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Purpose:The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer–testing laboratory.Experimental Design:The 133 selected VUS were evaluated using a validated homology-directed double-strand DNA break repair (HDR) functional assay. Results were combined with clinical and genetic data from variant carriers in a rules-based variant classification model for BRCA2.Results:Of 133 missense variants, 44 were designated as non-functional and 89 were designated as functional in the HDR assay. When combined with genetic and clinical information from a single diagnostic laboratory in an ACMG/AMP-variant classification framework, 66 variants previously classified by the diagnostic laboratory were correctly classified, and 62 of 67 VUS (92.5%) were reclassified as likely pathogenic (n = 22) or likely benign (n = 40). In total, 44 variants were classified as pathogenic/likely pathogenic, 84 as benign/likely benign, and 5 remained as VUS.Conclusions:Incorporation of HDR functional analysis into an ACMG/AMP framework model substantially improves BRCA2 VUS re-classification and provides an important tool for determining the clinical relevance of individual BRCA2 VUS.

Supplementary Table from Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay

Germline pathogenic variants in DICER1 predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification are essential for reliable diagnosis of DICER1-related tumor predisposition and the identification of individuals who may benefit from surveillance. Since 2015, most labs have followed the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) sequence variant classification guidelines for DICER1 germline variant curation. However, these general guidelines lack gene-specific nuances and leave room for subjectivity. Consequently, a group of DICER1 experts joined ClinGen to form the DICER1 and miRNA-Processing Genes Variant Curation Expert Panel (VCEP) to create DICER1-specific ACMG/AMP guidelines for germline variant curation. The VCEP followed the FDA-approved ClinGen protocol for adapting and piloting these guidelines. A diverse set of 40 DICER1 variants were selected for piloting, including 14 known pathogenic/likely pathogenic (P/LP) variants, 12 known benign/likely benign (B/LB) variants, and 14 variants classified as variants of uncertain significance (VUS) or with conflicting interpretations in ClinVar. Clinically meaningful classifications (i.e., P, LP, LB, or B) were achieved for 82.5% (33/40) of the pilot variants, with 100% concordance among the known P/LP and known B/LB variants. Half of the VUS or conflicting variants were resolved with four variants classified as LB and three as LP. These results demonstrate that the DICER1-specific guidelines for germline variant curation effectively classify known pathogenic and benign variants while reducing the frequency of uncertain classifications. Individuals and labs curating DICER1 variants should consider adopting this classification framework to encourage consistency and improve objectivity.

Purpose: The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer–testing laboratory. Experimental Design: The 133 selected VUS were evaluated using a validated homology-directed double-strand DNA break repair (HDR) functional assay. Results were combined with clinical and genetic data from variant carriers in a rules-based variant classification model for BRCA2. Results: Of 133 missense variants, 44 were designated as non-functional and 89 were designated as functional in the HDR assay. When combined with genetic and clinical information from a single diagnostic laboratory in an ACMG/AMP-variant classification framework, 66 variants previously classified by the diagnostic laboratory were correctly classified, and 62 of 67 VUS (92.5%) were reclassified as likely pathogenic (n = 22) or likely benign (n = 40). In total, 44 variants were classified as pathogenic/likely pathogenic, 84 as benign/likely benign, and 5 remained as VUS. Conclusions: Incorporation of HDR functional analysis into an ACMG/AMP framework model substantially improves BRCA2 VUS re-classification and provides an important tool for determining the clinical relevance of individual BRCA2 VUS.

Carrier screening programs that identify the presence of known mutations have been effective for reducing the incidence of autosomal recessive conditions in the Ashkenazi Jewish (AJ) population and other populations. Yet, these programs have not realized their full potential. Furthermore, many known autosomal recessive and dominant conditions are not screened for and the molecular basis of other conditions for which screening might be offered is unknown. Through literature review and annotation of full sequenced genomes from healthy individuals, we expanded the list of mutations. Mutations were identified in a sample of 128 fully sequenced AJ genomes that were filtered through clinical databases and curated manually for clinical validity and utility using the American College of Medical Genetics and Genomics scoring (ACMG) system. Other known mutations were identified through literature review. A panel of 163 mutations was identified for 76 autosomal recessive, 24 autosomal dominant, and 3 X-linked disorders. Screening for a broader range of disorders not only could further reduce the incidence of autosomal recessive disorders but also could offer the benefits of early or presymptomatic diagnosis. Genet Med 18 5, 522–528.

