Genotype-first approach to the detection of hereditary breast and ovarian cancer risk,and effects of risk disclosure to biobank participants

Genotype-first approach allows to systematically identify carriers of pathogenic variants in BRCA1/2 genes conferring a high risk of familial breast and ovarian cancer. Participants of the Estonian biobank have expressed support for the disclosure of clinically significant findings. With an Estonian biobank cohort, we applied a genotype-first approach, contacted carriers, and offered return of results with genetic counseling. We evaluated participants’ responses to and the clinical utility of the reporting of actionable genetic findings. Twenty-two of 40 contacted carriers of 17 pathogenic BRCA1/2 variants responded and chose to receive results. Eight of these 22 participants qualified for high-risk assessment based on National Comprehensive Cancer Network criteria. Twenty of 21 counseled participants appreciated being contacted. Relatives of 10 participants underwent cascade screening. Five of 16 eligible female BRCA1/2 variant carriers chose to undergo risk-reducing surgery, and 10 adhered to surveillance recommendations over the 30-month follow-up period. We recommend the return of results to population-based biobank participants; this approach could be viewed as a model for population-wide genetic testing. The genotype-first approach permits the identification of individuals at high risk who would not be identified by application of an approach based on personal and family histories only.Subject terms: Genetic counselling, Population screening, Cancer genomics     

Characteristics associated with genetic counseling referral and BRCA1/2 testing among women in a large integrated health system

BackgroundEvidence shows underutilization of cancer genetics services. To explore the reasons behind this underutilization, this study evaluated characteristics of women who were referred for genetic counseling and/or had undergone BRCA1/2 testing.MethodsAn ovarian cancer risk perception study stratified 16,720 eligible women from the Henry Ford Health System into average-, elevated-, and high-risk groups based on family history. We randomly selected 3,307 subjects and interviewed 2,524 of them (76.3% response rate).ResultsAmong the average-, elevated-, and high-risk groups, 2.3, 10.1, and 20.2%, respectively, reported genetic counseling referrals, and 0.8, 3.3, and 9.5%, respectively, reported having undergone BRCA testing. Personal breast cancer history, high risk, and perceived ovarian cancer risk were associated with both referral and testing. Discussion of family history with a doctor predicted counseling referral, whereas belief that family history influenced risk was the strongest BRCA testing predictor. Women perceiving their cancer risk as much higher than other women their age were twice as likely (95% confidence interval: 2.0–9.6) to report genetic counseling referral.ConclusionIn a health system with ready access to cancer genetic counseling and BRCA testing, women who were at high risk underutilized these services. There were strong associations between perceived ovarian cancer risk and genetic counseling referral, and between a belief that family history influenced risk and BRCA testing.Genet Med advance online publication 19 June 2014     

Next step in molecular genetics of hereditary breast/ovarian cancer: Multigene panel testing in clinical actionably genes and prioritization algorithms in the study of variants of uncertain significance

IntroductionBRCA1 and BRCA2 are the two main genes causing hereditary breast and ovarian cancer (HBOC). However, thanks to the development of Next Generation Sequencing (NGS), other genes linked to this syndrome (CHEK2, BRIP1, ATM and PALB2 among others) can be analysed.Material and methodsan analysis by multigene panel testing was performed in 138 index cases (ICs) from HBOC Spanish families with a previous non-informative result for BRCA1/2. The BRCA Hereditary Cancer Master? Plus kit, including 26 actionable and candidate genes related to HBOC was employed. Once classified, an algorithm was employed to prioritized those variants of unknown significance with a higher risk of having a deleterious effect. Moreover, a mRNA splicing assay was performed for the prioritized VUS c.3402+3A > C in ATM, located at intron 23.ResultsA total of 82 variants were found: 70 VUS and 12 pathogenic or probably pathogenic variants. The diagnostic yield in actionable genes non-BRCA was 7.97% of the total tested ICs. Overall, 19 VUS were prioritized, which meant 27% of the 70 total VUS. RNA analysis of the variant 3402+3A > C confirmed a deleterious impact on splicing.DiscussionThe implementation of a multigene panel in HBOC studied families improved the diagnostic yield, concordant with results obtained in previous publications. Due to the important number of VUS obtained in NGS, the application of a prioritization algorithm is needed in order to select those variants in which it is necessary to conduct further studies.     

Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia

PurposeLarge-scale, population-based biobanks integrating health records and genomic profiles may provide a platform to identify individuals with disease-predisposing genetic variants. Here, we recall probands carrying familial hypercholesterolemia (FH)-associated variants, perform cascade screening of family members, and describe health outcomes affected by such a strategy.MethodsThe Estonian Biobank of Estonian Genome Center, University of Tartu, comprises 52,274 individuals. Among 4776 participants with exome or genome sequences, we identified 27 individuals who carried FH-associated variants in the LDLR, APOB, or PCSK9 genes. Cascade screening of 64 family members identified an additional 20 carriers of FH-associated variants.ResultsVia genetic counseling and clinical management of carriers, we were able to reclassify 51% of the study participants from having previously established nonspecific hypercholesterolemia to having FH and identify 32% who were completely unaware of harboring a high-risk disease-associated genetic variant. Imaging-based risk stratification targeted 86% of the variant carriers for statin treatment recommendations.ConclusionGenotype-guided recall of probands and subsequent cascade screening for familial hypercholesterolemia is feasible within a population-based biobank and may facilitate more appropriate clinical management.     

Diagnosing hereditary cancer predisposition in men with prostate cancer

PurposeWe describe the pathogenic variant spectrum and identify predictors of positive results among men referred for clinical genetic testing for prostate cancer.MethodsOne thousand eight hundred twelve men with prostate cancer underwent clinical multigene panel testing between April 2012 and September 2017. Stepwise logistic regression determined the most reliable predictors of positive results among clinical variables reported on test requisition forms.ResultsA yield of 9.4–12.1% was observed among men with no prior genetic testing. In this group, the positive rate of BRCA1 and BRCA2 was 4.6%; the positive rate for the mismatch repair genes was 2.8%. Increasing Gleason score (odds ratio [OR] 1.19; 95% confidence interval [CI] 0.97–1.45); personal history of breast or pancreatic cancer (OR 3.62; 95% CI 1.37–9.46); family history of breast, ovarian, or pancreatic cancer (OR 2.32 95% CI 1.48–3.65); and family history of Lynch syndrome–associated cancers (OR 1.97; 95% CI 1.23–3.15) were predictors of positive results.ConclusionThese results support multigene panel testing as the primary genetic testing approach for hereditary prostate cancer and are supportive of recommendations for consideration of germline testing in men with prostate cancer. Expanding the criteria for genetic testing should be considered as many pathogenic variants are actionable for treatment of advanced prostate cancer.     

The reckoning: The return of genomic results to 1444 participants across the eMERGE3 Network

PurposeThe goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants.MethodsRoR processes were developed and approved by each eMERGE institution’s internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant’s disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed.ResultsOf the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052).ConclusionThe real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.     

Disparities in uptake of BRCA1/2 genetic testing in a randomized trial of telephone counseling

PurposeAs genetic counseling and testing become more fully integrated into clinical care, alternative delivery models are increasingly prominent. This study examines predictors of genetic testing for hereditary breast/ovarian cancer among high-risk women in a randomized trial of in-person versus telephone-based genetic counseling.MethodsMethods include multivariable logistic regression and interaction analyses.ResultsOf the 669 participants, 600 completed counseling and 523 received test results. As previously reported, participants randomized to telephone counseling were significantly less likely to be tested. In intention-to-treat analyses, completion of counseling and testing was associated with: race/ethnicity (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.20–3.20), perceived stress (OR = 0.89, 95% CI: 0.81–0.98), knowledge (OR = 1.12, 95% CI: 1.02–1.23), and randomization group (OR = 1.48, 95% CI: 1.01–2.16). Further, race/ethnicity moderated the association between randomization group and testing; minority women receiving telephone counseling were least likely to complete testing.ConclusionEvidence for logistical and communication-based explanations for this interaction is presented. The overall increased access made possible with telephone genetic counseling should be considered in light of the possibility that this may also lead to lower rates of testing among high-risk minority women. Additional care should be taken to assess and address potential barriers when services are delivered by telephone.Genet Med17 6, 467–475.     

