Understanding how BRCA test results are classified

IN THIS ARTICLE

Reporting test results

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 can interpret a report from the diagnostics laboratory.

There are standards and best practice guidelines to assist in the interpretation of results, including the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer and the American College of Medical Genetics and Genomics (ACMG) standards. These guidelines also cover best practice for reporting genetic test results.1,2

Different names of classification system
Different names of classification system

Understanding how genetic test results are reported

The results of genetic tests are not always straightforward, which often makes them challenging to interpret. In a clinical setting, the main goal of 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 results4-6

A mutation is identified and is pathogenic or deleterious

  • A pathogenic/deleterious mutation has been identified, and the patient is ‘positive’ for a BRCA mutation5,7,8
  • Guideline recommendations are available to help guide management decisions1
  • View the complete guidelines at NCCN.org1

A mutation is identified and is believed not to be pathogenic or deleterious

  • A mutation has been identified, but it is not clinically relevant7
  • Depending on the mutation found, other types of genetic test may be recommended to determine any wider risks7,8

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 harmless7
  • 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 evidence7
  • Pathologists should log any VUS results, and monitor the patient, as well as test family members to determine potential risks and medical management techniques7

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 risk4,5
  • 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 genes7

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.13

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.14-16

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.4 The differences in names of the classification systems are outlined in the table below.

Different names of classification system
Different names of classification system
Different names of classification system
Different names of classification system

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.14,20

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

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.

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:

  1. Referenced with permission from the NCCN Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V6.2020. National Comprehensive Cancer Network, Inc. All rights reserved. [Accessed February 2021]. To view the most recent and complete version of the guideline go online to NCCN.org.
  2. Richards, S et al. Genet Med. 2015; 17: 405-423.
  3. Claustres, M et al. Eur J Hum Gen. 2014; 22: 160-70.
  4. Blueprint Genetics. A guide to understanding variant classification. Available at:
    https://blueprintgenetics.com/wp-content/uploads/2019/04/Variant_Classification_WP_VARA41-05-1.pdf [Accessed February 2021].
  5. Committee on Practice Bulletins–Gynecology et al. Obstet Gynecol. 2017; 130: e110-e126.
  6. Stanislaw C et al. Cancer Biol Med. 2016; 13: 55-67.
  7. Miller-Samuel S et al. Semin Oncol. 2011; 38: 469-480.
  8. Be BRCA Aware. BRCA Test Results: What Do They Mean? Available at:
    https://www.bebrcaware.com/i-know-my-brca-status/understanding-brca-test-results.html [Accessed February 2021].
  9. BRCA Exchange. Available at: http://brcaexchange.org/. [Accessed February 2021].
  10. Beroud C et al. Hum Mutat. 2016; 37: 1318-1328.
  11. National Human Genome Research Unit. Available at: https://research.nhgri.nih.gov/bic/. [Accessed February 2021].
  12. NCBI. Available at: https://www.ncbi.nlm.nih.gov/clinvar/. [Accessed February 2021].
  13. Li MM et al. J Mol Diagn. 2017; 19: 4-23.
  14. Plon SE et al. Hum Mutat. 2008; 29: 1282-1291.
  15. Wallis Y et al. Association for Clinical Genetic Science. Available at:
    https://www.acgs.uk.com/media/10791/evaluation_and_reporting_of_sequence_variants_bpgs_june_2013_-_finalpdf.pdf. [Accessed February 2021]
  16. Tavtigian SV et al. Hum Mutat. 2008; 29(11); 1261-1264.
  17. Khawaja F and Wolstenholme N. Ensuring Accurate Classification of BRCA Variants – Run 1. Available at:
    https://www.emqn.org/wp-content/uploads/2018/03/BRCA-Variants-Webinar-v1.pdf [Accessed February 2021].
  18. Mehta, A et al. Cancer Manag Res. 2018; 10: 6505-6516.
  19. OncologyPRO. BRCA1 and BRCA2 in Ovarian Cancer: ESMO Biomarker Factsheet. Available at:
    https://oncologypro.esmo.org/education-library/factsheets-on-biomarkers/brca1-and-brca2-in-ovarian-cancer [Accessed February 2021].
  20. Spurdle AB et al. J Med Genet. 2019; 56: 347-357.
  21. Genomics Education Programme. The perils of clinical interpretation of genomic variants. Available at:
    https://www.genomicseducation.hee.nhs.uk/blog/the-perils-of-clinical-interpretation-of-genomic-variants [Accessed February 2021].
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