Understanding how BRCA test results are classified
IN THIS ARTICLE
This section describes best practices in reporting the results of BRCA tests and describes how an oncologist can interpret a report from the diagnostics laboratory.1
There are standards and best practice guidelines to assist in the interpretation of results, including the American College of Medical Genetics and Genomics (ACMG) standards. These recommendations provided interpretative categories of sequence variants and an algorithm for the interpretation, and classification of sequence variants using criteria informed by expert opinion and empirical data.1
Understanding how genetic test results are reported
In a clinical setting, the main goal of genetic diagnostics is to determine whether the patient carries a pathogenic or likely pathogenic variant, as this knowledge can influence the care and treatment of the patient and their family members. Thus, we begin by evaluating the potential pathogenicity of variants by evaluating all existing evidence. If there is no or very little evidence to confidently support or rule out pathogenicity, the variant is classified as a variant of uncertain significance (VUS).2
Possible test results
A mutation is identified and is pathogenic or deleterious
- A pathogenic/deleterious mutation has been identified, and the patient is ‘positive’ for a BRCA mutation.3
A mutation is identified and is believed not to be pathogenic or deleterious
- A VUS is detected. Which means there is no known clinical relevance of the specific variant identified.4
- When a mutation is found in any highly penetrant cancer-related gene, interpreting the phenotypic presentation of the family is always important when making clinical recommendations.4
A VUS is detected
- A VUS was detected. The patient does have a BRCA mutation, but the specific mutation has not been previously classified as harmful or harmless.4
- A VUS result means that the variant has not been previously described in the literature or the clinical significance is unclear based upon currently available evidence.4
- Pathologists should log any VUS results, and monitor the patient, as well as test family members to determine potential risks and medical management techniques.4
No mutation is identified
- No pathogenic or deleterious mutation has been identified, and the patient likely does not have a BRCA mutation or at least not one that impacts their risk.3
- The patient may still have a mutation in a gene that was not tested by the panel – discussions should be had about whether the patient should undergo a larger panel of genetic tests to look for mutations in other genes.4
Analysis of sequencing results for BRCA testing
The results of BRCA testing must be interpreted to determine the clinical significance of any variants found during testing. In a diagnostic setting, variant classification forms the basis for clinical decision-making. Proper classification of variants is therefore critical to appropriately manage patients.5
It is standard practice across the genetic diagnostics industry for every company to develop and use its own variant classification system. Most of the guidelines follow the recommendations of the ACMG guidelines, however, there are differences between the classification systems. This can be quite confusing, especially when it results in different classifications of the same variant. Our five-tiered variant classification system describes the amount and quality of evidence needed to classify a genetic variant.2
How classification results influence clinical decisions
The diagram below shows variant classification information, whether the variant can be used to make a clinical decision and whether family members should be tested.2
CLASS 1:
Pathogenic variant2
Impact on patient management
The variant is well established as disease causing in the databases and literature, and a wide consensus on the variant’s pathogenicity exists. In these cases, significant family seggregation has been verified and several publications support pathogenicity. Additional criteria are shown to the right.
Predictive testing in at-risk relatives
We recommend family member testing and genetic counseling.
CLASS 2:
Likely not pathogenic or of little significance
Impact on patient management
A clear genotype-phenotype correlation exists. In these cases, it is essential to have thorough background information from the referring clinician about the patient’s phenotype, which helps to determine the probable pathogenicity.
Predictive testing in at-risk relatives
We recommend family member testing and genetic counseling, but the variant alone should not be used for family risk stratification.
CLASS 3:
Variant of uncertain significance (VUS)
Impact on patient management
The variant has characteristics of being an independent disease-causing mutation, but insufficient or conflicting evidence exists.
Predictive testing in at-risk relatives
We do not recommend family member testing in a diagnostic setting. However, in some cases family member testing may be useful, especially when the disease affects multiple individuals in the family and the variant has several characteristics that suggest it is disease-causing.
CLASS 4:
Likely pathogenic
Impact on patient management
The variant is not likely to be the cause of the tested disease. Genetic tests with only likely benign variants are considered negative test results.
Predictive testing in at-risk relatives
Yes
CLASS 5:
Benign variant
Impact on patient management
The variant is not considered to be the cause of the tested disease. Genetic tests with only likely benign variants are considered negative test results.
Predictive testing in at-risk relatives
No
NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
ADP, adenosine diphosphate; ACMG, American College of Medical Genetics and Genomics; BRCA, breast cancer gene; DNA, deoxyribonucleic acid; EMQN, European Molecular Genetics Quality Network; ESMO, European Society for Medical Oncology; gBRCAm, germline BRCA mutation; HER2, human epidermal growth factor receptor 2; IARC, International Agency for Research on Cancer; NGS, next generation sequencing; NCCN, National Comprehensive Cancer Network; VUS, variant of unknown significance; TNBC, triple-negative breast cancer.
References:
- Richards, S et al. Standards and guidelines for the interpretation of sequence variants. Genet Med. 2015; 17: 405-423.
- Blueprint Genetics. A guide to understanding variant classification. Available at: https://blueprintgenetics.com/app/uploads/2019/04/Variant_Classification_WP_VARA41-05.pdf. Last Accessed: April 2022.
- Committee on Practice Bulletins–Gynecology et al. Hereditary Breast and Ovarian Cancer Syndrome Obstet Gynecol. 2017; 130: e110-e126.
- Miller-Samuel S et al. Variants of Uncertain Significance in Breast Cancer–Related Genes Semin Oncol. 2011; 38: 469-480.
- Li MM et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer J Mol Diagn. 2017; 19: 4-23.
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General recommendations for the best practice of reporting genetic test results:3
- BRCA test results must be reported in a brief and unambiguous way to ensure ease of interpretation.
- The terms “positive” and “negative” can be ambiguous and should not be used.
- The report should include details of the laboratory that performed the test along with accreditation numbers (for example, International Organization for Standardization, ISO or Clinical Pathology Accreditation, CPA).
- Unequivocal patient identifiers must also be included on each page of a multi-page report.
- It is recommended that results for each unrelated patient should be reported in a separate and unique document.