How do I interpret the results of a BRCA test and what does it mean for patients?
IN THIS ARTICLE
Classification and clinical interpretation of genetic variants is intricate and complex. This section describes best practice in reporting the results of BRCA tests and describes how an oncologist or urologist can interpret a report from the diagnostics laboratory.
NCCN Guidelines for Prostate Cancer and the American College of Medical Genetics and Genomics (ACMG) standards provide guidance to assist in the interpretation of results from BRCA testing.1,2 The ACMG standards also cover for reporting genomic test results.2
Understanding how genomic test results are reported
In a clinical setting, the main goal of genomic testing 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 as well as the risk to other family members.
Genetic diagnostics laboratories evaluate the potential pathogenicity of variants by evaluating all existing evidence. Variants are evaluated using evidence from population and gene/disease-specific databases, in silico prediction tools, variant databases, and the relevant scientific literature. 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).4
Possible test results4,5
A mutation is identified and is pathogenic or deleterious
- A pathogenic/deleterious mutation has been identified, and the patient is ‘positive’ for a BRCA mutation6,7
- Guideline recommendations are available to help guide management decisions1,8
- View complete guidelines at NCCN.org1 or ESMO.org8
A mutation is identified and is believed not to be pathogenic or deleterious
- A mutation has been identified, but it is not clinically relevant6
- Depending on the mutation found, other types of genomic test may be recommended to determine any wider risks6,7
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 harmless6
- 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 evidence6
- Pathologists should log any VUS results, and monitor the patient, as well as test family members to determine potential risks and medical management techniques6
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 risk4
- 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 genomic tests to look for mutations in other genes6
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.10
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 potentially confusing, especially when it results in different classifications of the same variant.4
In order to overcome this potential confusion around nomenclature, the proposed IARC 5-tier system is widely used to understand and organise BRCA variant classifications, based on the probability of pathogenicity associated with different variants.2,12 The differences in names of the classification systems and how they compare to this proposed system are outlined in the table below.
| IARC/EMQN classification Systems2,13 | ACMG guidelines2,14 | Other names |
|---|---|---|
Not pathogenic |
Benign variant | Of no significance |
| Likely not pathogenic | Likely benign variant | Of little significance |
| Uncertain | Variant of unknown significance (VUS) | Variant of unknown significance (VUS) |
| Likely pathogenic | Likely pathogenic variant | |
| Definitely pathogenic | Pathogenic variant | Disease-causing mutation, predisposing mutation or susceptibility gene mutation |
How classification results influence clinical decisions
Variants can be used to make clinical decisions based on whether family members should be tested. The variant classification information is shown in the diagram below.15,16
CLASS 1:
Not pathogenic or of no significance
Impact on patient management
- Treat as “no mutation detected”
- No evidence to change the clinical management
- Additional tests possible, if the analytical techniques used do not cover certain mutation types
Predictive testing in at-risk relatives
No
CLASS 2:
Likely not pathogenic or of little significance
Impact on patient management
- Treat as “no mutation detected”
- No evidence to change the clinical management
- Additional tests possible, if the analytical techniques used do not cover certain mutation types
- Further follow up studies may help reclassification to Class 1
Predictive testing in at-risk relatives
No
CLASS 3:
Uncertain
Impact on patient management
- VUS detected: Clinical significance unknown
- No evidence to change the clinical management – management plan based on family history and other risk factors
- May warrant further follow up studies to clarify significance
Predictive testing in at-risk relatives
No
CLASS 4:
Likely pathogenic
Impact on patient management
- Treat as Class 5 patients, despite small risk of over-treatment
- Result can be used for clinical management
- May warrant additional follow up studies to assess significance and potentially reclassify, e.g. segregation studies, tumour histopathology, in vitro assays
Predictive testing in at-risk relatives
Yes
CLASS 5:
Definitely pathogenic
Impact on patient management
- Disease-associated mutation detected
- Result can be used for clinical management
Predictive testing in at-risk relatives
Yes
Class 4 and 5 variants are defined as likely pathogenic or pathogenic and these results impact patient management.15 If a patient with prostate cancer has a germline and/or somatic BRCA1/2 mutation, the NCCN Guidelines or ESMO-ESGO Consensus Recommendations for prostate Cancer recommend the use of certain PARP inhibitors as an option for therapy for select patients with metastatic castrate resistant prostate cancer (mCRPC).1,8
Ensuring accurate classification of variants in BRCA and other HRR genes.
