Results: Patient with cancer and a constitutional (germline) variant of uncertain significance

A 57-year-old man has been diagnosed with metastatic castrate-resistant prostate cancer. He has a confirmed family history of breast and ovarian cancer that meets eligibility criteria for constitutional (germline) testing of relevant cancer susceptibility genes. Testing of a panel of these genes is undertaken and no pathogenic variants are identified; however, a variant of uncertain significance (VUS) is reported in the BRCA2 gene.

• A VUS is a genetic change that has been identified through genomic testing but is not known to cause disease based on current available evidence. For this reason, it is not deemed clinically actionable.
• BRCA2 is a tumour suppressor gene with a central role in the homologous recombination repair (HRR) pathway.
• Pathogenic variants in BRCA2 are linked to an inherited predisposition to breast, ovarian and other cancers. However, as a VUS result does not explain the cause of cancer, it should be treated as an uninformative result unless future evidence suggests otherwise.

Referral to clinical genetics

• If a patient has had a VUS reported, refer them to the local clinical genetics service to discuss the result in detail. The VUS will be reviewed at a clinical genetics multidisciplinary team (MDT) meeting to assess whether further investigations are required, with the purpose of generating more evidence to facilitate reclassification of the variant.
• Variant reclassification is possible if and when new information becomes available.

Management of the current cancer

• Identification of a constitutional (germline) VUS should not alter current cancer management. In rare cases, where suspicion of pathogenicity is high (and depending on available evidence), some treatment options may be considered following discussion at a specialist MDT that includes genomics and oncology professionals.

Management of the future cancer risk

• As a VUS result does not explain the cause of cancer, it should be treated as an uninformative result unless future evidence suggests otherwise.
• The patient may still be eligible for additional cancer screening based on their family history. Assess their family history based on current screening guidance or refer the case to the local cancer family history service.

Management of the family’s risk

• Predictive genomic testing is not available for unaffected relatives when a VUS is identified.
• First-degree relatives should seek advice through their GP about additional cancer screening.
• Other relatives affected by cancer may wish to seek genomic assessment through their GP or treatment team, or may be asked to do so by the clinical genetics team if information about their genotype will be helpful in clarifying the significance of the familial variant.

For clinicians

• NHS England Genomics Education Programme: The challenges of genomic variant classification

References:

• Hoffman-Andrews L. ‘The known unknown: The challenges of genetic variants of uncertain significance in clinical practice‘. Journal of Law and the Biosciences 2017: volume 4, issue 3, pages 648–657. DOI: 10.1093/jlb/lsx038

For patients

• NHS England Genomics Education Programme: Let’s Talk About… Possible Results (video, two minutes 36 seconds)
• NHS England Genomics Education Programme: Let’s Talk About… Variants of Uncertain Significance (video, one minute 34 seconds)