Genomics: Insight

Genetic Counseling: Genomic Screening Programs Illustrate an Astounding Number of Unknown Pathogenic Variants

Anna Duemler
August 26, 2020

The ability to look at your own genes seems like something from the far future, but is becoming increasingly accessible. Often, this information is used to determine genetic predispositions to disease. While this is helpful, it is also complex, as there is still much to be discovered. Genetic counseling professionals are trained in the biology of genetics, and increasingly genomics, as well as in counseling1. The main purpose of genetic counselors is to ensure that the patient has enough knowledge and information to make an educated decision about their health. In a typical clinical setting, patients who present with a heritable genetic condition are referred to a genetic counselor. The psychological burden of having a genetic variant can deeply affect patients. Genetic counselors work to support patients'; mental health and advocate for their optimal treatment plan. However, genomics poses many challenges that health professionals continue to struggle with, even genetic counselors. Some of these challenges include lack of diversity in tested populations, access to testing and outreach, the implications of secondary findings, variant interpretation, and others.  Unfortunately, even though a large number of healthcare professionals value genetic counselors, there are still many individuals unaware of their genetic variants within the population.

“ Genetic counselors work to support patients’ mental health and advocate for their optimal treatment plan ”

A recent study by Buchanan et al. highlights these unknown variants and the role of genetic counselors when they are found. They investigated the outcomes of the Geisinger's MyCode project in which participants underwent exome sequencing followed by an assessment for actionable genetic variants2. This was an observational study of the electronic health records of individuals with a genetic variant that have evidence of significant association with disease (tier I genetic finding) disclosed between 5/2015-2/2018. Genetic findings are classified into a four tiered system associated with the evidence base of their clinical significance. A tier I genetic finding indicates that the genetic variant has evidence of significant association with disease3. While this study focuses on tier I variants, all tiers within the system are shown in table 1.

Table 1. Clinical Significance and Evidence of the Different Tiers of Genetic Variants3


Tier of Genetic Variant




Strong clinical significance

-FDA approved therapies
-Strong studies with consensus from experts


Potential clinical significance

-FDA approved investigational therapies
-Therapies for different tumor types
-Preclinical trials or case reports associated


Unknown significance

-Not observed at significant frequencies in databases
-No published literature evidence of disease association


Known insignificance

-Observed at significant frequency in databases
-No published evidence of known disease association


The study looked at genes related to three tier I genetic conditions  that have interventions that reduce mortatlity and morbidity2. The conditions explored included hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome, and familial hypercholesterolemia (FH). There are several genes that contribute to these conditions. If these genes have a variant that directly causes disease or disease risk, the variant is classified as pathogenic. For example, in HBOC BRCA1 and BRCA2 are the two main genes involved in risk for breast, ovarian and other cancers (Table 2). This relationship between pathogenic or likely pathogenic variants and disease is illustrated in the other conditions as well. Table 2 shows how the risk increases with a pathogenic or likely pathogenic genetic variant compared to the risk in the general population. A total of 351 individuals in this study had a pathogenic or likely pathogenic result. Of these individuals an astonishing 87% were unaware of their genetic result and increased risk, prior to the MyCode project. Additionally, 65% of these individuals already had electronic health records documenting family history and past medical conditions associated with their genetic finding. Once results were disclosed there was a significant increase in risk management2. In addition, disclosure by a genetic counselor significantly increased a patient’s compliance with recommended risk management4. For example, 28% of individuals who had an FH variant had a clinical diagnosis in need of management after results disclosure. Genetic counselors thoroughly review genetic results with the patient, advocate for risk management, provide support, and also encourage communication throughout the family.


Table 2. Risks and genes associated with Hereditary Breast and Ovarian Cancer Syndrome5,6, Lynch Syndrome7,8, and Familial Hypercholesteremia9, 10


Associated Genes


Risk in General Population

Risk with Pathogenic Variant



Hereditary Breast and Ovarian Cancer Syndrome


Cancers of the breast, ovaries, prostate, and pancreas


Risk of Breast:

BRCA1: 46-87%

BRCA2: 38-84%

-Breast exams starting at age 25
-Breast MRIs annually (25-29)
-annual mammograms (30-75)
-Risk reducing Mastectomy

Lynch Syndrome


Cancers of the colon, rectum, stomach, small intestine, brain, skin, ovaries and uterus

Colorectal Cancer- 5.5%

Risk of Colorectal Cancer: 52-82%

-Colonoscopies starting at age 20-25
-Colonoscopies begin 2-5 years prior to earliest familial colon cancer

Familial Hypercholesteremia


High cholesterol levels, coronary artery disease

Coronary Artery Disease- 6.7%

Risk of Coronary Artery Disease:

20-22 fold increased risk without treatment

-Children with FH should have lipids checked before age 10
-Avoid smoking, obesity, and sedentary lifestyle


Genetic counseling not only encourages necessary familial communication but also facilitates it. Genetic counselors are able to identify who is at risk, where the family members are able to get local services and discuss if and how to communicate this crucial information. There are two ways this happens. First, family history is strongly indicative of a disease being genetically heritable. In Buchanan et al. 65% of the participants who did not have prior knowledge of their genetic result had a family history consistent with their genetic variant2. Genetic counseling has a strong emphasis on family history, where in each session a family pedigree is created that is meant to include all medical conditions in the family. Often, some medical conditions aren’t included in the family history as it is limited to only what the patient communicates to the provider. Second, genetic counseling in addition to genetic testing could help families through cascade testing, where the rest of the family of an individual effected by a high-risk variant could receive the screening and care they need. 


