clinical dossier - amazon s3€¦ · gene testing.10 then in 2016, its high risk colorectal...

1CLINICAL DOSSIER

ClinicalDossier

2CLINICAL DOSSIER

TABLE OF CONTENTS

Executive Summary A New Clinical Dilemma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Solution: Clinically Targeted Hereditary Cancer Multi-Gene Panel Test . . . . . . . . . . . . . . . . . . . . . . .

Intended Use Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analytical Validity Technical Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Clinical Utility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Gene Table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Gene Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Medical Management Tool (MMT) Sample report - Positive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sample report - Negative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sample report - Negative with Variant of Unknown Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Societal Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Health Economics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Supporting Publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

myVision® Variant Classification Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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3CLINICAL DOSSIER

Hereditary cancer testing has been utilized for decades to ensure highest risk patients were identified and offered medical management options to prevent cancer or reduce the likelihood of subsequent cancer diagnosis. Yet, the approach of testing for a small subset of genes for individual hereditary cancer syndromes is known to omit many individuals within this same highest risk population who would benefit from these interventions.

Data have emerged demonstrating that there are many genes in addition to BRCA1 and BRCA2 that are associated with an increased risk for breast cancer and ovarian cancer.1-3 Known as genetic heterogeneity (different genes leading to the same cancers), it is now recognized through an increasing amount of published literature that the same type of cancer or family history of cancer can be caused by mutations in different genes. As well, the characteristics of one hereditary cancer syndrome can overlap with those of another syndrome.4-7 With the technological advances in molecular diagnostics, testing for these additional genes can be performed simultaneously with BRCA1 and BRCA2.

Over the past 20 years, over 2 million patients have undergone hereditary cancer testing.8 Approximately 10% of breast cancer is known to be hereditary.9 Patients who tested positive indicating a diagnosis of hereditary cancer risk received individualized guideline-based medical management.10-12 The remaining 90% of patients tested negative for a single syndrome. Despite having concerning histories that met the NCCN criteria, this large patient population may be over- or under-managed creating immediate and long-term waste in healthcare spend. Without the complete information of patients’

hereditary cancer risk, clinicians are not able to assess a patient for proper medical management. An incomplete diagnosis will lead to delays, which the Institute of Medicine’s (IOM) Improving Diagnosis and Healthcare states is a medical error. According to the IOM, a delayed diagnosis should be defined by recognizing “[…] the number of times each year that an opportunity to make a diagnosis occurred [the denominator], how often the diagnosis was not made in a timely and accurate manner [numerator a], and how often the explanation was not communicated to the patient [numerator b].”13 Based on the IOM’s example, testing in a step-wise fashion increases the chances of a delayed diagnosis and medical error. The impact upon the patient, which the IOM emphasizes, is that there would be lost opportunities for results to impact medical management. Additionally, testing in this step-wise fashion creates a number of unintended consequences for the payer and the patient, including but not limited to increased cost, multiple prior-authorization requests, potential appeals, and lost opportunities for results to impact medical management (surgery already completed).10,14

Given that many additional genes can contribute to hereditary cancer risk, it is important to consider new testing policies in order to most effectively and cost-efficiently manage the 90% of patients still in need of a more comprehensive result.10 NCCN initiated this change when in 2014 it added to its Hereditary Breast and Ovarian Cancer syndrome (HBOC) guidelines that these patients should be considered for multi-gene testing.10 Then in 2016, its high risk colorectal hereditary cancer guidelines incorporated multi-gene testing to reflect the genetic heterogeneity discoveries.12

A NEW CLINICAL DILEMMA

“With the technological advances in molecular diagnostics, testing for these additional genes can be performed

simultaneously with BRCA1 and BRCA2 ”

EXECUTIVE SUMMARY

4CLINICAL DOSSIER

Myriad myRisk Hereditary Cancer analyzes 28 genes that have been shown to increase the risk for hereditary cancer. Most importantly, myRisk does not expand the intended use population. The same patient population who meet NCCN testing criteria for BRCA or Lynch syndrome testing is targeted, while providing more comprehensive genetic risk assessment.

The power of the myRisk solution is multi-faceted. One key feature is the test result that providers and patients receive. Instead of a test result only indicating whether the patient is positive or negative for a gene mutation, the myRisk test provides a clinical decision support tool. This tool outlines patients’ cancer risks and the medical management recommendations endorsed by societal guidelines. Uniquely, all reports are based upon the individual’s genetic test result and family history, when provided. Patients and providers utilize this tool to tailor management plans targeted to patients’ specific cancer risks.

Variants of uncertain significance (VUS) are inevitable outcomes of genetic testing. An implicit benefit of myRisk is the strength and integrity of its myVision® Variant Classification Program. myVision is Myriad Genetic Laboratories’ commitment to accurately identify and interpret variants to promote responsible healthcare spending and medical management.15 A dedicated staff of genetic experts analyzes and reclassifies genetic variants to confidently catalogue variants as deleterious disease-causing mutations or benign. For this group of experts to be successful Myriad developed proprietary tools that augment accuracy and speed to classify variants. These tools are validated in peer-reviewed publications that demonstrate a greater than 99% confidence in the statistical methods that are utilized to classify variants.16,17

With myRisk also comes Myriad’s lifetime commitment to inform providers and patients of all reclassification changes. This new information is essential to patients’ medical management and their overall care. With this commitment, Myriad pledges to provide the right information to the right patient at the right time — all with the intention to mitigate overall healthcare spend while

improving personalized medical outcomes. Myriad’s lifetime commitment extends to payers through its promise not to charge for update testing ordered by a physician for patients who have paid for and received a negative myRisk test result previously, upon new genes added to the myRisk panel. Myriad recognizes that as science continues to progress its understanding of hereditary cancer, the myRisk panel will also evolve in order to provide the most clinically actionable results for patients. Myriad believes patients who have already had coverage for myRisk testing but received a negative result should benefit from scientific advances in hereditary cancer through update testing.

SUMMARY Mutations in the genes included in Myriad myRisk are documented to result in hereditary cancer risks that are great enough to warrant changes in management supported by medical societal recommendations. myRisk is proven to increase the identification of mutation carriers within the same NCCN recommended testing population.1,2 myRisk is a unique, multi-faceted solution to meet NCCN and other medical societal recommendations for hereditary cancer genetic testing.

