Familial Disclosure and Cascade Testing in High-Risk Families is Influenced by Gene Variant Penetrance: Implications...

Point of care genetic testing has grown but cascade testing of At-Risk Relatives (ARR) remains underutilized. Between July and September 2023, we surveyed 912 individuals enrolled in the Cancer Prone Study, a registry of diverse high-risk families who received genetic counseling from cancer genetic experts. We analyzed correlates of familial disclosure and cascade testing among carriers of pathogenic/likely pathogenic variants (PV). Data on carrier status of PV in cancer-predisposing genes, penetrance level of variants, receipt of a family letter, familial disclosure, and follow up cascade testing of ARRs were collected.

Of 912 respondents, 39.4% were carriers of PV. Among these carriers, 78% had highly penetrant PVs (most common genes were BRCA1: 39% and BRCA2: 18%) and 17.5% had moderate penetrance PVs; Rate of disclosure of PV to at least one family member; receipt of family letter explaining genetic test results; and sharing of information with ARRs were 98%, 69% and 82% respectively. Cascade testing was more likely among carriers with highly penetrance PV (91.1%) compared to those with moderate penetrance PV (58.3%) (adjusted odds ratio [AOR], 5.70; 95% CI, 2.03-16.02), and among carriers who received a family letter than among those who did not receive (87.2% vs. 73.0%; AOR, 3.70; 95% CI, 1.42-9.61). These data suggest that access to family-based counseling facilitated by cancer genetic experts improves understanding of familial risks and improves cascade testing following results disclosure. Our data support family based clinical interventions to optimize precision prevention and cancer control in high-risk individuals.