RE: BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

The recently reported association of K3326X variant with the risk of developing breast and ovarian cancers independently of other pathogenic variants in BRCA2 (1) presents three major clinical issues: 1) the indication for cascade family screening and related monitoring decisions in relatives who carry the variant; 2) the role of the variant in decision-making (risk-reducing surgery) in affected carrier patients; 3) the potential use of poly(ADP-ribose) polymerase (PARP) inhibitors in K3326X carriers with platinum-sensitive, relapsed serous ovarian cancer. The clinical relevance of the data reported by Meeks and coauthors (1) may impact the clinical management of patients and families.

According to major BRCA mutation databases (https://research.nhgri.nih.gov/projects/bic/), the K3326X truncation-predicting variant (rs11571833) does not carry clinical importance and there are no functional data supporting its potential pathologic role; with “301 # of times recorded” through Septemper 24, 2015, this variant is still clinically classified in the pending category. We, and other breast cancer units worldwide, systematically consult existing databases before releasing and signing genetic reports and use reported data as reference for interpretation of genetic findings. In a consecutive series of 755 probands with hereditary breast and ovarian cancer (HBOC), which we systematically analyzed by sequencing and Multiplex ligation-dependent probe amplification (MLPA) both BRCA1 and BRCA2 genes, we identified 103 pathologic mutations in BRCA1 and 111 in BRCA2 (28.3%), including four major rearrangements. In an additional 13 probands, we identified the K3326X variant that was associated with a mutation in only one case (BRCA1 p.Thr1677_Asn1678fs). We managed the information about the K3326X variant as for other variants of uncertain significance; we did not suggest cascade genetic family screening, with the exception of the proband that carried both p.Thr1677_Asn1678fs in BRCA1 and K3326X in BRCA2.

Now, after publication of these new data, we are going to propose further counseling to inform patients about the novel risk estimate and the possibility of performing family cascade genetic testing. Correspondingly, we have to manage decisions on treatment in platinum-sensitive, relapsed serous ovarian cancer: Given the prior interpretation of the K3326X as VUS, we did not consider this variant a criterion for treatment with PARP inhibitor. Finally, indication to preventive surgery in carriers of the K3326X remains to be established. The way of informing patients, however, is now a major issue to be managed by the clinical community: Should we now deal with K3326X as we do other certain pathologic mutations, or should we advise caution in transmitting information about risk? While congratulating the authors for their valuable contribution, we would appreciate knowing their opinion and the modifications done in their clinical work-plans. Suggestions, if not precise indications, would help all breast and ovarian cancer units to manage appropriate information, family screening, and clinical decisions.

Note

The authors have no conflicts of interest to disclose.