PurposeTelephone disclosure of genetic test results can improve access to services. To date, studies of its impact have focused on return of Mendelian risk information, principally hereditary cancer syndromes.MethodsIn a multisite trial of Alzheimer disease genetic risk disclosure, asymptomatic adults were randomized to receive test results in person or via telephone. Primary analyses examined patient outcomes 12 months after disclosure.ResultsData from 257 participants showed that telephone disclosure occurred 7.4 days sooner and was 30% shorter, on average, than in-person disclosure (both P 0.001). Anxiety and depression scores were well below cutoffs for clinical concern across protocols. Comparing telephone and in-person disclosure protocols, 99% confidence intervals of mean differences were within noninferiority margins on scales assessing anxiety, depression, and test-related distress, but inconclusive about positive impact. No differences were observed on measures of recall and subjective impact. Subanalyses supported noninferiority on all outcomes among apolipoprotein E (APOE) ɛ4-negative participants. Subanalyses were inconclusive for APOE ɛ4-positive participants, although mean anxiety and depression scores were still well below cutoffs for clinical concern.ConclusionTelephone disclosure of APOE results and risk for Alzheimer disease is generally safe and helps providers meet demands for services, even when results identify an increased risk for disease.

Purpose: This study evaluates the Alzheimer disease risk perceptions of individuals who accurately recall their genetics-based Alzheimer disease risk assessment. Methods: Two hundred forty-six unaffected first-degree relatives of patients with Alzheimer disease were enrolled in a multisite randomized controlled trial examining the effects of communicating APOE genotype and lifetime Alzheimer disease risk information. Results: Among the 158 participants who accurately recalled their Alzheimer disease risk assessment 6 weeks after risk disclosure, 75 (47.5%) believed their Alzheimer disease risk was more than 5% points different from the Alzheimer disease risk estimate they were given. Within this subgroup, 69.3% believed that their Alzheimer disease risk was higher than what they were told (discordant high), whereas 30.7% believed that their Alzheimer disease risk was lower (discordant low). Participants with a higher baseline risk perception were more likely to have a discordant-high risk perception (P < 0.05). Participants in the discordant-low group were more likely to be APOE e4 positive (P < 0.05) and to score higher on an Alzheimer disease controllability scale (P < 0.05). Conclusion: Our results indicate that even among individuals who accurately recall their Alzheimer disease risk assessment, many people do not take communicated risk estimates at face value. Further exploration of this clinically relevant response to risk information is warranted.

A genetic marker known as apolipoprotein E provides a clear signal of a person's risk of developing Alzheimer's disease and thus that person's future need for long-term care. People who find that they have the variant of the trait that increases Alzheimer's disease risk are more likely to purchase long-term care insurance after receiving this information. If the information is widely introduced into the insurance market, coverage rates could be affected in different ways, depending on who possesses that information. Policymakers will eventually need to confront the issue of the use of this and other markers in the pricing of long-term care insurance.

To facilitate the development of a therapeutic alliance in genetic counseling, it is important that the counselor understands how families might perceive the condition that constitutes the reason for the referral. Through training and professional practice, genetic counselors develop a thorough understanding of families’ perceptions of the conditions that are common indications for genetic counseling. But, for referral indications that are less frequent, like serious mental illnesses, genetic counselors may feel less confident in their understanding of the family’s experience, or in their ability to provide psychosocial support when serious mental illness is reported in a family history. This may impede the establishment of a therapeutic alliance. As research shows that most referrals for genetic counseling related to serious mental illness are for female first-degree family members of affected individuals, we sought to explore how this group perceives serious mental illness. To provide a frame of reference with which genetic counselors may be more familiar, we explored how women perceived serious mental illness compared to other common complex disorders in their family. We conducted semi-structured interviews with women who had a child with a serious mental illness (schizophrenia, schizoaffective disorder, bipolar disorder) and a first-degree relative with another common complex disorder (diabetes, heart disease, cancer). Interviews were transcribed and subjected to thematic analysis. Saturation was reached when nine women had participated. Serious mental illness was perceived as being more severe and as having a greater impact on the family than diabetes, heart disease, or cancer. Themes identified included guilt, stigma, and loss. Some of the most important issues that contribute to mothers’ perceptions that serious mental illness is more severe than other common complex disorders could be effectively addressed in genetic counseling. Developing a heightened awareness of how family members experience a relative’s mental illness may help genetic counselors to be better able to provide psychosocial support to this group, whether serious mental illness constitutes the primary reason for referral or appears in the family history during counseling for a different referral reason.

This study evaluates the extent to which psychological adaptation (validated measures of depressive symptoms, anxiety, and test-specific distress) after genetic susceptibility testing is influenced by changes in beliefs about Alzheimer's disease (AD) and sharing of test results with others. Adult children of AD patients (N=269) from a randomized clinical trial involving genetic testing for apolipoprotein E (APOE) provided information before, as well as 6 weeks and 12 months after results disclosure. The levels of adaptation varied highly among participants at 12-month assessment. Participants who learned that they were ɛ4 negative (lower risk) had a reduction in perceived risk and concern about developing AD compared with those who learned that they were ɛ4 positive. Those who received results through an extended educational protocol (three in-person visits) had a larger decline in AD concern than those in a condensed protocol (educational brochure and two in-person visits). Increase in AD concern 6 weeks after disclosure was associated with increase in depression scores (b=0.20, P