THE SOLUTION:CLINICALLY TARGETED HEREDITARY CANCER MULTI-GENE PANEL TEST

MYRIAD EXPERIENCETwo decades of testing ~2 million patients• Provides the most accurate lab results • Optimizes lab processes and services

ACCURACY• Supports claims with publications• Testing volume drives the largest classification database in the industry• Development of variant classification tools based on testing volume

SERVICE• Physician and patient education• Innovative contracting solutions• Collaborative business solutions

UTILIZATION MANAGEMENT• 12,000 tests cancelled in 2016 due to unmet testing criteria• Test and bill for appropriate test components• Ensure no retesting of previously tested patients

EXECUTIVE SUMMARY

5CLINICAL DOSSIER

The target population for the Myriad myRisk Hereditary Cancer test is patients meeting current medical policy or testing criteria for HBOC or hereditary colon cancer syndromes (Lynch syndrome and familial polyposis syndromes). Studies of patients appropriate for HBOC or Lynch syndrome testing have shown a 40-60% relative increase in clinical sensitivity with myRisk compared to the single syndrome approach for HBOC or Lynch syndrome.1-3

Table 1: In 3 studies of patients meeting criteria for HBOC or Lynch syndrome, the Myriad myRisk approach to testing identified more mutations compared to the single syndrome approach.

Note: Single syndrome testing = BRCA1/2 and Lynch syndrome testing

INTENDEDUSE POPULATION

LIFETIME COMMITMENT• Patients who paid for and received negative myRisk results will not be charged for additional gene updates• Patients who paid for and received negative BRCA1/2 results only pay for myRisk update testing• Providers receive amended reports for their patients with a VUS result •>300 amended reports sent weekly •>40 variants reclassified each month

Myriad myRisk™ Clinical Summary • 8 •

Langer et al: 6

In a population of ovarian cancer patients, using the Myriad myRisk™ Hereditary Cancer test, 40% of carriers

were found to have a mutation in clinically actionable genes other than BRCA1 and BRCA2. Overall, 63% more

clinically actionable mutations were detected with Myriad myRisk™ Hereditary Cancer versus what would have

been identified with BRACAnalysis® testing alone.

An additional study with the Myriad myRisk™ Hereditary Cancer test in this target population evaluated the rationale

for a pan-cancer panel approach by assessing the spectrum of mutations in genes outside the cancer-specific genes

suspected based on clinical history. The study is summarized below and full details are included in Appendix B.

Kaushik et al: 19

In a population of patients meeting the National Comprehensive Cancer Network® (NCCN®) criteria for Lynch

syndrome testing, approximately 30% of identified mutations were found in clinically actionable genes that are

associated with cancers other than colorectal or endometrial cancers. In a separate population of patients meeting

NCCN® criteria for Hereditary Breast and Ovarian Cancer syndrome testing, about 6% of identified mutations

were found in either mismatch repair genes associated with Lynch syndrome or other clinically actionable genes

associated with cancers other than breast or ovarian cancer.

Figure 3: In three studies of patients meeting testing criteria for HBOC or Lynch Syndrome, the Myriad myRiskTM approach to testing identified more mutations compared to the single syndrome approach, translating into a 40-60% relative increase in clinical sensitivity with the Myriad myRiskTM Hereditary Cancer test.

*BRCA1/2†Lynch syndrome

1Prevalence of Gene Mutations Among Hereditary Breast and Ovarian Cancer Patients Using a 25 Gene Panel, Nadine Tung et al. Presented at ACMG in March 2014

2Multi-gene panel testing in patients suspected to have Lynch syndrome, Matthew B. Yurgelun et al. Presented at ASCO June 2014

3A Study of Ovarian Cancer Patients Tested With a 25-gene Panel of Hereditary Cancer Genes, Lucy R. Langer et al. Presented at ASCO June 2014

moremutations

moremutations

moremutations

Mutations Identified

in Patients with

Breast Cancer1

Mutations Identified

in Patients with

Ovarian Cancer3

79

165

43

114

42

62

Mutations Identified in

Patients Suspicious

for LS2

104

157Myriad myRisk™

Single syndrometesting* †

244

6CLINICAL DOSSIER

Judkins T, et al. Development and analytical validation of a 25-gene next generation sequencing panel that includes the BRCA1 and BRCA2 genes to assess hereditary cancer risk. BMC Cancer 2015 Apr 2; 15:215.

NGS and Sanger sequencing were 100% concordant for the 3,923 collective variants across all genes.

Sanger DNA sequencing has been the gold standard for detecting genetic variants for many years. However, Sanger sequencing is labor-intensive and costly for the analysis of multiple genes. Next generation sequencing (NGS) allows for efficient analysis of multiple genes simultaneously; however, an equivalent sensitivity and specificity must be demonstrated. While a number of NGS panel tests are currently available for clinical use, not all laboratories offering this testing have provided data regarding optimization of assay design, test validation, and the accuracy of result interpretation.

Myriad recognizes that optimized assay design and validation are critical to maximize the analytical sensitivity and specificity of NGS assays, and to ensure high quality interpretation for clinical decision making. The Myriad myRisk validation study demonstrated 100% concordance between Myriad myRisk Hereditary Cancer next generation sequencing and the gold standard Sanger sequencing with an analytical sensitivity of >99.92% (lower bound of the 95% confidence interval) and 100% concordance in large rearrangement validation. This data provides confidence to test users that deleterious gene mutations will not be missed by shifting to Myriad’s new technology. The complete technical specifications of the test include a description of the validation study, as well as information on test methodology, performance characteristics, and interpretive criteria.

Myriad myRisk is supported by a number of peer-reviewed publications addressing analytical validity, clinical validity, and clinical utility, with numerous studies demonstrating the increased sensitivity of using panel testing to assess hereditary cancer risk across various tumor types.18-27

ANALYTICALVALIDITY

TECHNICAL SPECIFICATIONS

http://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1224-y

https://myriad.com/managed-care/myriad-myrisk/

7CLINICAL DOSSIER

Yurgelun MB, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J of Clin Onc 2017 Apr 1;35(10):1086-1095.

Panel testing may replace targeted genetic testing.

