CTA: Most hereditary cancer-gene testing is for BRCA1/2-associated breast and ovarian cancers, correct? Are men underrepresented across the test data?

Dr Ross: We need to increase our screening of men [for this mutation]. I knew the number of men tested would be lower than women, but I didn’t know how extreme that would be. A tiny minority of men were tested. One caveat is that since the test results were only from one clinical laboratory, it is possible there is an ascertainment bias and more men are being tested at other laboratories. The reason we knew there would be more women is because we frequently test people with breast cancer or family histories of breast and ovarian cancer, and so, women are the most likely to [be tested]. Still, some of the most common causes of hereditary prostate cancer are now known to be [due to] BRCA1 and BRCA2 mutations. Since this fact is relatively new knowledge compared [with the mutations’] roles in breast and ovarian cancer, it makes sense that men would not be tested as often — yet.

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 The limited number of men tested does allow me to emphasize how often we are not testing for the most common hereditary cancer syndrome, Lynch Syndrome. The genetic awareness campaign in the early days was to increase BRCA1/2 mutation testing, not testing for Lynch Syndrome mutations [MLH1, MSH2, MSH6, PMS2, EPCAM], which are collectively even more common. We need to increase awareness about Lynch Syndrome, as once a person knows [he or she has] the syndrome, [the individual] can do a lot to prevent future cancers (eg, frequent colonoscopies and endoscopies, total abdominal hysterectomy with bilateral salpingo-oophorectomy).

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CTA: What did your team’s analysis reveal about reclassification rates across patients of different races or ethnicities?

Dr Ross: As expected, for minority populations (such as Hispanic or African American groups) the VUS rates were higher because these populations have had less testing in the past; there are variations in the spelling of genes that are specific to those populations. This is analogous to how different dialects or languages are used by distinct populations. The rates of reclassification were not found to be significantly different between populations. But I was surprised by how often information about ancestry was not filled in by the clinicians on test request forms. Therefore, information on ancestry was limited. Why would clinicians leave such easy-to-get information off these forms?

CTA: VUS reclassification represented the majority of changes, and in more than 90% of VUS reclassifications, your team found that they had been downgraded from VUS to benign or likely benign. What did the remaining, upgraded VUSs have in common?

Dr Ross: Great question. We wish the upgraded variations had something in common. There is simply no way for us to predict at this time who gets upgraded and who gets downgraded. The key thing was that when more patient information came in or more was published, the better the chance it was classified up or down. But nothing was similar that made us say, ‘you’re likely to see this VUS be reclassified to a pathogenic mutation in the future.’

However, based on the frequencies of reclassifications we can say, ‘you’re much more likely to see this VUS reclassified to a benign rather than pathogenic sequence in the future.’


  1. Mersch J, Brown N, Pirzadeh-Miller S, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320(12):1266-1274.