Informational needs of individuals from families harboring BRCA pathogenic variants: A systematic review and content analysis

PurposePersonalized information is paramount to patient-centered communication and decision-making regarding risk management in hereditary cancer syndromes. This systematic review identified information needs of individuals from families harboring BRCA pathogenic variants and compared findings based on gender (women vs men) and clinical characteristics (patients with cancer vs previvors and BRCA heterozygotes vs untested relatives).MethodsWe screened 8115 studies identified from databases and citation searching. The quality of selected studies was assessed using the Mixed Methods Appraisal Tool. Narrative synthesis was conducted based on content analysis.ResultsFrom 18 selected studies including 1063 individuals, we identified 9 categories of information needs. Risk of bias in the selected studies was moderate. Men, untested relatives, and racial and ethnic minorities were underrepresented. Frequently required information was personalized cancer risk and risk-reducing strategies, including decision-making, family implications of hereditary cancers, psychological issues, and cascade testing. Subgroup analyses showed that information needs depended on gender, personal cancer history, and cascade testing in relatives.ConclusionWe identified comprehensive and detailed informational needs of individuals from families harboring BRCA pathogenic variants and gaps in international guidelines. Needs for personalized information varied based on gender, health, and genetic testing status. Findings of this study have implications for genetic counseling, tailoring educational materials, and personalizing interventions.     

Comparison of risk management strategies between women testing positive for a BRCA variant of unknown significance and women with known BRCA deleterious mutations

PurposeThe aim of this article is to describe cancer risk–reducing behaviors of women with BRCA variants of unknown significance.MethodsA retrospective chart review from 1995 to 2012 identified women with BRCA mutations in a northern California community system. Exclusion criteria included loss of membership/death within 1 year of testing, prior ovarian cancer, or bilateral salpingo-oophorectomy. Primary outcomes were rate of risk-reducing mastectomy and risk-reducing salpingo-oophorectomy.ResultsThe mean age of the 69 variant of unknown significance carriers was 50 vs. 47 years for the 305 women with a deleterious mutation. Women with a variant of unknown significance were followed for a median of 69 months. Among women with a variant of unknown significance, 30% underwent risk-reducing salpingo-oophorectomy and 11% underwent risk-reducing mastectomy, as compared with 74 and 44%, respectively, for women with a deleterious mutation. Women with a deleterious mutation were more likely to undergo surveillance in the first year after testing. The odds ratios are as follows: 2.1 for mammogram, 6.0 for magnetic resonance imaging, 7.7 for Ca-125, and 5.0 for transvaginal ultrasound. Fifty-six percent of women with a variant of unknown significance were reclassified after a median of 39 months, longer than the median time to risk-reducing salpingo-oophorectomy (18.6 months) or risk-reducing mastectomy (20.1 months).ConclusionUptake of risk-reducing strategies among women with a variant of unknown significance is lower than among women with a deleterious mutation. Given the prognostic uncertainty and high rate of reclassification for women with a variant of unknown significance, individualizing counseling and directing efforts toward surveillance, chemoprevention, or salpingectomy are recommended.Genet Med16 12, 896–902.     

Cost-effectiveness analysis of germ-line BRCA testing in women with breast cancer and cascade testing in family members of mutation carriers

PurposeTo evaluate the cost-effectiveness of BRCA testing in women with breast cancer, and cascade testing in family members of BRCA mutation carriers.MethodsA cost-effectiveness analysis was conducted using a cohort Markov model from a health-payer perspective. The model estimated the long-term benefits and costs of testing women with breast cancer who had at least a 10% pretest BRCA mutation probability, and the cascade testing of first- and second-degree relatives of women who test positive.ResultsCompared with no testing, BRCA testing of affected women resulted in an incremental cost per quality-adjusted life-year (QALY) gained of AU$18,900 (incremental cost AU$1,880; incremental QALY gain 0.10) with reductions of 0.04 breast and 0.01 ovarian cancer events. Testing affected women and cascade testing of family members resulted in an incremental cost per QALY gained of AU$9,500 compared with testing affected women only (incremental cost AU$665; incremental QALY gain 0.07) with additional reductions of 0.06 breast and 0.01 ovarian cancer events.ConclusionBRCA testing in women with breast cancer is cost-effective and is associated with reduced risk of cancer and improved survival. Extending testing to cover family members of affected women who test positive improves cost-effectiveness beyond restricting testing to affected women only.     

