How do you counsel a woman with a BRCA1 VUS with a high-risk personal history of breast cancer?

There is real harm to patients by ‘acting’ on the presence of VUS in BRCA1; the majority are reclassified as benign. For those who have access to genetics resources, it is very helpful to discuss these results with certified genetics counselors, and formal post-test counseling for patients is recommended.

I agree with previous comments in confirming the reported pathogenicity of the germline alteration across different labs/vendors from public databases such as ClinVar. Pathogenicity depends on several factors including functional abrogation of BRCA1 protein using in-silico analyses. At this time, BC survivors with VUS in BRCA1 should be counseled on screening and risk reduction for second primaries based on family or personal history. The...

I consider a VUS a 'variant of unknown significance' that may be re-classified at some point in the future, and is more likely to be re-classified as benign than pathogenic, so I seldom make clinical recommendations based on that finding, but I would not ignore it altogether. If by a 'high-risk personal history of breast cancer' you mean that she has already been diagnosed with breast cancer at a young age, particularly if it was triple-negative, this would support re-classifying her VUS as pathogenic (even if the testing companies aren't ready to do so) and suggest that she consider bilateral mastectomies. Similarly, if she does not have a breast cancer diagnosis herself but has one or more first-degree relatives who were diagnosed with br...

With the expanding use of germline testing, this question is becoming more relevant. While I generally agree with Dr. @Dr. First Last's approach, I would like to add a few things.

There are multiple commercial labs (Ambry, Myriad, Invitae, GeneDx, etc) that offer germline testing, but most of them rely on expert consensus when it comes to VUS versus pathogenic variant classification. Very few can afford expensive functional studies to see if the protein product of genetic variants actually affects cell function. Furthermore, mammalian studies are even more expensive and very limited. So, when it comes to expert consensus, those labs will review existing literature and decide whether there is enough evidence to classify the variant into path...

I greatly appreciate the additional comments and clarifications from Drs. @Dr. First Last and @Dr. First Last, and the references provided. I completely agree with utilizing whatever expertise is available - whether locally or at a regional cancer center or thru the testing company - to help clinicians make the most informed recommendations to our patients and their families. In regards to the use of adjuvant olaparib in patients with a BRCA VUS who would have been eligible for OlympiA, I would follow the same pathway - hoping that the drug will be covered if, following this evaluation and consultations, you conclude that the VUS is likely to turn out to be a pathogenic mutation.