This study explored the extent to which recipients of genetic susceptibility testing for Alzheimer's disease (AD) communicated their results to others. It also examined demographic characteristics, along with beliefs about AD, associated with such communication. Participants (N = 271) in a randomized clinical trial involving genetic testing for Apolipoprotein E (APOE) gene variants among first-degree relatives of AD patients reported their communication behaviors 6 weeks after the results disclosure. Information on beliefs about AD and genetic testing was collected at baseline. Eighty-two percent of participants receiving APOE genotype information shared their results with someone. Specifically, 64% shared with family members, 51% with spouse or significant others, 35% with friends, and 12% with health care professionals. Greater AD treatment optimism was associated with communicating results to family (OR = 1.43), spouse (OR = 1.62), friends (OR = 1.81), and health care professionals (OR = 2.20). Lower perceived risk (OR = 0.98) and higher perceived importance of genetics in the development of AD (OR = 1.93) were associated with results communication in general. Lower perceived drawbacks of AD genetic testing was associated with results communication to friends (OR = 0.65). Beliefs about AD risks and causes, genetic testing, and development of treatments partly may determine the interpersonal communication patterns of genetic susceptibility test results.

Perceived risk is a complex concept that influences the genetic counseling process and can affect client coping and behavior. Although the association between family history and risk perception is well recognized in the literature, no studies have explored this relationship specifically in those seeking genetic susceptibility testing for a common chronic condition. REVEAL is a randomized trial assessing the impact of APOE disclosure and genetic risk assessment for Alzheimer’s disease (AD). Using baseline REVEAL data, we hypothesized that there would be a significant association between the degree of AD family history and risk perception of AD, and that this relationship would be stronger in those who believed that genetics is a very important AD risk factor. In our sample of 293 participants, we found that a higher self-perceived risk of AD was associated with strength of family history of AD (p < 0.001), belief in genetics as an important AD risk factor (p < 0.001), being female (p < 0.001) and being Caucasian (p = 0.02). These results are the first to demonstrate the association between family history and risk perception in persons volunteering for genetic susceptibility testing for a common complex disease.

score was 4.97 (SD 5.32; range 0-20) with Cronbach’s alpha 0.92. In comparison, a separate population-based cohort of 205 women aged 65 years (mean 74.4; SD 5.5; range 65-86) had a mean GAI score of 2.32 (SD 4.03; range 0-19); a separate clinical sample of 46 male and female psychogeriatric patients (mean age 78.8 years; SD 6.7; range 66-94) had a mean GAI score of 5.22 (SD 5.83). As expected, GAI score was correlated with NPI anxiety severity (r 0.31; p 0.0037), NPI anxiety distress (r 0.32; p 0.0031) and GDS (r 0.62; p 0.000). GAI was also correlated with Barthel score (r -0.2837; p 0.0118), and leisure activities score (r 0.32; p 0.0050). Conclusions: The mean levels of clinic attendees’ self-reported anxiety were much higher than those reported by normal older volunteers but somewhat lower than those reported by psychogeriatric patients. Higher levels of anxiety were reported by patients with higher levels of physical dependency whereas lower levels of anxiety were reported by patients with greater involvement in leisure activities.

Increasing use of genetic testing raises questions about disclosing secondary findings, including pleiotropic information.To determine the safety and behavioral effect of disclosing modest associations between apolipoprotein E (APOE) genotype and coronary artery disease (CAD) risk during APOE-based genetic risk assessments for Alzheimer disease (AD).Randomized, multicenter equivalence clinical trial. (ClinicalTrials.gov: NCT00462917).4 teaching hospitals.257 asymptomatic adults were enrolled, 69% of whom had 1 AD-affected first-degree relative.Disclosure of genetic risk information about AD and CAD (AD+CAD) or AD only (AD-only).Primary outcomes were Beck Anxiety Inventory (BAI) and Center for Epidemiologic Studies Depression Scale (CES-D) scores at 12 months. Secondary outcomes were all measures at 6 weeks and 6 months and test-related distress and health behavior changes at 12 months.At 12 months, mean BAI scores were 3.5 in both the AD-only and AD+CAD groups (difference, 0.0 [95% CI, -1.0 to 1.0]), and mean CES-D scores were 6.4 and 7.1 in the AD-only and AD+CAD groups, respectively (difference, 0.7 [CI, -1.0 to 2.4]). Both confidence bounds fell within the equivalence margin of ±5 points. Among carriers of the APOE ε4 allele, distress was lower in the AD+CAD groups (difference, -4.8 [CI, -8.6 to -1.0]) (P = 0.031 for the interaction between group and APOE genotype). Participants in the AD+CAD groups also reported more health behavior changes, regardless of APOE genotype.Outcomes were self-reported by volunteers without severe anxiety, severe depression, or cognitive problems. Analyses omitted 33 randomly assigned participants.Disclosure of pleiotropic information did not increase anxiety or depression and may have decreased distress among persons at increased risk for 2 conditions. Providing risk modification information about CAD improved health behaviors. Findings highlight the potential benefits of disclosure of secondary genetic findings when options exist for decreasing risk.National Human Genome Research Institute.