The rationale for the myRisk test is the ability to increase the identification of clinically-actionable mutations in patients, many of which would not otherwise be detected. Among patients who meet accepted criteria for HBOC, testing for only BRCA1/BRCA2 mutations does not address the potential overlap in clinical presentations associated with mutations in numerous genes. The consequences of missing mutation carriers are significant; including the unnecessary diagnosis of a second cancer due to under-management of the patient’s presenting cancer in the absence of genetic test results. Therefore, testing patients who are already at risk for HBOC using a panel approach will more broadly target potentially causative genes and improve clinical sensitivity for hereditary cancer diagnoses.

Coffee B, et al. Detection of somatic variants in peripheral blood lymphocytes using a next generation sequencing multigene pan cancer panel. Cancer Genetics 2017; 211:5-8.

Pearlman R, et al. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol 2016 Dec. doi:10.1001/jamaoncol.2016.5194.

Langer LR. Hereditary cancer testing in patients with ovarian cancer using a 25- gene panel. JCSO 2016 July; 14:314-19.

Tung N, et al. Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol 2016 May 1; 34(13):1460-8.

Saam J, et al. Patients tested at a laboratory for hereditary cancer syndromes show an overlap for multiple syndromes in their personal and familial cancer histories. Oncology 2015; 89(5):288-93.

Yorczyk A, Robinson LS, Ross TS. Use of panel tests in place of single gene tests in the cancer genetics clinic. Clin Genet 2015 Sep;88(3):278-82.

Yurgelun MB, et al. Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology 2015 Sep; 149(3):604-13.

Tung N, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 2015 Jan 1; 121(1):25-33.

CLINICALVALIDITY

Figure 1: Multi-gene testing captures additional patients who would have otherwise tested negative for a single syndrome, affecting medical management.1-3

1,781 Patients with breast cancer32% pathogenic mutations identified were outside BRCA2

1,260 Patients suspicious for Lynch syndrome27% pathogenic mutations identified were outside of genes associated with Lynch syndrome

3.088 Patients with ovarian cancer27% pathogenic mutations identified were outside BRCA 1/2 and genes associated with Lynch syndrome

Lynch syndrome

http://www.mdedge.com/jcso/article/110784/gynecologic-cancer/hereditary-cancer-testing-patients-ovarian-cancer-using-25

http://www.ncbi.nlm.nih.gov/pubmed/26976419

http://www.karger.com/Article/FullText/437307

http://onlinelibrary.wiley.com/doi/10.1111/cge.12488/abstract%3Bjsessionid%3DE87C5CBD3153BD7FD00544A39FC6C5AD.f02t02

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550537/

http://onlinelibrary.wiley.com/doi/10.1002/cncr.29010/abstract%3Bjsessionid%3DA1C3293A9AC6559EF468A6EFC574A4AE.f01t03

http://ascopubs.org/doi/abs/10.1200/JCO.2016.71.0012

http://www.sciencedirect.com/science/article/pii/S2210776217300133%3Fnp%3Dy

http://jamanetwork.com/journals/jamaoncology/fullarticle/2593042

8CLINICAL DOSSIER

Buys SS, et al. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer 2017. 123(10): 1721-30. doi:10.1002/cncr.30498.

Multigene testing is likely to alter cancer risk assessment, clinical management, and familial testing recommendations.

Mutations in the genes included in the Myriad myRisk Hereditary Cancer test are associated with cancer risks substantial enough to warrant changes in medical management. Reduced cancer rates and improved outcomes have been documented for guideline-based management of the common hereditary cancer syndromes such as HBOC and Lynch syndrome.31,32 For example, Domchek et al. found that BRCA1/BRCA2 mutation carriers who underwent risk-reducing salpingo-oophorectomy had a significantly lower risk of ovarian cancer, first breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality compared to mutation carriers who did not undergo risk-reducing surgery.31 In a population of patients with Lynch syndrome, those who followed recommended frequent colonoscopy screening guidelines had a greater than 50% reduction in colorectal cancer and a 65% reduction in mortality.32 It is expected that analogous guideline-based management of more recently discovered syndromes, based on level of cancer risk, will similarly result in reduced cancer rates and improved outcomes. The Myriad myRisk Hereditary Cancer test results include a clinical decision support tool with summaries of guideline-endorsed management changes that differ from recommendations for the general population.

Multiple studies demonstrate the increased number of mutation carriers identified for potential changes in their medical management with a panel than a syndrome-specific test.22,24,25 The clinical utility of myRisk was evaluated through a study of 1,111 patients undergoing testing.33 Providers were surveyed pre- and post-test regarding their management recommendations for breast, ovarian, endometrial and colorectal cancers for each patient being tested. Over 74% of providers used both the

Giri VN, Obeid E, Gross L, et al. Inherited mutations in men undergoing multigene panel testing for prostate cancer: emerging implications for personalized prostate cancer genetic evaluation [published online May 4, 2017]. JCO Prec Oncol. doi: 10.1200/PO.16.00039.

Rosenthal ET, et al. Increased identification of candidates for high-risk breast cancer screening through expanded genetic testing. J Am Coll Radiol 2017; 14:561-8. doi:10.1016/j.jacr.2016.10.003.

Saam J, et al. Hereditary cancer-associated mutations in women diagnosed with two primary cancers: an opportunity to identify hereditary cancer syndromes after the first cancer diagnosis. Oncology 2015; 88(4):226-33.

Desmond A, et al. Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncol 2015; 1(7):943-51.

Howarth DR, et al. Initial results of multigene panel testing for hereditary breast and ovarian cancer and Lynch syndrome. Am Surg 2015 Oct; 81(10):941-4.

CLINICALUTILITY

http://onlinelibrary.wiley.com/doi/10.1002/cncr.30498/abstract

http://www.ajmc.com/newsroom/multigene-testing-can-inform-predisposition-to-inherited-prostate-cancer?utm_term=Multigene%20Testing%20Can%20Inform%20Predisposition%20to%20Inherited%20Prostate%20Cancer&utm_campaign=AJMC%20MC%20Minute%205-23-17&utm_content=email&utm_source=Act-On+Software&utm_medium=email&cm_mmc=Act-On%20Software-_-email-_-White%20House%20Budget%20to%20Cut%20Medicaid%3A%20Managed%20Care%20Minute%2C%20May%2023%2C%202017-_-Multigene%20Testing%20Can%20Inform%20Predisposition%20to%20Inherited%20Prostate%20Cancer

http://www.sciencedirect.com/science/article/pii/S1546144016310328%3Fvia%253Dihub

http://www.karger.com/Article/FullText/368836


https://www.ncbi.nlm.nih.gov/pubmed/26463285

9CLINICAL DOSSIER

CLINICAL UTILITY

Rosenthal ET, et al. Outcomes of clinical testing for 76,000 patients utilizing a panel of 25 genes associated with increased risk for breast, ovarian, colorectal, endometrial, gastric, pancreatic, melanoma and prostate cancers. Scientific poster presented at the American Society for Clinical Oncology Annual Meeting in Chicago, IL, June 2015.