Genome sequencing as a first-line genetic test in familial dilated cardiomyopathy

PurposeWe evaluated genome sequencing (GS) as an alternative to multigene panel sequencing (PS) for genetic testing in dilated cardiomyopathy (DCM).MethodsForty-two patients with familial DCM underwent PS and GS, and detection rates of rare single-nucleotide variants and small insertions/deletions in panel genes were compared. Loss-of-function variants in 406 cardiac-enriched genes were evaluated, and an assessment of structural variation was performed.ResultsGS provided broader and more uniform coverage than PS, with high concordance for rare variant detection in panel genes. GS identified all PS-identified pathogenic or likely pathogenic variants as well as two additional likely pathogenic variants: one was missed by PS due to low coverage, the other was a known disease-causing variant in a gene not included on the panel. No loss-of-function variants in the extended gene set met clinical criteria for pathogenicity. One BAG3 structural variant was classified as pathogenic.ConclusionOur data support the use of GS for genetic testing in DCM, with high variant detection accuracy and a capacity to identify structural variants. GS provides an opportunity to go beyond suites of established disease genes, but the incremental yield of clinically actionable variants is limited by a paucity of genetic and functional evidence for DCM association.     

Timing of BRCA1/BRCA2 genetic testing in women with ovarian cancer

PurposeTo determine when, in reference to the course of their treatment, women with ovarian cancer are seen for genetic counseling, as well as to determine what factors influence this timing.MethodsSingle institution retrospective chart review of patients with ovarian cancer who underwent BRCA1/BRCA2 genetic testing.ResultsThirty-three percent of our sample (n = 100) were seen for genetic counseling after ovarian cancer recurrence. In four cases, genetic test results were disclosed to next of kin. Thirty percent of women seen for genetic counseling after recurrence received their initial treatment elsewhere. Women with a history of breast cancer were significantly more likely to be seen for genetic counseling at an earlier phase of their treatment than women with no history of breast cancer.ConclusionWe found that one third of patients with ovarian cancer who underwent genetic testing were seen for initial genetic counseling after disease recurrence. In some cases, genetic counseling took place during the end of life care, with genetic test results disclosed to next of kin. Given the poor prognosis of women with recurrent ovarian cancer, we advocate providing genetic counseling at the time of initial ovarian cancer treatment both in comprehensive cancer centers and in community oncology settings.     

Mainstream genetic testing for breast cancer patients: early experiences from the Parkville Familial Cancer Centre

The demand for genetic testing of hereditary breast cancer genes such as BRCA1 and BRCA2 has continued to increase with the lowering costs of testing, raised awareness in the general public, and implications for breast cancer treatment when a patient is identified as having a germline pathogenic variant. Historically within Australia, patients affected by high genetic risk breast cancers have been referred to a familial cancer centre (FCC) for assessment and testing, resulting in wait times for an appointment for pre- and post-test genetic counselling and an increased demand on the public-funded FCC. To improve patient access and pace of genetic testing, as well as refocus FCC resources, a mainstream clinical genetic testing program was rolled out in September 2017 through the Parkville FCC (PFCC) in Australia at 10 hospital sites. This program enables specialist doctors of eligible patients affected by breast cancer to arrange genetic testing directly at an oncology/surgical appointment and follow up the results as part of the patients’ routine clinical care. In this model, the specialist doctor is responsible for any treatment implications of the genetic test result, and the PFCC is responsible for result interpretation, future cancer risk, family cascade testing and segregation testing where warranted. To date the program has had successful uptake, a notable pathogenic variant detection rate, reduced the burden on the PFCC enabling a reallocation of resources and has streamlined the process of genetic testing for eligible patients. Investigation into the patient and clinician experiences of the mainstream program is required.Subject terms: Genetic testing, Genetic counselling, Cancer genetics, Breast cancer, Genetic counselling     

Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer

PurposeClinical testing for germ-line variation in multiple cancer susceptibility genes is available using massively parallel sequencing. Limited information is available for pretest genetic counseling regarding the spectrum of mutations and variants of uncertain significance in defined patient populations.MethodsWe performed massively parallel sequencing using targeted capture of 22 cancer susceptibility genes in 278 BRCA1/2-negative patients with early-onset breast cancer (diagnosed at younger than 40 years of age).ResultsThirty-one patients (11%) were found to have at least one deleterious or likely deleterious variant. Seven patients (2.5% overall) were found to have deleterious or likely deleterious variants in genes for which clinical guidelines exist for management, namely TP53 (4), CDKN2A (1), MSH2 (1), and MUTYH (double heterozygote). Twenty-four patients (8.6%) had deleterious or likely deleterious variants in a cancer susceptibility gene for which clinical guidelines are lacking, such as CHEK2 and ATM. Fifty-four patients (19%) had at least one variant of uncertain significance, and six patients were heterozygous for a variant in MUTYH.ConclusionThese data demonstrate that massively parallel sequencing identifies reportable variants in known cancer susceptibility genes in more than 30% of patients with early-onset breast cancer. However, only few patients (2.5%) have definitively actionable mutations given current clinical management guidelines.Genet Med17 8, 630–638.     

Overview of hereditary breast and ovarian cancer (HBOC) guidelines across Europe

Hereditary breast and ovarian cancer (HBOC) is a syndrome defined by an increased risk of developing breast and/or ovarian cancer most commonly due to germline disease-causing variants in the BRCA1 and BRCA2 genes, but also other causative genes such as PALB2, ATM and CHEK2. As genetic testing becomes more prevalent and new clinical data emerge, updates of national guidelines are required to incorporate these advances in our knowledge. The aim of this work is to review the guidelines for HBOC genetic testing and clinical surveillance across European countries, mostly affiliated to the European Reference Network (ERN) for Genetic Tumor Risk Syndroms (GENTURIS). Young onset breast cancer (BC), triple negative phenotype, or bilateral BC are considered as criteria for genetic testing in all, with differences in age limits. Testing of invasive epithelial non-mucinous ovarian cancer is also universally accepted. While breast magnetic resonance imaging (MRI) is consistently recommended in high-risk individuals, age of onset for mammograms differ between 30 and 40 years. Risk-reducing mastectomy is commonly offered as an option, while risk-reducing salpingo-oophorectomy is universally recommended. The largest differences are observed with respect to ovarian surveillance prior to risk-reducing salpingo-oophorectomy and in breast surveillance for carriers of non-BRCA1/2 genes. These differences in national guidelines reflect the variations in clinical consensus that may be reached in the absence of consistent evidence for some recommendations.     

Clinical implementation of genetic testing in adults for hereditary hematologic malignancy syndromes

PurposeAs research on hereditary hematologic malignancy syndromes (HHMS) are accumulating, cancer genetics clinics are identifying more adult hematology patients with an inherited component to their disease. However, investigations for HHMS are complex, and there is no formal consensus on genetic testing criteria.MethodsWe developed genetic testing criteria for adult hematology patients through a comprehensive literature review and our experience at the Princess Margaret Cancer Centre. We validated our criteria by applying them retrospectively to patients referred to our clinic for HHMS assessment.ResultsOur genetic testing criteria are comprehensive of myeloid malignancies, lymphoid malignancies, and bone marrow failure, including age at diagnosis, family history, and genetic test results in blood and bone marrow. Of the 104 patients who met the criteria, 26% had at least 1 actionable variant in any gene associated with an increased risk of cancer and 13% had an actionable variant resulting in an HHMS diagnosis. A total of 15 patients had incidental findings, including 11 patients with a pathogenic variant associated with carrier status for an autosomal recessive disorder and 4 patients with a mosaic result.ConclusionOur high gene positivity rate shows the utility of a broad approach to germline testing in an adult hematology population.     

Genetic testing for BRCA1 and BRCA2 in the Province of Ontario

In 2001, genetic testing for BRCA1 and BRCA2 was introduced in Ontario, for women at high‐risk of breast or ovarian cancer. To date over 30,000 individuals have been tested throughout Ontario. Testing was offered to all Ontario residents who were eligible under any of 13 criteria. We report the results of tests conducted at Mount Sinai Hospital from 2007 to 2014. A total of 4726 individuals were tested, 764 (16.2%) were found to carry a pathogenic variant (mutation). Among 3684 women and men who underwent testing without a known familial BRCA mutation, 331 (9.0%) were found to carry a mutation. Among 1042 women and men tested for a known family mutation, 433 (41.6%) were positive. There were 603 female mutation carriers, of these, 303 were affected with breast or ovarian cancer (50%) and 16 with another cancer (2.3%). Of 284 unaffected female carriers, 242 (85%) were tested for a known family mutation and 42 (15%) were the first person in the family to be tested. By placing greater emphasis on recruiting unaffected female relatives of known mutation carriers for testing, greater than one‐half of newly identified carriers will be unaffected.     

Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families

PurposeIntegration of gene panels in the diagnosis of hereditary breast and ovarian cancer (HBOC) requires a careful evaluation of the risk associated with pathogenic or likely pathogenic variants (PVs) detected in each gene. Here we analyzed 34 genes in 5131 suspected HBOC index cases by next-generation sequencing.MethodsUsing the Exome Aggregation Consortium data sets plus 571 individuals from the French Exome Project, we simulated the probability that an individual from the Exome Aggregation Consortium carries a PV and compared it to the estimated frequency within the HBOC population.ResultsOdds ratio conferred by PVs within BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, BRIP1, CHEK2, and MSH6 were estimated at 13.22 [10.01–17.22], 8.61 [6.78–10.82], 8.22 [4.91–13.05], 4.54 [2.55–7.48], 5.23 [1.46–13.17], 3.20 [2.14–4.53], 2.49 [1.42–3.97], 1.67 [1.18–2.27], and 2.50 [1.12–4.67], respectively. PVs within RAD51C, RAD51D, and BRIP1 were associated with ovarian cancer family history (OR = 11.36 [5.78–19.59], 12.44 [2.94–33.30] and 3.82 [1.66–7.11]). PALB2 PVs were associated with bilateral breast cancer (OR = 16.17 [5.48–34.10]) and BARD1 PVs with triple-negative breast cancer (OR = 11.27 [3.37–25.01]). Burden tests performed in both patients and the French Exome Project population confirmed the association of PVs of BRCA1, BRCA2, PALB2, and RAD51C with HBOC.ConclusionOur results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of HBOC and suggest that the other genes are involved in an oligogenic determinism.     

BRCA1 in the family: A case description of the psychological implications

Our experience with the first family in the Netherlands for whom predictive DNA-testing for Hereditary Breast and Ovarian Cancer (HBOC) became an option is described. This serves to illustrate the complex emotional impact on a family as a whole, and upon the members separately, of becoming aware that breast and ovarian cancer is hereditary, and the implications of undergoing predictive testing. All family members received genetic counseling and were offered pre- and post-test psychological follow-up. We observed two important roles within the family. One member became “the messenger of the news” informing the relatives of the hereditary character of cancer in the family. Another was “the first utilizer” of the new options; namely, the predictive DNA-test and preventive surgery. This first utilizer became the example to the rest of the family. Decisions made about preventive treatment (prophylactic ovariectomy and/or mastectomy) were based on the experiences within the family, whether one identified with an affected family member with breast or with ovarian cancer. The actions and reactions perceived were illustrative of what kind of support provisions should be provided in addition to the genetic and oncological counseling for HBOC. Moreover HBOC should be considered both as an individual and a family problem and be treated as such in genetic counseling. Am. J. Med. Genet. 71:63–71, 1997. © 1997 Wiley-Liss, Inc.     

The impact of variant classification on the clinical management of hereditary cancer syndromes

PurposeThe reclassification of genetic variants poses a significant challenge for laboratories and clinicians. Variant review has resulted in the reclassification of variants of unknown significance as well as the reclassification of previously established pathogenic and likely pathogenic variants. These reclassifications have the potential to alter the clinical management of patients with hereditary cancer syndromes.MethodsResults were reviewed for 1694 patients seen for hereditary cancer evaluation between August 2012 and May 2017 to determine the frequency and types of variant reclassification. Patients with reclassifications with high potential for impact were monitored for alterations in organ surveillance, prophylactic surgery, and cascade testing.ResultsOne hundred forty-two variants were reclassified representing 124/1694 (7.3%) patients; 11.3% of reclassifications (16/142) had a high potential for clinical impact with 94% (15/16) altering clinical management of patients with 56% (9/16) changing multiple areas of management.ConclusionWhile reclassifications are rare, the impact on clinical management is profound. In many cases, patients with downgraded pathogenic/likely pathogenic variants had years of unnecessary organ surveillance and underwent unneeded surgical intervention. In addition, cascade testing misidentified those at risk for developing cancers, thereby altering the management across generations. The frequency and types of alterations to clinical management highlight the need for timely variant reclassification.