[part 1]
(1:02:31)
Ensuring accurate classification of variants in BRCA and other HRR genes.
[part 2]
(58:35)
Optimising the bioinformatics of BRCA testing.
DR MIGUEL DE LA HOYA
(28:10)
Best practice for the interpretation of BRCA mutations.
DR EMMA HOWARD
(35:00)
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.
Abbreviations:
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® (NCCN®); VUS=variant of unknown significance.
References:
- Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.2.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed [June, 23, 2021]. To view the most recent and complete version of the guideline, go online to NCCN.org.
- Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med Off J Am Coll Med Genet. 2015;17(5):405-424. doi:10.1038/gim.2015.30.
- Claustres M, Kožich V, Dequeker E, et al. Recommendations for reporting results of diagnostic genetic testing (biochemical, cytogenetic and molecular genetic). Eur J Hum Genet. 2014;22(2): 160-70..doi:10.1038/ejhg.2013.125.
- Blueprint Genetics. A guide to understanding variant classification. Accessed July 4, 2021. https://blueprintgenetics.com/wp-content/uploads/2019/04/Variant_Classification_WP_VARA41-05-1.pdf.
- Stanislaw C, Xue Y, Wilcox WR. Genetic evaluation and testing for hereditary forms of cancer in the era of next-generation sequencing. Cancer Biol Med. 2016;13(1):55-67. doi:10.28092/j.issn.2095-3941.2016.0002.
- Miller-Samuel S, MacDonald DJ, Weitzel JN, et al. Variants of Uncertain Significance in Breast Cancer–Related Genes: Real-World Implications for a Clinical Conundrum. Part One: Clinical Genetics Recommendations. Semin Oncol. 2011;38(4):469-480. doi:10.1053/j.seminoncol.2011.04.008.
- What Do Your BRCA Test Results Mean? | beBRCAware. Accessed April 7, 2021. https://www.bebrcaware.com/i-know-my-brca-status/understanding-brca-test-results.html.
- Prostate Cancer | ESMO. Accessed April 7, 2021. https://www.esmo.org/guidelines/genitourinary-cancers/prostate-cancer.
- BRCA Exchange. Accessed April 7, 2021. https://brcaexchange.org/.
- Béroud C, Letovsky SI, Braastad CD, et al. BRCA Share: A Collection of Clinical BRCA Gene Variants. Hum Mutat. 2016;37(12):1318-1328. doi:10.1002/humu.23113.
- National Human Genome Research Institute Home | NHGRI. Accessed April 7, 2021. https://www.genome.gov/.
- Plon SE, Eccles DM, D.F Easton, et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat. 2008;29(11):1282-1291.
- Wallis Y, Payne S, McAnulty C, Bodmer D, Sister E. Practice Guidelines for the Evaluation of Pathogenicity and the Reporting of Sequence Variants in Clinical Molecular Genetics. Published online 2013:16.
- Khawaja F, Wolstenholme N. Ensuring Accurate Classification of BRCA Variants. :59.
- Li MM, Datto M, Duncavage EJ, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer. J Mol Diagn JMD. 2017;19(1):4-23. doi:10.1016/j.jmoldx.2016.10.002.
- Spurdle AB, Greville-Heygate S, Antoniou AC, et al. Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report. J Med Genet. 2019;56(6):347-357. doi:10.1136/jmedgenet-2018-105872.
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General recommendations for the best practice of reporting genomic 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.
The nature of the DNA sequence change in a gene may have a significant impact on the structure of the protein whose production it specifies – e.g., nonsense or frameshift mutations can result in a truncated or altered protein. Others may be missense changes – these typically cause less drastic changes to proteins, but some may have been found so often in association with a disease (and never in the general population) that they are recognised as pathogenic.16
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. Medical management decisions should be based on personal and family history. Family studies may help better understand the clinical significance of this variant.6
A VUS is found in 12-13% of patients with prostate cancer tested for BRCA1 and BRCA2 mutation status.6
- Sharing variant information allows VUS to be efficiently reclassified; as either more likely to be pathogenic or non-pathogenic, to make any possible clinical actions clearer.
- The BRCA Exchange aims to advance our understanding of the genetic basis of prostate cancer, breast cancer, ovarian cancer and other diseases by pooling data on BRCA1/2 genetic variants and corresponding clinical data from around the world.9 Visit brcaexchange.org to find out more. Other portals are available such as BRCA Share10 and ClinVar.11,12