Dealing With BRCA1/2 unclassified variants in a cancer genetics clinic: Does cosegregation analysis help?

Background: Detection of variants of uncertain significance (VUSs) in BRCA1 and BRCA2 genes poses relevant challenges for counseling and managing patients. VUS carriers should be managed similarly to probands with no BRCA1/2 variants detected, and predictive genetic testing in relatives is discouraged. However, miscomprehension of VUSs is common and can lead to inaccurate risk perception and biased decisions about prophylactic surgery. Therefore, efforts are needed to improve VUS evaluation and communication at an individual level. Aims: We aimed at investigating whether cosegregation analysis, integrated with a careful review of available functional data and in silico predictions, may improve VUSs interpretation and counseling in individual families. Methods: Patients with Breast Cancer (BC) and/or Ovarian Cancer (OC) fulfilling established criteria were offered genetic counseling and BRCA1/2 testing; VUSs identified in index cases were checked in other relatives affected by BC/OC whenever possible. As an alternative, if BC/OC clustered only in one branch of the family, the parental origin of the VUS was investigated. Public prediction tools and databases were used to collect additional information on the variants analyzed. Results: Out of 1045 patients undergoing BRCA1/2 testing in the period October 2011-April 2018, 66 (6.3%) carried class 3 VUSs. Cosegregation analysis was performed for 13 VUSs in 11 kindreds. Seven VUSs (53.8%) did not cosegregate with breast/ovarian cancer in the family, which provided evidence against their role in cancer clustering in those families. Among the 6 cosegregating VUSs, for two (BRCA1 c.5152+2T > G and BRCA2 c.7975A > G) additional evidence exists from databases and in silico tools supporting their pathogenicity, which reinforces the hypothesis they may have had a predisposing effect in respective families. For the remaining four VUSs (31%), cosegregation analysis failed to provide relevant information. Conclusion: Our findings suggest that cosegregation analysis in a clinical context may be helpful to improve test result interpretation in the specific family and, therefore, should be offered whenever possible. Besides, obtaining and sharing cosegregation data helps gathering evidence that may eventually contribute to VUS classification.