variants-of-uncertain-significanceAs genetic testing panels get larger, strategies to manage the downstream implications of testing are important.

In many scenarios, it is now easier for labs to perform multi-gene sequencing panels than it is to target specific individual genes. This situation has been used to call for less management of molecular genetic testing utilization, a particularly concerning area of waste and spend in the healthcare system. However, what is often forgotten is that while panel size increases, so do the risks of harm and costs of downstream misuse associated with the results of these tests. Utilizing our own internal data, we demonstrate how connecting patients and providers with genetics experts through the care system can reduce these risks. 

Large multi-gene panel tests are becoming the norm in hereditary cancer testing

Hereditary cancer testing has evolved rapidly from focused, tiered testing for specific syndromes to the concurrent analysis of multiple hereditary cancer syndromes using multigene panels. In addition to single-syndrome tests, many laboratories offer panel tests that target specific cancer type(s), as well as larger pan-cancer panels that include genes associated with multiple cancers. Studies conducted by testing laboratories indicate pan-cancer panels can increase disease-causing variant detection by as much as 69% [1,2] compared to single-syndrome or cancer-specific panel testing.  

Larger cancer panels also yield higher numbers of variants of uncertain significance (VUS) compared to cancer-specific panels or single-syndrome testing [3,4,5]. VUS can cause difficulty in clinical interpretation for healthcare providers, increased patient anxiety, and overtreatment [6-14].  

Larger testing panels result in higher risk for VUS

Our team reviewed 2,559 large hereditary cancer panels performed over the course of 1 calendar year. Of these 2,559 test results, there were 236 (9.22%) that were pathogenic/likely pathogenic (positive), 1635 (63.89%) that were negative, and 688 (26.89%) had a VUS without a positive result. Of the positive results, 27 (11.44%) also had a VUS. Of the tests with a VUS result, 132 had multiple VUS reported.

VUS increase the risk that a patient may receive inappropriate treatment or care

Multiple studies have reported that a VUS result can increase patient anxiety, lead to inappropriate medical management and that patients and providers alike frequently misinterpret the clinical meaning of a VUS [3,6-14,19,20]. Certified genetic counselors and geneticists are specially trained to assist patients in understanding and applying the results of genetic testing to their care, including in the context of VUS results. 

Although patients with a VUS result should be managed based on their personal and family history because the VUS result is uninformative [19], in the absence of involvement of genetics experts, many patients with a VUS result are managed clinically as if a pathogenic variant had been identified. This includes undergoing prophylactic surgeries, such as bilateral mastectomies and salpingoophorectomies, expensive surgeries with associated risks that are often without benefit [10,14,19]. One study found that approximately half of breast cancer patients with a VUS in BRCA1/BRCA2 who were at average risk underwent a bilateral mastectomy [20]. This study showed that many surgeons self-reported managing their patients with a VUS in BRCA1/BRCA2 the same as patients with a pathogenic variant in BRCA1/BRCA2.

A 2020 study found that of 1566 women who underwent an oophorectomy, 467 did not have a guideline-based indication for this surgery. Of these 467 women, 92 (19.7%) had a VUS in a gene associated with ovarian cancer, 241 (51.6%) had a personal history of breast cancer and no genetic risk or VUS in a gene associated with ovarian cancer, and 119 (25.5%) had no personal history of breast cancer and no VUS in an ovarian cancer gene. Additionally, the study reported 405 women with a pathogenic or likely pathogenic mutation in CHEK2, a gene associated with increased risks for breast, colon, and prostate cancers, but not ovarian cancer. Of these 405 women, 11.4% underwent an oophorectomy. Even more concerning, 13.2% of women with a VUS in CHEK2 underwent an oophorectomy. Similar results were seen in other genes that do not confer an increased risk for ovarian cancer like ATM and PALB2. Nearly half of the women who discussed an oophorectomy with their provider indicated that their provider recommended the oophorectomy. Overall, 10-15% of women with a pathogenic variant or VUS in genes not associated with a high risk of ovarian cancer reported having an oophorectomy without a clear indication for it (Domchek; ASCO 2020 abstract). 

VUS are challenging for clinicians, especially those without genetics expertise

With the increased utilization of large panel tests, clinicians and patients often suffer from data overload [21-23], where large amounts of information increase the burden on clinicians to navigate patient management with limited evidence to guide them [21,24]. Pan-cancer panel testing often yields secondary findings, such as VUS or disease-causing variants in genes with unknown or variable expressivity, that are not directly relevant to the family history. Since management recommendations are based on a combination of family history and genetic test results, management based on genetic test results alone may not be supported by the evidence and can increase confusion in clinical decision-making. 

One of the mechanisms for decreasing patient and provider confusion and potential harm is the provision of pre-and post-test genetic counseling by qualified genetics professionals, which is recommended by multiple medical professional societies [16-18]. Unfortunately, despite the national availability of such services via telephone and telemedicine, recent data suggest many patients do not receive these guidelines-recommended services [16].  

In the described cohort of 2,559 patients who underwent panel testing, 688 patients were found to carry a VUS in a hereditary cancer gene. While all of these patients received pre-test genetic counseling, based on the recently published data by Domcheck et al and Kurian et al, approximately 103 un-indicated prophylactic oophorectomies and 344 unnecessary prophylactic mastectomies would be predicted if genetics expert guidance had not been involved. It is currently unknown to what extent genetics expertise in post-test counseling reduces unnecessary interventions, but there is clearly a role for improving these statistics. Even if only a quarter of patients avoid unnecessary surgeries and the associated financial, medical, and other costs, this would represent a significant improvement over the current state. 

Panel testing can be cost-effective compared with sequential testing of single genes, yet the broader impact of panel testing on downstream health services and associated costs is largely unknown for most tested genes. Unnecessary surgeries and/or cancer screenings that are often offered to patients with a VUS place a burden on the healthcare system, and collaborative strategies to accelerate and streamline variant reclassification are needed. Based on recent trends, the utilization of both cancer-specific and pan-cancer panel tests will continue to increase. Due to the increased complexity of genetic test results, pre-and post-test genetic counseling by qualified genetics professionals is recommended by multiple professional societies [16-18] as an essential component of multigene panel testing.  The benefits include increased patient understanding, satisfaction, and the potential for better-informed decision-making, including avoiding unnecessary interventions.

Patients may not understand the resulting costs of electing a test that is not covered. 


At InformedDNA, we leverage the expertise of the largest, most experienced, fully employed staff of lab-independent, board-certified genetics specialists in the U.S. to help ensure that patients, health plans, health systems, hospitals, pharmaceutical companies, and healthcare providers all have access to the highest quality genetics expertise and services. 

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