Myriad myRisk Hereditary Cancer genetic test result and the myRisk Medical Management Tool (MMT) to make management decisions. Patients with positive genetic test results had management changes 78% of the time and patients with negative test results had management changes in approximately 25% of cases based on information gained from the myRisk MMT.

A recent analysis evaluated the distribution of mutations identified in a cohort of 76,574 patients that received Myriad myRisk testing, which represents the largest clinical data set for panel testing in the United States. Compared with testing for BRCA1 and BRCA2 alone, the Myriad myRisk test led to a 2.3 fold increase in the number of patients identified with a mutation. Approximately 90% of pathogenic mutations identified were in genes for which there are professional society guidelines for modification of medical management.29

Langer LR, et al. 25-Gene panel testing and integrated risk management tool impacts medical management in hereditary cancer syndrome evaluation. Scientific poster presented at the American Society for Clinical Oncology Annual Meeting in Chicago, IL, June 2014.

Myriad myRisk Clinical ExperienceClinical Indications11,12,19,29,34

• ~94% of tested patients meet the NCCN testing criteria for HBOC or Lynch syndrome

• 98% of pathogenic variants are in genes with explicit professional society management

recommendations

• myRisk testing increases clinical sensitivity up to 50% compared to single syndrome testing

Figure 2: Distribution of mutations identified (~76,000 patients tested)

https://myriad.com/managed-care/myriad-myrisk/clinical-utility/

https://myriad.com/managed-care/myriad-myrisk/clinical-utility/

10CLINICAL DOSSIER

GENE TABLEThe Myriad myRisk test analyzes genes associated with well-defined cancer syndromes, such as HBOC and Lynch syndromes, genes for which the contribution to related cancers is well understood, and newly discovered genes clearly associated with similar patterns of cancer. Genes were selected based on published data demonstrating a level of cancer risk that would be clinically actionable. Genes were not included based upon speculation, hypothetical associations, biochemical studies in the absence of clinical data, small elevations of cancer risk, or genome wide association studies (GWAS). Overall,

genes included in the myRisk test meet the following criteria:

• Established heritable contribution to at least one of the cancers of focus • Association with overlapping hereditary cancer syndromes • Gene-associated cancer risk of at least 2-3 times the general population • Increased cancer risk based on guidelines and/or 60+ publications• Change in management inferred based on risk level

Genes Breast Ovarian Colorectal Endometrial Melanoma Pancreatic Gastric Prostate Other

BRCA1, BRCA2 • • • • •

MLH1, MSH2, MSH6PMS2,EPCAM • • • • • • •

APC, BMPR1A, SMAD4 • • • •

MUTYH Biallelic • •

MUTYH Monoalleic •

CDKN2A (p16INK4a), CDKN2A (p14ARF),CDK4

• •

Figure 3: Myriad myRisk Gene Table

https://new.myriadpro.com/products/myriad-myrisk/myrisk-gene-table/

11CLINICAL DOSSIER

GENE TABLE

Genes Breast Ovarian Colorectal Endometrial Melanoma Pancreatic Gastric Prostate Other

TP53 • • • • • • • • •

PTEN • • • • •

STK11 • • • • • • •

CDH1 • • •

PALB2, ATM • •

CHECK2 • •

NBN • •

BARDI •

BRIP1, RAD51C, RAD51D •

GREM1, POLE, POLD1 •

12CLINICAL DOSSIER

GENE SELECTIONCancer Site Focus

Heritable contribution

Association with overlapping syndromes

PenetranceCancer risk is at least 2- to 3-fold over the general population OR

Absolute cancer risk is ≥ 5%

Clinically ActionableIncreased cancer risk based on guidelines and/or 60+ publications

Change in management inferred based on risk level

Figure 4: Genes on the myRisk hereditary cancer panel

13CLINICAL DOSSIER

MEDICAL MANAGEMENT

TOOLThe myRisk result provides a clinical decision support tool incorporating guideline-based medical management recommendations tailored to an

individual’s genetic result. This tool is designed to initiate a shared decision-making conversation to develop an appropriate medical management plan.

Figure 5: Sample report - Positive with medical management changes

CONFIDENTIAL*52530060*

52530060

Integrated BRACAnalysis® with Myriad myRisk® Hereditary Cancer

myRisk Genetic ResultRECEIVING HEALTHCARE PROVIDERTest HCP, MDTest Medical Center123 Main StTestville, TX 55555

SPECIMENSpecimen Type: BloodDraw Date: Dec 02, 2016Accession Date: Dec 02, 2016Report Date: Dec 05, 2016

PATIENTName: Pt Last Name,

Pt First NameDate of Birth:Patient ID: Patient idGender: FemaleAccession #: 07001396-BLDRequisition #: 7001396

RESULT: POSITIVE - CLINICALLY SIGNIFICANT MUTATION IDENTIFIEDNote: "CLINICALLY SIGNIFICANT," as defined in this report, is a genetic change that is associated with thepotential to alter medical intervention.

GENE INTERPRETATIONMUTATION

MSH6 c.xxxxx (p.xxx*)Heterozygous

High Cancer RiskThis patient has Lynch syndrome/Hereditary Non-Polyposis ColorectalCancer (HNPCC).

DETAILS ABOUT: MSH6 c.xxxxx (p.xxx*): NM_000179.2; (aka: xxxxx)

Functional Significance: Deleterious - Abnormal Protein Production and/or FunctionThe heterozygous germline MSH6 mutation c.xxxx is predicted to result in the premature truncation of the MSH6 protein at amino acid positionxxx (p.xxx*).

Clinical Significance: High Cancer RiskThis mutation is associated with increased cancer risk and should be regarded as clinically significant.

