Current strategies in BRCA1/BRCA2 molecular testing

Tumor Genetic Testing


We summarize here strategies to adopt when testing individuals for BRCA1 and BRCA2 mutations based on positive or negative family history. Any comments or personal experiences are welcome in the comments section. For an introduction on the BRCA1 and BRCA2 genes, you can read our BRCA1 and BRCA2 deep dive page here or our clinical card on hereditary breast and ovarian cancer syndrome.

Probands from a family with an as yet unknown BRCA1/BRCA2 pathogenic variant

Families with recurrent breast and ovarian cancer across generations are usually evaluated for BRCA1/BRCA2 testing. A set of software, such as BRCApro, can be utilized to combine the number and relationship of affected family members with age of onset and cancer histological subtypes in order to calculate the likelihood of a BRCA1/BRCA2 pathogenic mutation in the family. Once the study is complete, a family member must be selected for testing. In order to maximize the outcome of the test, it is recommended that BRCA1/BRCA2 sequencing is administred to an affected family member (index patient). If the index patient is not available for testing, any at risk unaffected family member can be tested, although he/she must be informed about the limitations of molecular testing when the index patient is not available (e.g. limitations in interpreting possible variants of unknown significance). BRCA1/BRCA2 molecular testing usually starts with sequence analysis (by NGS or Sanger sequencing). If negative, large deletions/duplications testing must be considered. If negative again, a mutation in any of the other breast/ovarian cancer genes should be considered (multigene panel testing to include selected additional genes other than BCRA1 and BRCA2 is always recommended).

See our panels for hereditary breast and ovarian cancer:

Probands from a family with a known BRCA1 or BRCA2 pathogenic variant

In most cases, relatives at risk need only to be tested for the family-specific germline variant with a targeted analysis. The molecular testing consists of sequence analysis of the limited DNA region including the pathogenic variant, or deletion/duplication testing in case the pathogenic variant is a large genomic rearrangement (LRG).
However, it should be paid attention to the following exceptions:
1- individuals of Ashkenazi Jewish heritage should be tested for all three founder germline pathogenic variants because of reports of the coexistence of more than one founder germline pathogenic variant in some Ashkenazi Jewish families.
2- individuals in whom a BRCA1 or BRCA2 germline pathogenic variant may be present in both maternal and paternal lines.

Proband of Ashkenazi Jewish ancestry
As first step, it is recommended to proceed with targeted analysis of the three Ashkenazi Jewish founder variants. This sequence analysis performed only on three limited DNA region of the BRCA genes is an effective and cost-efficient way to assess the carrier status of the proband.
In case no pathogenic variant is identified, as second step it is recommended to proceed with full gene sequencing analysis.
Since no exon or multiexon large deletions have been detected in this population so far, the additional step of deletion/duplication testing may not be needed.

In general, genetic testing for hereditary breast and ovarian cancer is not recommended for at-risk individuals younger than age 18 years. Guidelines by the American College of Medical Genetics and the American Society of Human Genetics state that predictive genetic testing should only be performed in individuals younger than age 18 years when it will affect their medical management. Management for hereditary breast and ovarian cancer is recommended to begin at approximately age 25, which is why it is recommended that the decision to test be postponed until an individual reaches adulthood and can make an independent decision. It is important to highlight, anyway, that since rare cases of individuals with hereditary breast and ovarian cancer diagnosed with at very young ages are reported, it is recommended to individualize the screening based on the earliest diagnosis in the family.

Predictive testing for hereditary breast and ovarian cancer is generally offered only to adults at risk, who have had an appropriate counseling and are fully informed and wish to proceed.
The international guidelines recommend that individuals who undergo this kind of predictive testing are seen for two to four counselling sessions, spread over a 3-month period, before disclosure of the test results.
The pre-test counselling sessions allow for advance consideration of medical options and the impact that test results may have on the individual as well as on family members.
The post-test counseling provides a valuable opportunity for health-care providers to interpret test results and to decide whether additional genetic testing is needed. In this step it is also significant to highlight the importance of continuing and regular preventive activity for patient, as well as for female who receives a negative result (in this case they can receive a personalised and intensified breast surveillance protocol in agreement with increased familial cancer risk).
If a pathogenic mutation is found, counseling must be offered to the family and others involved.

See our panels for hereditary breast and ovarian cancer:


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National Institute for Health and Care Excellence (NICE): Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer.

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Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Moyer VA; U.S. Preventive Services Task Force. Ann Intern Med. 2014 Feb 18;160(4):271-81. PMID: 24366376


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