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GI Update

Variants of Unknown Significance (VUS) and Other Uncertain Findings

The majority of variants of uncertain significance (VUS) end up being normal polymorphisms that are not linked to increased cancer risk. Rarely, a VUS is later reclassified as a pathogenic variant that would then inform medical management recommendations. In these cases, patients with the reclassified VUS are contacted for follow-up consultation, sometimes years after the gene test was performed.

The presence of a newly identified pathogenic variant can also raise difficulties for advising patients. The result may be found in a gene for which we do not yet appreciate the full spectrum of cancers and the lifetime risks associated with these cancers, and screening recommendations are not necessarily developed.

Further, multi-gene panel testing can result in a variety of unexpected findings. For example, a pathogenic variant may be found in a breast cancer susceptibility gene in a family with only colorectal cancer. Conversely, a pathogenic variant that predisposes to colorectal cancer may be found in a family with breast cancer only. Patients have also been reported where a pathogenic variant was detected in the CDH1 gene that predisposes to hereditary diffuse gastric cancer and lobular breast cancer, where prophylactic gastrectomy is recommended after 20 years of age, and yet the family is devoid of gastric cancer. Are these patients best served by prophylactic gastrectomy? The question remains unanswered and clinical management is left up to the best judgement of care providers and the individual patient.

Related reading on VUS and case examples:

  1. Young EL, Feng BJ, Stark AW, Damiola F, Durand G, Forey N, Francy TC, Gammon A, Kohlmann WK, Kaphingst KA, McKay-Chopin S, Nguyen-Dumont T, Oliver J, Paquette AM, Pertesi M, Robinot N, Rosenthal JS, Vallee M, Voegele C, Hopper JL, Southey MC, Andrulis IL, John EM, Hashibe M, Gertz J; Breast Cancer Family Registry, Le Calvez-Kelm F, Lesueur F, Goldgar DE, Tavtigian SV. Multigene testing of moderate-risk genes: be mindful of the missenseJ Med Genet. 2016 Jan 19. piijmedgenet-2015-103398. doi: 10.1136/jmedgenet-2015-103398. [Epub ahead of print] PubMed PMID: 26787654.
  2. Slavin TP, Niell-Swiller M, Solomon I, Nehoray B, Rybak C, Blazer KR, Weitzel JN. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk ManagementFront Oncol. 2015 Sep 29;5:208. doi: 10.3389/fonc.2015.00208. eCollection 2015. Erratum in: Front Oncol. 2015;5:271.

Penn State Health Gastroenterology and Hepatology provides comprehensive services in the diagnosis, medical management and endoscopic treatment of diseases affecting the digestive system and liver.

Penn State Health Colon and Rectal Surgery consists of highly skilled, board-certified surgeons specializing in the treatment of patients with complicated colorectal disease. Each surgeon uses advanced diagnostic capabilities, the latest drug therapies, and leading-edge surgical techniques to provide the most effective medical care possible.

The mission of Penn State Health Gastroenterology and Hepatology and Penn State Health Colorectal Surgery is to provide world-class care and to advance the knowledge of disorders of the digestive system and liver through research, as well as to train the physicians of the future. The physicians participate in studies to determine the usefulness of novel treatments through clinical research studies and also in research which advances the basic knowledge of the disorders in this field.

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