As more people receive genetic testing and up to half will receive ‘uncertain’ results, the SingHealth Duke-NUS Genomic Medicine Centre shares how the implications of such results can be managed.
As more people receive genetic testing and up to half will receive ‘uncertain’ results, the SingHealth Duke-NUS Genomic Medicine Centre shares how the implications of such results can be managed.
INTRODUCTION
Germline genetic testing plays a vital role in the detection of hereditary cancer syndromes, allowing for the prevention or early detection of cancers. However, results from genetic testing and management thereafter are not always straightforward – aside from positive or negative results, there is the possibility of getting an ‘uncertain’ result. This article will share how uncertain results can affect patient management.
WHAT ARE THE TYPES OF GENETIC TEST RESULTS?
Genetic testing identifies any genetic variants (or changes) in the DNA sequence that are different from the reference sequence. The reference DNA sequence is used as a baseline for comparing and identifying genetic variants.
There are multiple classification systems that have been developed to interpret and classify genetic variants detected. The most widely used system is the five-tier system (Table 1) recommended by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP).1,2
Variant classification is essential for providing appropriate care, counselling and support to individuals and families with or at risk of hereditary cancer syndromes.
HOW COMMON IS A VARIANT OF UNCERTAIN SIGNIFICANCE (VUS)?
It is not uncommon to receive an uncertain result,5-8 especially for Asians. A local study has revealed that 50% of patients are found to have one or more VUS results.5 This is consistent with several other studies that have shown that the VUS rate is double in Asians compared to Europeans.6-8
This can be attributed to the fact that reference DNA sequences are predominantly derived from individuals of European ancestry.6-8
HOW SHOULD A VUS BE MANAGED?
Clinicians should not use VUS results to change or affect clinical management without close consultation with the genetics team.
There have been cases whereby VUS results were misinterpreted as pathogenic, resulting in women undergoing unnecessary risk-reducing surgeries.9
For instance, there have been breast or ovarian cancer patients with a BRCA1/2 VUS that have been mistakenly considered as pathogenic, and thus were offered risk-reducing surgery like mastectomies or oophorectomies – which are unnecessary and harmful to those whose BRCA1/2 VUS were discovered to be benign.5,10
Ultimately, the management of patients with VUS is best personalised, using their personal and family history of cancer3,11 to guide screening and surveillance recommendations.
HOW DO MOST PEOPLE REACT TO HEARING THEY HAVE A VUS?
There was initial concern that uncertain results can induce anxiety or distress among cancer patients due to a lack of a clear answer.12-15
However, this has largely been mitigated by genetic counselling that can prepare patients for the possibility of VUS results16, and patients have reported feelings of relief and reassurance to know that an uncertain result does not equate to hereditary cancer risk14,16.
HOW ARE VUS RECLASSIFIED?
Patients with VUS results do not need to repeat genetic testing to receive updates of their VUS results, as genetic test results do not change over a lifetime. Instead, laboratories will periodically consolidate and analyse data to determine if a VUS can be reclassified.
If the VUS consistently segregates with cancer in several different families, it might be the information that laboratories need to upgrade a VUS.1,2 This is one example of evidence that laboratories use to reclassify variants.
Therefore, there is growing emphasis on the importance of diversity in genetic databases – to account for more ethnicities to aid in efficient variant interpretation and reclassification as more people undergo genetic testing.17-20
Findings from a reclassification study
Patients seen at the Cancer Genetics Service at National Cancer Centre Singapore were evaluated for VUS reclassifications. We found that half of the patients received VUS result(s), but only 7% of these variants were reclassified over a six-year period5. They were largely downgrades to benign, with a small portion (6%) that were upgrades.
Downgrades have no impact on patient management, but VUS upgrades or pathogenic variant downgrades will result in changes to patient management in terms of screening and/or risk-reducing surgery recommendations. More research needs to be done to support variation curation and reclassification efforts, especially for ethnically-diverse populations like ours.
