Diagnostic Results Related to Patient Symptoms or Primary Results: Pathogenic and Likely Pathogenic Variants

Key Points

  • Pathogenic variants in disease genes related to phenotype (or symptoms) means that a cause of the patient’s symptoms has been identified.
  • Clinically, both pathogenic and likely pathogenic variants are treated the same—as if they are likely disease causing.
  • Identifying a specific genetic diagnosis may provide information on the likelihood of other associated medical problems and more specific disease management.
Genomic variants are typically classified on a five-point scale to indicate the likelihood that the particular variant is associated with disease.

Genomic variants are typically classified on a five-point scale to indicate the likelihood that the particular variant is associated with disease.

Often when a whole exome or whole genome sequence test is performed, the primary goal is to answer a diagnostic question about a patient with a specific set of symptoms (phenotype). When a genetic cause is identified that is believed to account for the symptoms, the result is described as a primary result with one or more “pathogenic” or “likely pathogenic” variants in disease genes related to the phenotype. In other words, there is an answer and a definitive or highly probable cause to return to the patient and  provider.

If the particular variant found has been previously associated with the condition, the variant will  be classified as “pathogenic.” However, frequently, there is insufficient evidence that a variant is the definite cause for symptoms. The term “likely pathogenic” means that the variant most likely has a harmful effect. When a gene is associated with a disease that overlaps with the patient’s symptoms, it then represents the likely diagnosis and cause. Sometimes, the gene has been linked to disease and the clinical features of the condition overlap with the patient’s symptoms, but the exact gene variant identified in the patient has not been previously observed, making interpretation difficult.

Many factors are considered in assessing whether a variant is pathogenic. Clinically, pathogenic and likely pathogenic variants are usually treated the same—as if they are likely disease causing—and clinical management is tailored based on this diagnosis.

A patient presents with vision loss, obesity, renal failure, and cognitive deficits. Genomic sequencing identifies a variant in the BBS10 gene. The BBS10 gene is associated with Bardet-Biedl syndrome and is consistent with all of the clinical features in the patient. In addition, the specific variant has been repeatedly described in the literature in patients diagnosed with Bardet-Biedl syndrome. Based on this evidence, the variant would be classified as pathogenic. In contrast, if sequencing identified a different variant in BBS10 that had not been previously observed in either healthy or symptomatic populations, the variant would probably be classified as “likely pathogenic.” With time and as more individuals are sequenced, many “likely pathogenic” variants are reclassified to “pathogenic.”

Next Steps to Consider

  • Learn more about the condition with which the patient has been diagnosed through GeneReviews and other resources
  • Referral to genetic services (medical geneticist and/or genetic counselor) for medical follow-up and discussion of recurrence risks and implications for other family members
  • Identification of relevant patient support groups and resources specific to diagnosis
  • Identification of relevant research studies or clinical trials specific to diagnosis



  • ClinicalTrials.gov (https://clinicaltrials.gov/): a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world.
  • GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1116/): a resource for clinicians that provide clinically relevant and medically actionable information for inherited condition. This resource includes information on diagnostic criteria, management, and information about genetic counseling for patients and their families. There are chapters available about many, but not all, genetic conditions.
  • National Society of Genetic Counselors (http://nsgc.org/): the professional organization for genetic counselors, with patient and provider resources and a searchable tool to “find a genetic counselor” near you.