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Mar 3, 2016 01:15PM
Jan 7, 2017 07:32PM
Your experience illustrates the point: The fact that experts may know nothing about a variant of unknown significance is exactly why a second opinion is in order for kleigh1.
For the reasons noted in my post above, if a person with a VUS has received advice to pursue prophylactic surgery, an expert second opinion is advisable and may indeed be illuminating, because it may not confirm the advice received.
I should add that there is a second guideline available at www.NCCN.org, also recently updated, entitled "Breast Cancer Risk Reduction" (Version 1.2016). Because any particular recommendation may or may not apply in the particular case, it is important to always confirm your understanding with a professional familiar with the guidelines by the nature of their practice and familiar with the details of your situation.
As I mentioned above, the estimated lifetime risk associated with a known pathogenic mutation in any particular gene, such as BRCA2, may vary depending on the particular pathogenic mutation and on the particular type of cancer in question. With regard to ovarian cancer, per the NCCN guideline "Breast Cancer Risk Reduction" (Version 1.2016) notes (BRCA2 range in bold):
"Although the risk for ovarian cancer is lower than the risk for breast cancer in a BRCA1/2 mutation carrier (eg, estimated lifetime risks of 36%–46% and 10%– 27% in BRCA1 and BRCA2 mutation carriers, respectively (89,99-102)."
The lifetime risk, IF ANY, associated with a VUS is unknown. This concept is a challenge for patients and clinicians alike, who very naturally tend to attribute a cancer diagnosis to a VUS, despite the possibility that the VUS may possibly be a neutral variant (also called "nonpathogenic," "of no clinical significance," or "benign").
Robson (2015) ASCO Policy Statement: "ASCO Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility": http://ascopubs.org/doi/abs/10.1200/JCO.2015.63.0996
"VUSs are alterations in the genetic code that may or may not affect the function of the protein. VUSs are more common in broad-panel testing both because of the number of genes tested and because of the limited understanding of the range of normal variation in some of these genes. It is usually inappropriate to change the clinical management of a patient based on the finding of a VUS. Unfortunately, there is some evidence that clinicians may overinterpret VUSs and make recommendations that should be reserved for individuals with clearly deleterious mutations."
For more information about variants of unknown significance and the complex issues and challenges they present in clinical practice, these articles in the BRCA area can be instructive. I would venture to say that many everyday medical professionals are not familiar with this body of literature.
Eccles ENIGMA (2015) pdf: http://annonc.oxfordjournals.org/content/26/10/205...
Cheon (2014): http://link.springer.com/article/10.1186%2Fs13073-...
Lindor (2013): http://theoncologist.alphamedpress.org/content/18/...
This is an extremely complex and highly specialized area. These articles are for information only and are not a substitute for current, case-specific expert professional medical / genetic advice regarding any specific VUS in any specific gene, in the context of your personal medical and family history.
[EDITED to update link to ASCO policy statement]
Stage IA IDC, 9/2013 BMX. Right: IDC (1.5 mm, grade 2) with DCIS (5+ cm), 0/4 nodes, pN0. Left: DCIS (5+ cm), 0/1 node, pN0(i+).