Sometimes, individuals are not interested in getting tested to find out if they have a genetic variant. Genetic counselors are still able to help people understand their risk and healthcare implications, even if they don’t make the decision to get tested. Common decisions associated with risk management are frequent screening, communication of variants to the rest of the family, and risk reducing surgeries11. While individual screening is a good starting point, it is imperative that familial risk is understood. Genetic counselors play a vital role in ensuring that patients understand their genetic status and can communicate it effectively to relatives at risk.

“ Genetic counselors play a vital role in ensuring that patients understand their genetic status and can communicate it effectively to relatives at risk ”

The genomic screening program described above has many benefits. Increasing awareness of the prevalence of variants in a large cohort is arguably the most important. However, a clear problem within this study was the lack of diversity. The study showed that 99% of people identified as European descent and non-Hispanic. Out of the 351 participants only two were of color, one being African American and the other being Latino2. Lack of diversity in genetics has been a disparity for years and needs to be addressed in order to fully understand the human genome. According to a recent commentary, 78% of data used in genome-wide association studies come from people of European descent while they only make up 16% of the global population12. Understanding of human genetics and increased risk needs to become common in healthcare. Genetic counselors could play a main role in making genetic testing more uniform.

A main principle of genetic counseling is advocating for the patient. There are many individuals in the standard healthcare system who are looked past when it comes to genetic testing. Many medical societies recommend that any woman diagnosed with ovarian cancer receive genetic testing, yet only about 30% of those diagnosed are tested13. This baffling number of untested patients yields the question of whether it may be more beneficial to explore other avenues to ensure genetic testing. The traditional genetic counseling model consists of an in-person consultation between the patient and a genetic counselor. While this is certainly effective, it requires identification of a need for referral to a genetic counselor by a physician or other healthcare provider.

This begs the question if there are more effective ways to identify genetic variations and implement care. Genetic counselors have the potential to play an essential role in developing a system to identify individuals in need of genetic testing. A system within each institution with a genetic counselor in a leadership role could assess genetic testing prevalence and overall infrastructure of departments. The team could then help other healthcare professionals identify individuals who have a disease or family history that warrants genetic testing. This way a team of genetic counselors is incorporated into each medical institution educating physicians and other healthcare providers on eligibility for genetic testing and counseling. Implementing a system with genetic counselors has the potential to assist with disparities by providing genetic assessment, identification, and testing equitably. 

This genomic screening program sheds light on the astounding numbers of unknown clinically relevant genetic variants within the population for which there is an established indication for genetic testing. Buchanan observed that having genetic counseling readily available for patients after results were disclosed, had a significant relationship with proceeding with recommended risk management2. Benefits from genetic counseling are abound, with the demand for genetic counselors growing daily. Providing a leadership role for genetic counselors would assure that institutions are able to appropriately identify optimal mechanisms for the collection and interpretation of family history. This system would ultimately identify which populations are in need of genetic testing and counseling. Implementation of this genetic counseling program can reduce overall healthcare costs14, morbidity and mortality2, and ensure that all individuals have equal accessibility to genetic testing.


1) Who are Genetic Counselors? National Society of Genetic Counselors.

2) Buchanan, A. H., Kirchner, H. L., Schwartz, M. L. B., Kelly, M. A., Schmidlen, T., Jones, L. K., … Sturm, A. C. (2020). Clinical outcomes of a genomic screening program for actionable genetic conditions. Genetics in Medicine.

3) Li, M., Datto, M., Duncavage, E., Kulkarni, S., Lindeman, N., Roy, S., . . . Nikiforova, M. (2017, January). 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. Retrieved August 12, 2020, from

4) Pal, T., Lee, J., Besharat, A., Thompson, Z., Monteiro, A., Phelan, C., . . . Narod, S. (2013, March 21). Modes of delivery of genetic testing services and the uptake of cancer risk management strategies in BRCA1 and BRCA2 carriers. Retrieved August 13, 2020, from

5) Petrucelli, N. (2016, December 15). BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. GeneReviews® [Internet].

6) Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. National Comprehensive Cancer Network. (2019). Retrieved August 12, 2020, from

7) Kohlmann, W. (2018, April 12). Lynch Syndrome. Retrieved August 1, 2020, from

8) Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network. (2020, July 21). Retrieved August 13, 2020, from

9) Youngblom, E. (2016, December 08). Familial Hypercholesterolemia. Retrieved August 4, 2020, from

10) Heart Disease Facts. (2020, June 22). Retrieved August 10, 2020, from

11) National Institutes of Health. Why is it important to know my family medical history? - Genetics Home Reference - NIH. U.S. National Library of Medicine.

12) Sirugo, G., Williams, S. M., & Tishkoff, S. A. (2019). The Missing Diversity in Human Genetic Studies. Cell, 177(4), 1080.

13) Konstantinopoulos, P. A., Lacchetti, C., & Annunziata, C. M. (2020). Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline Summary. JCO Oncology Practice.

14) Haidle, J. (2017, August 10). Genetic Counselors Save Costs Across the Genetic Testing Spectrum. Retrieved August 11, 2020, from

About the Author

Anna Duemler

Anna Duemler is in the Postbaccalaureate training program at the National Institutes of Health. She received her bachelor’s degree in biology from the Pennsylvania State University in 2018. She plans to apply to genetic counseling programs in the fall.