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Variant classification in the sequencing era
of tumor mutation burden;19 (ii) the presence of a genetic aberration is frequently used as a marker for monitoring minimal (measurable) residual disease (MRD).20 A germline variant would not be eradicated by treatment (with the exception of allogeneic bone marrow transplan- tation), and is therefore not informative as a MRD mark- er; (iii) germline variants can predispose to or cause cancer and other diseases. Tarailo-Graovac et al. found that 2.8% of individuals from the ExAC database have variants which are implicated in a wide variety of Mendelian dis- orders.21 The 2017 World Health Organization classifica- tion now also recognizes neoplasms with germline pre- disposition and mutations in ETV6, RUNX1 and other genes.3 Knowledge of pathogenic germline variants is of importance for family counseling and to determine whether family members can be considered as stem cell donors. Germline variants are important modulators of a patient’s outcome and treatment response. An aberration in the DNA damage repair pathway could increase the risk of therapy-related myeloid neoplasms.22
An impressive example that the variant itself is of greater importance than its origin is the response to treat- ment with olaparib. Patients respond if they have either a germline or acquired variant of BRCA1/2.23 It is therefore essential to know whether the mutation is pathogenic or actionable. The definition of pathogenic or actionable is not trivial and is highly context-dependent. For inherited diseases, a pathogenic variant is usually understood as being causal. A clear variant-phenotype relationship has
been recognized in a few cases (e.g. cystic fibrosis), but for many other disease types such a relationship is more elusive. The five-tier system for the classification of hereditary variants currently recommended by the ACMG and AMP also recognizes the categories of “likely pathogenic” and “likely benign”.4
Here, we focus on variants in cancer. When translating genetic findings into the clinic, a variant might have a dif- ferent value depending on the immediate question at hand. Sukhai et al. proposed the term “actionable” to describe variants which affect patients’ management.24 The 2017 guidelines for variants in cancer from the AMP, American Society of Clinical Oncology (ASCO), and the College of American Pathologists (CAP) suggest a four- tier system: tier I, strong clinical significance; tier II, potential clinical significance; tier III, unknown clinical significance; and tier IV, a benign or likely benign variant (Figure 2).25 The interpretation should be further subdivid- ed into the categories “diagnostic”, “prognostic” and “predic- tive”. It is suggested that the four-tier system is applied to each category. The highest level of evidence is given to biomarkers that predict response or resistance to Food and Drug Administration-approved therapies and to vari- ants from professional diagnostic and prognostic guide- lines.25 The BRAF V600E mutation is such an example, as its presence allows vemurafenib treatment.26
At first glance, a tiered system seems to be a well-stan- dardized approach, but each case presents its own chal- lenges. One example would be a patient with cytopenia
Figure 2. Decision tree for variant classification and clinical-decision making. Sequencing data are used to answer different clinical questions. Here we separate the issue of germline versus somatic and biological functions (e.g. pathogenic vs. benign). The questions are closely related in everyday life, however the sources and evidence supporting decisions are different (examples are outlined here). The definitions of the clinical significance of the four-tier classification system are from the guidelines by Li et al.25 WES: whole-exome sequencing; WGS: whole-genome sequencing; VAF: variant allele frequency; FDA: Food and Drug Administration; SCT: stem cell transplantation; MRD: minimal/measurable residual disease.
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