ADDITIONAL FINDINGS: NO VARIANT(S) OF UNCERTAIN SIGNIFICANCE (VUS) IDENTIFIED

Details About Non-Clinically Significant Variants: All individuals carry DNA changes (i.e., variants), and most variants do not increase anindividual's risk of cancer or other diseases. When identified, variants of uncertain significance (VUS) are reported. Likely benign variants (FavorPolymorphisms) and benign variants (Polymorphisms) are not reported and available data indicate that these variants most likely do not causeincreased cancer risk. Present evidence does not suggest that non-clinically significant variant findings be used to modify patient medicalmanagement beyond what is indicated by the personal and family history and any other clinically significant findings.

Variant Classification: Myriad's myVisionTM Variant Classification Program performs ongoing evaluations of variant classifications. In certaincases, healthcare providers may be contacted for more clinical information or to arrange family testing to aid in variant classification. When newevidence about a variant is identified and determined to result in clinical significance and management change, that information will automatically bemade available to the healthcare provider through an amended report.

myRisk Genetic Result: Page 1 of 2

© 2016 Myriad Genetics, Inc. | 320 Wakara Way, Salt Lake City, Utah 84108 | PH: 1-800-469-7423 FX: 801-584-3615The format and contents of this report are proprietary and may not be copied or used without permission, except for purposes ofdiagnosing, counseling and treating the patient identified in the report and members of his or her family. Myriad, the Myriad logo,Myriad myRisk, BRACAnalysis, COLARIS, myVision and the myVision logo are either trademarks or registered trademarks ofMyriad Genetics, Inc. in the United States and other jurisdictions.

14CLINICAL DOSSIER

CONFIDENTIAL *52530060*52530060

myRisk Genetic ResultName: DOB: Accession #: Report Date:Pt Last Name, Pt First Name Dec 05, 201607001396-BLD

ADDITIONAL INFORMATIONIndication for Testing: It is our understanding that this individual was identified fortesting due to a personal or family history suggestive of a hereditary predisposition forcancer.

Associated Cancer Risks and Clinical Management: Please see the "myRiskManagement Tool" associated with this report for a summary of cancer risk andprofessional society medical management guidelines that may be useful in developing aplan for this patient based on test results and reported personal/family history, ifapplicable. Testing of other family members may assist in the interpretation of thispatient's test result.

Analysis Description: The Technical Specifications summary (https://www.myriadpro.com/documents-and-forms/technical-specifications/) describes the analysis, method,performance, nomenclature, and interpretive criteria of this test. Current testingtechnologies are unable to definitively determine whether a variant is germline or somaticin origin, which may significantly impact risk estimates and medical management;therefore, these results should be correlated with this patient's personal and familyhistory. The interpretation of this test may also be impacted if the patient has ahematologic malignancy or an allogeneic bone marrow transplant.

GENES ANALYZED

Unless otherwise noted sequencing and largerearrangement analyses were performed on thefollowing genes:

APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2,BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM(large rearrangement only), MLH1, MSH2, MSH6,MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C,RAD51D, SMAD4, STK11, TP53. Sequencing wasperformed for select regions of POLE and POLD1,and large rearrangement analysis was performed forselect regions of GREM1 (see technicalspecifications).

** Other genes not analyzed with this test may also beassociated with cancer.

THE CLASSIFICATION AND INTERPRETATION OF ALL VARIANTS IDENTIFIED IN THIS ASSAY REFLECTS THE CURRENT STATE OFMYRIAD'S SCIENTIFIC UNDERSTANDING AT THE TIME THIS REPORT WAS ISSUED. VARIANT CLASSIFICATION AND INTERPRETATIONMAY CHANGE FOR A VARIETY OF REASONS, INCLUDING BUT NOT LIMITED TO, IMPROVEMENTS TO CLASSIFICATION TECHNIQUES,

AVAILABILITY OF ADDITIONAL SCIENTIFIC INFORMATION, AND OBSERVATION OF A VARIANT IN MORE PATIENTS.

Please contact Myriad Medical Services at 1-800-469-7423 X 3850 to discuss any questions regarding this result.

This Authorized Signaturepertains to this laboratory report:

Benjamin B. Roa, PhDDiplomate ABMGLaboratory Director

Johnathan M. Lancaster, MD, PhDDiplomate FACOG, FACSChief Medical Officer

These test results should only be used in conjunction with the patient's clinicalhistory and any previous analysis of appropriate family members. The patient'sclinical history and test results should not be disclosed to a third party, unlessrelated to treatment or payment for treatment, without the patient's express writtenauthorization. It is strongly recommended that these results be communicated tothe patient in a setting that includes appropriate genetic consultation. This test wasdeveloped and its performance characteristics determined by Myriad GeneticLaboratories. It has not been cleared or approved by the U.S. Food and DrugAdministration (FDA). The FDA has determined that clearance or approval forlaboratory-developed tests is not required.



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myRisk Management ToolRECEIVING HEALTHCARE PROVIDERTest HCP, MDTest Medical Center123 Main StTestville, TX 55555

SPECIMENSpecimen Type: BloodDraw Date: Dec 02, 2016Accession Date: Dec 02, 2016Report Date: Dec 05, 2016

Name: Pt Last Name,Pt First Name

Date of Birth:Patient ID: Patient idGender: FemaleAccession #: 07001396-BLDRequisition #: 7001396

PATIENT

GENETIC TEST RESULTS SUMMARY INFORMATION

RESULT: POSITIVE - CLINICALLY SIGNIFICANT MUTATION IDENTIFIEDNote: "CLINICALLY SIGNIFICANT," as defined in this report, is a genetic change that is associated with thepotential to alter medical intervention.


THIS GENETIC TEST RESULT IS ASSOCIATED WITH THEFOLLOWING CANCER RISKS:

HIGH RISK: Endometrial, Colorectal

ELEVATED RISK: Ovarian, Gastric, Pancreatic

MUTATIONGENE

MSH6 c.xxxxx (p.xxx*)Heterozygous

PERSONAL/FAMILY HISTORY SUMMARY AND MANAGEMENT INFORMATION

DIAGNOSISAGE ATDIAGNOSIS

FAMILYMEMBER

This information was provided by a qualified healthcare provider on thetest request form and was not verified by Myriad. Family members listedas "other" are not included in personal/family history assessment.

