offit, K., Berger, M. F., Nafa, K., Ladanyi, M., & Zhang, L.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Ladanyi, Marc
- Zhang, Liying
- ORCID
- Venue
- BMC Medical Genomics
- Published
- 2017-05-19
- Volume
- 10
- Issue
- 1
- Pages
- 33-33
- ISSN
- 1755-8794 (ISSN-L)
- PMC
- PMC5437632
- OpenAlex
- W2614654783
- Cited by
- 158
- References
- 21
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 12 · 2023: 23 · 2022: 21 · 2021: 20 · 2020: 22 · 2019: 16 · 2018: 13 · 2017: 2
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- BMC Medical Genomics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Memorial Sloan-Kettering Cancer Center (CA008748, P30 CA008748)
- Geoffrey Beene Cancer Research Center (P30 CA008748)
- Farmer Family Foundation
- National Cancer Institute (P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- MSK-IMPACT, germline variant detection, cancer predisposition syndromes, cancer susceptibility genes, gene panel testing, founder mutation, BRCA1, BRCA2, CHEK2, APC, TP53, TSC2, ATM, VHL, copy number variation, single nucleotide variants, hereditary cancer
- MeSH terms
- Tuberous Sclerosis Complex 2 Protein, DNA Mutational Analysis, Humans, Neoplasm Proteins, Neoplasms, Biomarkers, Tumor, Reproducibility of Results, Tumor Suppressor Protein p53, Germ-Line Mutation, BRCA1 Protein, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, BRCA2 Protein, Tumor Suppressor Proteins, Adenomatous Polyposis Coli Protein, Von Hippel-Lindau Tumor Suppressor Protein, DNA Copy Number Variations, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2
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