Management of carriers of variants associated with reduced penetrance

BRCA1 c.5096G>A, (p.Arg1699Gln), (R1699Q)

At the National Cancer Genetics MDT on 16th Sept 2021, and UK CGG council meeting 21st September 2021, clinical management of carriers of the variant BRCA1 c.5096G>A, (p.Arg1699Gln), (R1699Q) was discussed, given that epidemiological studies have shown that the associated risks have been found to be lower than those associated with other pathogenic/likely pathogenic variants in this gene. 

The agreed national Consensus is that we should follow the proposed management guidelines in the JMG paper from ENIGMA*.

A summary of the recommendations from this paper is outlined here below:

  • For carriers of BRCA1 R1699Q 
    • The calculated cumulative risk of breast cancer (20% (95% CI 13%-32%)) does not by itself justify preventive mastectomy or breast MRI.
      • Recommended breast surveillance for female carriers (or transgender/non-binary carriers with breasts):
        • Annual mammogram between 40-50 years, inclusion in population screening thereafter
    • When family history is considered, the breast cancer risk in a carrier of BRCA1 p.R1966Q may be estimated to be higher than the estimated risks conferred by the variant alone. 
      • Management of such carriers should be individualised - higher intensity surveillance and/or other interventions may be considered, and should be guided by the family history.
    • Bilateral risk-reducing salpingo-oophorectomy may be postponed until age 50, based on the age-related cumulative risks for ovarian cancer obtained from the study.
  • For non-carriers of BRCA1*R1699Q from BRCA1*R1699Q families
    • Surveillance for females (or transmen/non-binary individuals with breasts) should be guided by the estimated breast cancer risk, based on personal/family history of cancer and other lifestyle/environmental modifiers of risk, by using programs like BOADICEA/CanRisk

For further information, click here to access the fulltext of the paper from the ENIGMA consortium*. 

Moghadasi S, Meeks HD, Vreeswijk MP, et al. The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium. J Med Genet. 2018 Jan;55(1):15-20. doi: 10.1136/jmedgenet-2017-104560. Epub 2017 May 10. PMID: 28490613.


Other variants?

Other variants associated with reduced penetrance have been reported in BRCA1, BRCA2 and other cancer predisposition genes. The absence of formal variant-specific epidemiological studies precludes generation of specific risk estimates and management guidelines. 

Where a variant is known to be associated with reduced penetrance, this should be specified on the laboratory report. Recommendations for screening and/or risk reducing surgery in carriers of such variants should be individualised, and consider other factors such as personal and family history, and other lifestyle/environmental or co-existing genetic modifiers of disease.