Patient Endometrial/Uterine 55

Father Colorectal 60

Aunt Paternal 1 Ovarian 57

Aunt Paternal 2 Breast, Invasive 45

Uncle Paternal Prostate 72

CANCER / CLINICALBEYOND THE GENETIC RESULT, NO MODIFIED

MANAGEMENT GUIDELINES IDENTIFIED; OTHERCLINICAL FACTORS MAY INFLUENCE

INDIVIDUALIZED MANAGEMENT

myRisk Management Tool: Page 1 of 7



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myRisk Management ToolName: DOB: Accession #: Report Date:Pt Last Name, Pt First Name Dec 05, 201607001396-BLD

OVERVIEWLynch syndrome: • This patient has been found to have a mutation in the MSH6 gene. Individuals with mutations in MSH6 have a condition called Lynch syndrome.

This condition is also known as Hereditary Non-Polyposis Colon Cancer (HNPCC). • Men and women with Lynch syndrome due to mutations in MSH6 have a high risk of developing colorectal cancer, often at younger ages than

seen in the general population. Colorectal cancer in patients with Lynch syndrome develops from adenomatous polyps which progress tocancer more quickly than polyps in individuals who do not have Lynch syndrome. Colorectal cancer risk may be somewhat lower in women thanin men, but there are no differences in the colorectal cancer screening guidelines for men and women.

• Women with Lynch syndrome due to mutations in MSH6 have a high risk for developing endometrial cancer and an elevated risk for ovariancancer, often at younger ages than typical in the general population.

• Patients with Lynch syndrome due to mutations in MSH6 are also believed to have an increased risk of developing a wide variety of other Lynchsyndrome associated cancers, including gastric, small bowel, urinary tract, hepatobiliary tract, brain (usually glioblastoma), sebaceous gland,and pancreatic. Precise risk estimates are not available because there is less information available for patients with MSH6 mutations comparedwith patients who have mutations in other Lynch syndrome genes. Although specific screening and prevention recommendations are notprovided for some of these cancer risks in MSH6 mutation carriers, it may be appropriate to consider available options for select patients, suchas those with a family history of any of these cancers.

• Studies have investigated the possibility that patients with Lynch syndrome have an increased risk for other cancers, including breast cancer,prostate cancer, and adrenocortical carcinoma. However, the data are not conclusive at this time and there are currently no medicalmanagement guidelines related to these cancers.

• Patients with Lynch syndrome have a high risk for developing second primary cancers following an initial diagnosis of colorectal or endometrialcancer. This includes a high risk for endometrial cancer in women following colorectal cancer and vice versa, a high risk for a second primarycolorectal cancer in any portions of the colon or rectum remaining after surgical treatment, and an increased risk for other Lynch associatedcancers, such as those of the upper gastrointestinal tract, urinary tract, and other sites.

• Although there are high risks for cancer in patients with Lynch syndrome, many of these risks can be greatly reduced with appropriate medicalmanagement. Guidelines for the medical management of patients with Lynch syndrome have been developed by the National ComprehensiveCancer Network (NCCN) and other expert groups. These are listed below. It is recommended that patients with an MSH6 mutation and adiagnosis of Lynch syndrome be managed by a multidisciplinary team with expertise in medical genetics and the care of patients with thiscondition.

WHAT ARE THE PATIENT'S GENE-RELATED CANCER RISKS?If more than one gene mutation increases a specific cancer risk (e.g., breast), only the highest cancer risk is shown. If this patient has more than onegene mutation, risks may be different, as this analysis does not account for possible interactions between gene mutations.

CANCER TYPE CANCER RISKRISK FOR

GENERAL POPULATION RELATED TO

ENDOMETRIAL

To age 70 16%-71% 1.6% MSH6

OVERALL CANCER RISK (LYNCH CANCERS)

Risk for a second Lynch-related cancer after a firstcancer diagnosis

Increased risk NA MSH6

COLORECTAL

To age 70 10%-30% 1.7% MSH6

OVARIAN

To age 70 Elevated risk 0.7% MSH6




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CANCER TYPE CANCER RISKRISK FOR

GENERAL POPULATION RELATED TO

GASTRIC


SMALL BOWEL


URINARY TRACT

To age 70 Elevated risk <1.0% MSH6

PANCREATIC


HEPATOBILIARY TRACT


CENTRAL NERVOUS SYSTEM


SEBACEOUS NEOPLASMS

To age 70 Elevated risk <1.0% MSH6

WHAT MANAGEMENT FOR CANCER RISKS SHOULD BE CONSIDERED?This overview of clinical management guidelines is based on this patient's personal and family history and genetic test results. Unless otherwise stated,medical management guidelines are limited to those issued by the National Comprehensive Cancer Network (NCCN). The reference provided shouldalways be consulted for more details. If management for a specific cancer (e.g. breast) is available due to multiple causes (e.g. a mutation and a familyhistory, or multiple mutations in different genes), only the most aggressive management is shown. Only guidelines for the patient's long-term care relatedto cancer prevention are included.

No information is provided related to treatment of a previous or existing cancer or polyps. These recommendations may require modification based onthe patient's personal medical history, surgeries and other treatments. Patients with a personal history of cancer, benign tumors or pre-cancerousfindings may be candidates for long term surveillance and risk-reduction strategies beyond what is necessary for the treatment of their initial diagnosis.Any discussion of medical management options is for general information purposes only and does not constitute a recommendation. While genetictesting and medical society guidelines provide important and useful information, medical management decisions should be made in consultationbetween each patient and his or her healthcare provider.

