Demographic information | |
Cancer phenotype | <specify cancer phenotype of proband> |
Sample tissue | □ Blood □ Saliva □ Primary tumour □ Distant metastasis □ Other (specify) |
Context | □ Diagnostic □ Prediction cancer risk □ Genotype directed treatment □ Other (specify) |
Variant identified | Variant description should be based on the Human Genome Organisation (HUGO) standard variant nomenclature and Human Genome Variation Society (HGVS). The use of HGVS nomenclature can be problematic for describing exon deletions/duplications (particularly where end points are unknown) and triplet repeat expansions. Therefore, such variants should also be described in words if this improves clarity. |
Level 1: variant classification* | Variant interpretation by the laboratory—variant classification based on all available data. |
ACMG/AMP or IARC variant classification | Pathogenic or likely pathogenic or uncertain significance or likely little clinical significance/likely benign or little clinical significance/benign. Assertion relates to dominant mode of inheritance for cancer phenotype. Details of the evidence supporting the variant classification are provided as supplementary documentation. |
Level 2: clinical validity* | Considers the strength of evidence for the genetic variant being related to the presenting cancer phenotype, new primary cancer risk, predicting the likely response to targeted treatment or relevance to recessive phenotypes. It is recognised that specific missense and protein truncating variants within the same gene may exhibit a differing magnitude of effect on cancer risk. |
Presenting cancer phenotype | There is strong evidence that this variant is making a (substantial
) contribution to the presenting cancer phenotype <insert reference>. or There is insufficient evidence to support an association between this variant and the presenting cancer phenotype <insert reference if available>.† |
Prediction cancer risk | There is strong evidence to support the prediction of a high (>fourfold) increase in future cancer risk <specify cancer type/s> when this variant is present in a family member (reference with associated risks). or There is strong evidence to support a moderate (twofold to fourfold) increase in future cancer risk <specify cancer type/s> when this variant is present in an family member and can be used for cancer risk stratification. This variant should not be considered in isolation. Information from the family history of disease, and other known genetic and environmental risk factors or polygenic risk scores may substantially modify overall cancer risk estimates <insert reference with associated risks>. or There is strong evidence from population studies to support that is variant is associated with a low (<twofold) increase in cancer risk <specify cancer type/s><reference with associated risks>. This variant is insufficiently predictive of future risk to be clinically actionable. Variants in this category may contribute towards a polygenic risk score. |
Genotype directed treatment | There is evidence to support consideration of <specify drug/drug type> in the context of <specify cancer type><insert reference/s>.‡ or There is currently <limited/no> evidence to support consideration of <specify drug/drugtype> in the context of <specify cancer type>. |
Biallelic inheritance | Evidence may support that biallelic (compound heterozygote or homozygote) variant inheritance is likely to cause recessive disease<specify disease name>. |
Level 3: clinical utility and actionability* | This final element comprises the discussion between physician and patient. It may take the form of a personalised assessment of risk based on the presenting cancer phenotype, clinical scenario and family history. If the reporting laboratory is not qualified to address this element of the report then it should be made clear that this is an additional requirement before determining any clinical management consequences. Proposed clinical interventions should be risk proportionate and take the individual clinical circumstances into account reflecting on any uncertainty around estimates of risk underpinning life-changing decisions such as risk reducing surgery or reproductive choices. It also requires consideration of cascade genetic testing for other relatives at risk. If preferred, the report may be shortened by referring to local guidelines for details. |
(i) Clinically actionable (high penetrance) |
Simplified report: follow clinical management guidelines for high penetrance predisposition genes according to local guidelines Or Detailed report presenting details from local guidelines—EXAMPLE provided: 1. Surveillance: high-risk surveillance if strong evidence for variant-specific high risk 2. Risk reducing surgery: consider risk reducing surgery only if the overall clinical picture is high risk (see above) and depending on cancer prognosis and treatment <specify appropriate risk reducing surgery>. 3. Cascade genetic testing: sequence variant may be used alone to inform clinical management and so cascade genetic testing is indicated. |
(ii) Clinically actionable but not in isolation (moderate penetrance) |
Simplified report: manage based on a comprehensive risk evaluation§ Additional moderate-risk or high-risk surveillance may be indicated. Clinical management recommendations should be determined on the basis of the absolute cancer risks conferred by <variant identified> in combination with the personal and/or family history of disease and other known genetic and environmental risk factors. Follow clinical management guidelines according to local guidelines. Or Detailed report presenting details from local guidelines—EXAMPLE provided: 1. Manage based on a comprehensive risk evaluation‡: additional moderate-risk or high-risk surveillance may be indicated. Clinical management recommendations should be determined on the basis of the absolute cancer risks conferred by <variant identified> in combination with the personal and/or family history of disease and other known genetic and environmental risk factors. 2. Risk reducing surgery: for moderate penetrance gene variants in isolation, there is currently no clear evidence of clinical benefit for risk reducing surgery. 3. Cascade genetic testing: predictive testing for this variant has limited clinical utility in isolation. |
(iii) Not clinically actionable (low penetrance) | Manage based on family history: Insufficiently predictive of future cancer risk to be clinically actionable. Clinical management recommendations for the <presenting cancer phenotype> should be determined on the basis of personal and/or family history of disease and other known genetic and environmental risk factors. Variants in this category may contribute towards a polygenic risk score. |
*We suggest that this should be repeated for each reportable variant identified in the sample submitted (usually the proband—defined as the person serving as the starting point for the genetic study of a family; may be a patient with cancer or not). For high-risk cancer susceptibility genes, the probability threshold for classification as likely pathogenic is 0.95 for the IARC classification scheme6 and 0.90 for the ACMG/AMP guidelines.5 It may be reasonable to consider the 0.90 threshold as more appropriate for moderate penetrance variants, where recommended management excludes irreversible surgical risk-reducing strategies. We suggest that only strong evidence supporting risk associations should be used to determine clinical validity of clinically actionable variants. We define strong evidence following recommendations published in the study by Easton et al,16 namely: “we consider it to be likely that a given risk will be above (or below) a certain threshold if the 90% confidence limit on the risk estimate exceeds (or is less than) the threshold".
†We suggest that individual results for risk alleles associated with small increase in risk of cancer (as determined by well-powered studies) should not be included in clinical genetic test reports in isolation but presented as a combined overall risk prediction score.
‡We do note that it cannot be assumed that all variants that are associated with increased disease risk will predict (the same) response to targeted therapy and vice versa. It is thus recommended that future iterations of multitier reporting schemes provide for distinct annotation of germline variants for disease risk and relevance to drug treatment.
§High-risk surveillance if comprehensive cancer risk (family history-based risk) stratification >30% absolute lifetime risk, moderate-risk surveillance if comprehensive cancer risk stratification (family history-based risk) 17%–30% absolute lifetime risk, population screening if comprehensive cancer risk stratification (family history-based risk) <17% absolute lifetime risk.
ACMG, American College of Medical Genetics and Genomics; AMP, Association for Molecular Pathology; IARC, International Agency for Research on Cancer.