This session proposal focuses on an increasingly important topic in inherited cancers: consideration of phenotypic risk on a continuum (rather than as a binary trait) and variant-based (rather than gene-based). Historically, penetrance estimates have been anchored to genes based on “typical” risks attributed through the literature. Furthermore, penetrance estimates have historically been ascertained “phenotype-first,” meaning from families with a notable personal or family history bringing them to medical attention. Phenotypic ascertainment can inflate penetrance estimates given selection based on personal and family history among those ascertained based on phenotype compared to genotype. The increasing availability of exome and genome sequenced population-scale cohorts linked to the electronic health record has greatly expanded the ability to use the “genotype-first” approach (or genomic ascertainment) to refine estimates of the prevalence of germline pathogenic or likely pathogenic variants (GPV), penetrance and phenotypic spectrum.

As an example, well-established cancer-predisposition genes such as the BRCA1 and BRCA2 (BRCA) are considered to be “high penetrance genes,” with lifetime breast cancer risk of 60-70%. “Moderate penetrance” CHEK2 and ATM genes are associated with a lifetime breast cancer risk of 20-30%. Yet, there exist genotype/phenotype-specific risks that substantially deviate from these risk estimates, such as the CHEK2 I157T GPV associated with <20% lifetime risk; or the ATM V2424G GPV associated with ~50-60% lifetime risk. Even for BRCA, considered the prototypic high-penetrance inherited breast cancer genes, there exist variants that confer more moderate risk (e.g., BRCA1 R1699Q). Risks may be refined based on additional factors beyond family history, such as hormonal and lifestyle factors and breast density, and in future, we anticipate risk estimates will be modified by polygenic risk scores (PRS).

Among individuals heterozygous for a GPV, considering risks on a continuum has implications on cancer-risk management guidelines. While current clinical recommendations are generally gene-specific, there are now tools to generate individualized risks to guide management. In fact, a risk continuum framework in conjunction with variant-specific genomic (rather than just phenotypic) ascertainment data should be part of clinical and policy decision-making. Moreover, anchoring guidance for cancer risk management to level of individual risk, rather than to a gene, has become increasingly achievable. Therefore, this session will fill an increasingly important practice gap that impacts both risk refinement and subsequent care among individuals with inherited cancer risk. The content to be discussed may directly be used by providers to refine care for their patients. Content and principles discussed during the session focused on lessons in inherited cancer are relevant to and will inform other non-cancer phenotypes.