Patient background
Ms Lily Chen*, aged 60 years old, was diagnosed with breast cancer at age 45 and reported to have a family history of gynaecological cancer. Her genetic test result identified a VUS in her BRCA1 gene.
Initial VUS result
Her VUS result meant that there was insufficient evidence to determine if the BRCA1 variant is associated with an increased risk of breast and ovarian cancer – and therefore no genetic testing was offered to her family members. Management recommendations were based on her family history, and considering she reported gynaecological cancer in her family, she was referred to a gynaecologist for heightened surveillance. Reclassification of VUS
Four years later, the laboratory reclassified this variant to ‘likely pathogenic’, thereby confirming the diagnosis of hereditary breast and ovarian cancer (HBOC) syndrome.
Implications of VUS upgrade to pathogenic
She was then recommended to undergo risk-reducing bilateral salpingo-oophorectomy (removal of the ovaries and fallopian tubes). It also meant that her family members are recommended to undergo their own genetic testing to understand their carrier status and options for risk management. *Name has been changed to protect the privacy of the patient
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This case emphasises the importance of maintaining open lines of communication between the laboratories, genetic counsellor and patient.16,19,20 However, the reclassification process may take months, years or decades. Some uncertain variants may never be reclassified if laboratories do have enough data to draw a definitive conclusion.
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THE ROLE OF GPs
Uniquely positioned as the first line of care
General practitioners (GPs) are the bedrock of the healthcare system. It has become increasingly important for GPs to be aware of genetic testing and the results it entails – to ensure that patient care is consolidated and continuity of care is maintained.
GPs are uniquely positioned as they are often the first point of contact with patients, many of whom they maintain long-term relationships with, and GPs often manage families over generations.
Understanding the implications of VUS results
As more people receive genetic testing, up to 50% of whom will receive VUS results, GPs must be equipped to understand what these results mean and whether it should or should not affect patient management.
It should be widely understood that VUS results are common and should not impact the recommendations for patient management.
More importantly, screening or surveillance should be offered in the context of the patients’ personal and family history of cancer.
For example, if your patient previously had breast cancer, she should be on yearly screening with breast mammograms and/or MRIs, regardless of her VUS result.
It is important to recommend screening based on your patient’s personal history of cancer, as VUS results should not affect clinical management in any way.
The next consideration would be her family history – if there is colorectal cancer in her family, it would be wise to recommend colonoscopy around 10 years before the age of the first colorectal cancer diagnosis.
As genetic knowledge is dynamic and complex, VUS often need to be managed within a multidisciplinary team of genetic counsellors, oncologists and researchers to ensure continued and holistic patient care, supported by their family doctors. If there is ever a scenario where there is uncertainty or confusion over the management of VUS results, or your patient requires further clarification of their genetic testing results, please refer them on to a specialist service that offers genetic counselling for appropriate care. If you suspect a patient to have a hereditary cancer syndrome or have patients with VUS who are interested in research, please also feel free to refer them on. We also welcome GPs who are keen to partner with us or to learn more about our educational and training opportunities to contact us.
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GPs may contact the Cancer Genetics Service, National Cancer Centre Singapore at: Tel: 6436 8000 / 6436 8288
Email: [email protected]
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CANCER GENETICS SERVICE
The Cancer Genetics Service (CGS) at National Cancer Centre Singapore provides individualised cancer risk assessment, genetic counselling and testing services for a broad range of genetic and hereditary conditions. This helps tailor clinical management and treatment for the individual and paves the way towards personalised medicine. CGS serves as a single unified platform coordinating patient care, research and education of genomic medicine.
Clinical research
CGS actively contributes to research on a national and international scale. It has multiple ongoing research studies to identify novel pathogenic gene variants that predispose individuals to cancer. It is also involved in health services research to understand the psychosocial impact of hereditary cancer syndromes, and is exploring the use of outreach methods to improve accessibility for cancer genetics testing. CGS is also interested in the design of novel drugs tailored for gene-directed targeted treatment of patients with metastatic cancer.