PROCEDURE AGE TO BEGINFREQUENCY(Unless otherwise

indicated by findings)RELATED TO




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ENDOMETRIAL

Patient education about endometrial cancer symptoms.3 Individualized NA MSH6

Consider pelvic examination, endometrial samplingand transvaginal ultrasound.2,3

30 to 35 years Annually MSH6

Consider hysterectomy.2,3 After completion of childbearing NA MSH6

COLORECTAL

Colonoscopy2,3 20 to 25 years, or 2 to 5 yearsyounger than the earliest

diagnosis in family if it is underage 25

Every 1 to 2 years MSH6

Colorectal surgical evaluation may be appropriate forsome patients3

Individualized NA MSH6

Consider the use of aspirin as a risk-reduction agent2,3 Individualized Individualized MSH6

OVARIAN

Consider bilateral salpingo-oophorectomy.2,3 Age 40 or after completion ofchildbearing

NA MSH6

Consider transvaginal ultrasound and CA-125measurement.2,3

30 to 35 years NA MSH6

GASTRIC

Treat for Helicobacter pylori infection if present.2 Individualized NA MSH6

Consider upper endoscopy, particularly for patientswith additional risk factors for gastric cancer, such asfamily history or Asian ancestry. Consider biopsy of theantrum.1,2,3

30 to 35 years Every 2 to 5 years MSH6

SMALL BOWEL

Consider upper endoscopy, particularly for patientswith additional risk factors for small bowel cancer, suchas family history.2,3

30 to 35 years Every 3 to 5 years MSH6

URINARY TRACT

Consider urinalysis.2,3 30 to 35 years Annually MSH6




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PANCREATIC

Consider available options for pancreatic cancerscreening, including the possibility of endoscopicultrasonography (EUS) and MRI/magnetic resonancecholangiopancreatography (MRCP). It is recommendedthat patients who are candidates for pancreatic cancerscreening be managed by a multidisciplinary team withexperience in the screening for pancreatic cancer,preferably within research protocols.4

Individualized NA MSH6

HEPATOBILIARY TRACT

Currently there are no specific medical managementguidelines for hepatobiliary cancer risk in mutationcarriers.3

NA NA MSH6


Physical/neurological examination3 25 to 30 years Annually MSH6

SEBACEOUS NEOPLASMS

Currently there are no specific medical managementguidelines for sebaceous neoplasm risk in mutationcarriers.

NA NA MSH6

Ajani JA, et al. NCCN Clinical Practice Guidelines in Oncology®: Gastric Cancer. V 2.2016. July 7. Available at http://www.nccn.org.1.Giardiello FM, et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol.2014 109:1159-79. PMID: 25070057.

2.

Provenzale D, et al. NCCN Clinical Practice Guidelines in Oncology® Genetic/Familial High-Risk Assessment: Colorectal. V 1.2016. June 13. Available at http://www.nccn.org.3.Canto MI, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 62:339-47.PMID: 23135763.

4.

Notes for Personalized Management:

INFORMATION ON HOW CANCER RISKS AND MANAGEMENT ARE DETERMINEDThe myRisk Management Tool provides cancer risk levels based on analysis of genetic test results (see myRisk Genetic Result) and managementrecommendations based on a combined analysis of genetic test results and, when possible, personal/family cancer history. Additional details can befound on myriadpro.com/gene-table.

• A comprehensive risk assessment may include other aspects of the patient's personal/family medical history, as well as lifestyle, environmentand other factors.

• Changes in personal/family history or additional data regarding specific genes/mutations may affect the cancer risk estimates and managementrecommendations within this report. Personal/family history should be updated with a healthcare provider on a regular basis.




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• Management recommendations are provided for personal/family history of colorectal adenomas, breast, colorectal, melanoma, pancreatic, andprostate cancers. Assessment is based on information provided on the test request form for the patient as well as first and second degreerelatives. Analysis of third degree relatives for relevant cancers may be included if sufficient information is provided. Assessment for AmsterdamII Criteria for Lynch syndrome may not be complete in certain cases due to Myriad's limited understanding of the family structure. The Clausmodel is used to determine when women are estimated to have a greater than 20% lifetime risk for breast cancer based on family history (ClausEB, Risch N, Thompson WD. Cancer 1994; Feb 1;73(3):643-51). Unaffected women meeting this threshold will receive appropriate guideline-based breast management recommendations. Additional family history assessment may be required. African American ethnicity, when reportedon the test request form, is used in assessment for prostate cancer management. Cancer risks and related management are included based onthe gender provided. When personal and family history assessment could not be provided in this result (e.g., Single Site testing, insufficienthistory for analysis), the patient risk and/or management recommendations may deviate from what has been provided within this report. Pleasecontact Myriad Medical Services at 1-800-469-7423 X 3850 for more information.

• No management recommendations are provided related to treatment of a previous or existing cancer or polyps. The recommendations providedmay require modification based on the patient's personal medical history, surgeries and other treatments. Patients with a personal history ofcancer, benign tumors or pre-cancerous findings may be candidates for long term surveillance and risk-reduction strategies beyond what isnecessary for the treatment of their initial diagnosis.

• Patients who have a clinical diagnosis of a genetic cancer syndrome (e.g., Lynch syndrome) may have different management recommendationsthan provided. Management should be personalized based on all known clinical diagnoses.

• The Genetic Test Result Summary includes: female breast, male breast, colorectal, endometrial, gastric, ovarian, pancreatic and prostatecancers, and melanoma. In this summary a gene associated cancer risk is described as "High Risk" for a cancer type if all of the followingconditions are met: the absolute risk of cancer is approximately 5% or higher, the increase in risk over the general population is approximately3-fold or higher, and there is significant data from multiple studies supporting the cancer risk estimate. A gene is described as "Elevated Risk"for a cancer type if there is sufficient data to support an increase in cancer risk over the general population risk, but not all criteria for "HighRisk" are met.

INFORMATION FOR FAMILY MEMBERSFamily members should talk to their healthcare providers about hereditary cancer testing to help define their own risk and assist in the interpretation ofthis patient's genetic test result.

• This patient's relatives are at risk for carrying the same mutation(s) and associated cancer risks as this patient. Cancer risks for females andmales who have this/these mutation(s) are provided below.

• Family members should talk to a healthcare provider about genetic testing. Close relatives such as parents, children, brothers, and sistershave the highest chance of having the same mutation(s) as this patient. Other more distant relatives such as cousins, aunts, uncles, andgrandparents also have a chance for carrying the same mutation(s). Testing of at-risk relatives can identify those family members with the samemutation(s) who may benefit from surveillance and early intervention. More resources for family testing are available at MySupport360.com.

• In rare instances, an individual may inherit mutations in both copies of the MSH6 gene, leading to the condition Constitutional Mismatch Repair-Deficiency syndrome (CMMR-D). Individuals with CMMR-D often have significant complications in childhood, including colorectal polyposis anda high risk for colorectal, small bowel, brain, and hematologic cancers. Individuals with CMMR-D often have café-au-lait spots. The children ofthis patient are at risk of inheriting CMMR-D only if the other parent is also a carrier of a MSH6 mutation. Screening the spouse/partner of thispatient for MSH6 mutations may be appropriate.

