Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Aug;18(8):823-32.
doi: 10.1038/gim.2015.166. Epub 2015 Dec 17.

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing

Lisa R Susswein  1 , Megan L Marshall  1 , Rachel Nusbaum  1 , Kristen J Vogel Postula  1 , Scott M Weissman  1 , Lauren Yackowski  1 , Erica M Vaccari  1 , Jeffrey Bissonnette  1 , Jessica K Booker  1 , M Laura Cremona  2 , Federica Gibellini  1 , Patricia D Murphy  1 , Daniel E Pineda-Alvarez  1 , Guido D Pollevick  2 , Zhixiong Xu  1 , Gabi Richard  1 , Sherri Bale  1 , Rachel T Klein  2 , Kathleen S Hruska  1 , Wendy K Chung  3
Affiliations

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing

Lisa R Susswein et al. Genet Med. 2016 Aug.

Erratum in

Abstract

Purpose: Germ-line testing for panels of cancer genes using next-generation sequencing is becoming more common in clinical care. We report our experience as a clinical laboratory testing both well-established, high-risk cancer genes (e.g., BRCA1/2, MLH1, MSH2) as well as more recently identified cancer genes (e.g., PALB2, BRIP1), many of which have increased but less well-defined penetrance.

Methods: Clinical genetic testing was performed on over 10,000 consecutive cases referred for evaluation of germ-line cancer genes, and results were analyzed for frequency of pathogenic or likely pathogenic variants, and were stratified by testing panel, gene, and clinical history.

Results: Overall, a molecular diagnosis was made in 9.0% of patients tested, with the highest yield in the Lynch syndrome/colorectal cancer panel. In patients with breast, ovarian, or colon/stomach cancer, positive yields were 9.7, 13.4, and 14.8%, respectively. Approximately half of the pathogenic variants identified in patients with breast or ovarian cancer were in genes other than BRCA1/2.

Conclusion: The high frequency of positive results in a wide range of cancer genes, including those of high penetrance and with clinical care guidelines, underscores both the genetic heterogeneity of hereditary cancer and the usefulness of multigene panels over genetic tests of one or two genes.Genet Med 18 8, 823-832.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Frequency of positive results. A positive result includes at least one pathogenic or likely pathogenic variant. “All patients” includes the entire testing population regardless of cancer history. “Affected” includes individuals reporting any type of cancer. Clinical information was not provided for 93 patients (94 panel tests); thus the sum of those affected and those unaffected does not equal the total number tested. HR, high risk.
Figure 2
Figure 2
Frequency of variant of uncertain significance (VUS) results. This represents the proportion of patients with a VUS as the overall test result. “All patients” includes the entire testing population regardless of cancer history. “Affected” includes individuals reporting any type of cancer. Clinical information was not provided for 93 patients (94 panel tests); thus the sum of those affected and those unaffected does not equal the total number tested. HR, high risk.
See this image and copyright information in PMC

References

    1. LaDuca H, Stuenkel AJ, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med 2014;16:830–837. - PMC - PubMed
    1. Tung N, Battelli C, Allen B, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 2015;121:25–33. - PubMed
    1. Easton DF, Pharoah PD, Antoniou AC, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 2015;372:2243–2257. - PMC - PubMed
    1. Richards CS, Bale S, Bellissimo DB, et al.; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee. ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008;10:294–300. - PubMed
    1. Landrum MJ, Lee JM, Riley GR, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 2014;42:D980–D985. - PMC - PubMed