Education
The team at CGS are strong advocates of raising awareness and providing education to both the public and healthcare professionals. CGS regularly conducts outreach programmes to educate the public on hereditary cancers. This is often done in conjunction with its annual ‘Jeans for Genes’ campaign in April to raise awareness for such cancers.
CGS contributes knowledge through various channels which include GP education forums, multidisciplinary tumour board meetings, clinical rotation training, as well as local and international workshops, conferences and lectures.
In addition to training international aspiring genetics professionals, the service is actively involved in the training of medical students, doctors and nurses – where CGS is regarded as a regional and international centre for cancer genetics training.
Campaigns and events
The ‘Living with’ series of events are specially organised for patients and their families living with a hereditary cancer syndrome that predisposes them to certain cancer risks. These events are important in facilitating support networks for patients and their families. Connecting with others facing similar challenges can provide emotional support and practical advice, improving coping mechanisms and resilience.
Our yearly events include:
March: Living with Lynch Syndrome
May: Living with Li-Fraumeni Syndrome
May: Living with Neurofibromatosis
October: Living with hereditary breast and ovarian cancer syndrome
10 years of delivering individualised care
CGS is celebrating its 10th anniversary this year. This marks a decade of delivering individualised patient care, participating in clinical research as well as engaging in education and campaigns.
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Ms Tasmyn Scriven
Genetic Counsellor, Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore
Ms Tasmyn Scriven is a Genetic Counsellor at the National Cancer Centre Singapore. She has a passion for empowering patients with knowledge and psychosocial support as they navigate their cancer journey. She has a keen interest in public engagement and hopes to increase awareness of the genetic counselling profession as well as hereditary cancer syndromes.
Ms Jeanette Yuen
Principal Genetic Counsellor, Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore
Ms Jeanette Yuen is a genetic counsellor at the National Cancer Centre Singapore. She is dedicated to the holistic care of individuals with hereditary cancer syndromes and is committed to improving access and breaking down barriers to genetic testing. She is interested in health services and clinical research to improve patient outcomes in an evidence-based manner.
Clin Asst Prof Rose Fok Wai Yee
Consultant Family Physician, Division of Medical Oncology, National Cancer Centre Singapore
Clinical Assistant Professor Rose Fok is a family physician with a special interest in oncology. She practises at the National Cancer Centre Singapore, caring for breast and gynaecological cancer survivors. She is a strong advocate of community cancer survivorship and runs a risk management clinic to optimise surveillance for mutation-positive patients. She has a keen interest in health services research, especially in areas of oncology such as cancer prevention, screening, survivorship and high-risk surveillance.
Assoc Prof Joanne Ngeow
Head & Senior Consultant, Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore;
Deputy Head & Service Chief, Cancer Genetics, SingHealth Duke-NUS Genomic Medicine Centre;
Senior Consultant, Paediatric Brain and Solid Tumour Programme & Visiting Consultant, KK Breast Centre, KK Women’s and Children’s Hospital
Associate Professor Joanne Ngeow is a Senior Consultant in the Division of Medical Oncology, National Cancer Centre Singapore (NCCS) and Associate Professor at Lee Kong Chian School of Medicine, Nanyang Technological University. She heads the NCCS Cancer Genetics Service with an academic interest in hereditary cancer syndromes and translational cancer genetics. Her current clinical and research focus revolves around understanding cancer predisposition by studying cancers clustered in families, young adults with cancers and patients with multiple or rare cancers.
GPs can call the SingHealth Duke-NUS Genomic Medicine Centre for appointments at the following hotlines, visit the webpage for more information.
Singapore General Hospital: 6326 6060
KK Women's and Children's Hospital: 6692 2984
National Cancer Centre Singapore: 6324 8798
National Heart Centre Singapore: 6704 2222
