The impact of variant classification on the clinical management of hereditary cancer syndromes



The reclassification of genetic variants poses a significant challenge for laboratories and clinicians. Variant review has resulted in the reclassification of variants of unknown significance as well as the reclassification of previously established pathogenic and likely pathogenic variants. These reclassifications have the potential to alter the clinical management of patients with hereditary cancer syndromes.


Results were reviewed for 1694 patients seen for hereditary cancer evaluation between August 2012 and May 2017 to determine the frequency and types of variant reclassification. Patients with reclassifications with high potential for impact were monitored for alterations in organ surveillance, prophylactic surgery, and cascade testing.


One hundred forty-two variants were reclassified representing 124/1694 (7.3%) patients; 11.3% of reclassifications (16/142) had a high potential for clinical impact with 94% (15/16) altering clinical management of patients with 56% (9/16) changing multiple areas of management.


While reclassifications are rare, the impact on clinical management is profound. In many cases, patients with downgraded pathogenic/likely pathogenic variants had years of unnecessary organ surveillance and underwent unneeded surgical intervention. In addition, cascade testing misidentified those at risk for developing cancers, thereby altering the management across generations. The frequency and types of alterations to clinical management highlight the need for timely variant reclassification.

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  1. 1.

    Ricker C, Culver JO, Lowstuter K et al. Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort. Cancer Genet. 2016;209:130–7.

  2. 2.

    Hermel DJ, McKinnon WC, Wood ME et al. Multi-gene panel testing for hereditary cancer susceptibility in a rural familial cancer program. Fam Cancer. 2017;16:159–66.

  3. 3.

    Mauer CB, Pirzadeh-Miller SM, Robinson LD et al. The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience. Genet Med. 2014;16:407–12.

  4. 4.

    Yorczyk A, Robinson LS, Ross TS. Use of panel tests in place of single gene tests in the cancer genetics clinic. Clin Genet. 2015;88:278–82.

  5. 5.

    Nagy R, Sweet K, Eng C. Highly penetrant hereditary cancer syndromes. Oncogene. 2004;23:6445–70.

  6. 6.

    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;16:830–7.

  7. 7.

    Cragun D, Radford C, Dolinsky JS et al. Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clin Genet. 2014;86:510–20.

  8. 8.

    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.

  9. 9.

    Gallego CJ, Shirts BH, Bennette CS et al. Next-generation sequencing panels for the diagnosis of colorectal cancer and polyposis syndromes: a cost-effectiveness analysis. J Clin Oncol. 2015;33:2084–91.

  10. 10.

    Pugh TJ, Kelly MA, Gowrisankar S et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014;16:601–8.

  11. 11.

    Richards S, Aziz N, Bale S et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

  12. 12.

    Hirschhorn K, Fleisher LD, Godmilow L et al. Duty to re-contact. Genet Med. 1999;1:171–2.

  13. 13.

    Macklin S, Durand N, Atwal P et al. Observed frequency and challenges of variant reclassification in a hereditary cancer clinic. Genet Med. 2017;20:346–50.

  14. 14.

    Harris PA, Taylor R, Thielke R et al. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–81.

  15. 15.

    Biswas K, Das R, Eggington JM et al. Functional evaluation of BRCA2 variants mapping to the PALB2-binding and C-terminal DNA-binding domains using a mouse ES cell-based assay. Hum Mol Genet. 2012;21:3993–4006.

  16. 16.

    Howlett NG, Taniguchi T, Olson S et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002;297:606–9.

  17. 17.

    Rosenthal ET, Bowles KR, Pruss D et al. Exceptions to the rule: case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes. Clin Genet. 2015;88:533–41.

  18. 18.

    Bell DW, Kim SH, Godwin AK et al. Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts. Int J Cancer. 2007;121:2661–7.

  19. 19.

    Li MM, Datto M, Duncavage EJ et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19:4–23.

  20. 20.

    Weitzel JN, Chao EC, Nehoray B, et al. Somatic TP53 variants frequently confound germ-line testing results. Genet Med. 2017; doi:10.1038/gim.2017.196 PMID 29189820.

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We thank the genetic counselors, advanced practice nurses, and the patients and their families who were seen at the Vanderbilt Hereditary Cancer Clinic at Vanderbilt-Ingram Cancer Center for participating in this study. G.L.W. is supported through the Vanderbilt-Ingram Cancer Center (VICC).

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Correspondence to Scott A. Turner PhD.

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The authors declare no conflicts of interest.

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Turner, S.A., Rao, S.K., Morgan, R.H. et al. The impact of variant classification on the clinical management of hereditary cancer syndromes. Genet Med 21, 426–430 (2019).

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  • Hereditary cancer syndrome
  • Hereditary cancer clinic
  • Variant reclassification,
  • Clinical impact

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