CANCER RISK FOR MSH6 CLINICALLY SIGNIFICANT MUTATIONCANCER TYPE CANCER RISK RISK FOR GENERAL POPULATION

FOR FEMALE RELATIVES

To age 70 1.6%16%-71%

ENDOMETRIAL

To age 70 1.7%10%-30%

COLORECTAL



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CANCER TYPE CANCER RISK RISK FOR GENERAL POPULATION

FOR FEMALE RELATIVES

To age 70 0.7%Elevated risk

OVARIAN

FOR MALE RELATIVES

To age 70 2.2%22%-69%

COLORECTAL

FOR FEMALE AND MALE RELATIVES

Risk for a second Lynch-related cancer after a firstcancer diagnosis

NAIncreased risk

OVERALL CANCER RISK (LYNCH CANCERS)


GASTRIC


SMALL BOWEL

To age 70 <1.0%Elevated risk

URINARY TRACT


PANCREATIC


HEPATOBILIARY TRACT



To age 70 <1.0%Elevated risk

SEBACEOUS NEOPLASMS


END OF MYRISK MANAGEMENT TOOL



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Figure 6: Sample report - Negative with medical management changes



52530052



SPECIMENSpecimen Type: BloodDraw Date: Oct 18, 2016Accession Date: Oct 18, 2016Report Date: Oct 27, 2016



RESULT: NEGATIVE - NO CLINICALLY SIGNIFICANT MUTATION IDENTIFIEDNote: "CLINICALLY SIGNIFICANT," as defined in this report, is a genetic change that is associated with thepotential to alter medical intervention.







GENES ANALYZED








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myRisk Genetic ResultName: DOB: Accession #: Report Date:Pt Last Name, Pt First Name Oct 27, 201607000150-BLD








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PATIENT




No clinically significant mutations were identified in this patient. However, based on personal/family history, the patient's cancer risks may still beincreased over the general population. See information below.



FAMILYMEMBER


Patient None

Mother Breast, Invasive 55

Aunt Maternal Breast, Invasive 50

Father Colorectal 60

CANCER / CLINICAL

MODIFIED MEDICAL MANAGEMENT MAY BEAPPROPRIATE



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myRisk Management ToolName: DOB: Accession #: Report Date:Pt Last Name, Pt First Name Oct 27, 201607000150-BLD





FEMALE BREAST

Breast awareness - Women should be familiar withtheir breasts and promptly report changes to theirhealthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness.1

Individualized NA Family History (>20%lifetime risk)

Clinical breast examination1,3 10 years younger than the earliestdiagnosis in the family, but not

younger than 30

Every 6 to 12 months Family History (>20%lifetime risk)

Breast MRI in addition to mammography1,3 10 years younger than the earliestdiagnosis in the family, but not

younger than 30

Annually Family History (>20%lifetime risk)

Consider additional risk-reduction strategies.1,3 Individualized NA Family History (>20%lifetime risk)

COLORECTAL

Colonoscopy2 50 years Every 5 to 10 years Personal / FamilyHistory

Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 1.2015. July 15. Available at http://www.nccn.org.1.Provenzale D, et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 1.2016. June 23. Available at http://www.nccn.org.2.Claus EB et al. Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer. 1994 73:643-51. PMID: 8299086.3.






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Figure 7: Sample report - Negative with Variant of Unknown Significance



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ADDITIONAL FINDINGS: VARIANT(S) OF UNCERTAIN SIGNIFICANCE (VUS) IDENTIFIEDGENE INTERPRETATIONVARIANT(S) OF UNCERTAIN SIGNIFICANCE

UNCERTAIN CLINICAL SIGNIFICANCEThere are currently insufficient data to determine if these variantscause increased cancer risk.

BRCA1 c.xxxx (p.xxxx)(aka xxxx)






GENES ANALYZED






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myRisk Genetic ResultName: DOB: Accession #: Report Date:Pt Last Name, Pt First Name Oct 27, 201607000152-BLD










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PATIENT



ADDITIONAL FINDINGS: VARIANT(S) OF UNCERTAIN SIGNIFICANCE (VUS) IDENTIFIED

No clinically significant mutations were identified in this patient. However, based on personal/family history, the patient's cancer risks may still beincreased over the general population. See information below.



FAMILYMEMBER


Patient None

Mother Breast, Invasive 49

Aunt Maternal Breast, Invasive 45

CANCER / CLINICAL

MODIFIED MEDICAL MANAGEMENT MAY BEAPPROPRIATE



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FEMALE BREAST

Breast awareness - Women should be familiar withtheir breasts and promptly report changes to theirhealthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness.1

Individualized NA Family History (>20%lifetime risk)

Clinical breast examination1,2 10 years younger than the earliestdiagnosis in the family, but not

younger than 30

Every 6 to 12 months Family History (>20%lifetime risk)

Breast MRI in addition to mammography1,2 10 years younger than the earliestdiagnosis in the family, but not

younger than 30

Annually Family History (>20%lifetime risk)

Consider additional risk-reduction strategies.1,2 Individualized NA Family History (>20%lifetime risk)

Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 1.2015. July 15. Available at http://www.nccn.org.1.Claus EB et al. Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer. 1994 73:643-51. PMID: 8299086.2.







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SOCIETALSTATEMENTSThe advantages of panels are recognized in medical society statements.

American College of Obstetrician and Gynecologists Committee and the Society of Gynecologic Oncology, August 2017.

Genetic counseling and testing can be performed by an obstetrician-gynecologist or other gynecologic care provider.

“[E]valuating a patient’s risk of hereditary breast and ovarian cancer syndrome should be a routine part of obstetric and gynecologic practice. […] Multigene panel testing may be useful when more than one gene may be associated with an inherited cancer syndrome.”

National Society of Genetic Counselors (NSGC), March 2017

NSGC endorses multi-gene panel tests.

“The National Society of Genetic Counselors (NSGC) endorses the use of multi-gene panel tests when clinically warranted and appropriately applied. These tests can provide a comprehensive and efficient route to identifying the genetic causes of disease. Before ordering a multi-gene panel test, providers should thoroughly evaluate the analytic and clinical validity of the test, as well as its clinical utility. Additional factors to consider include, but are not limited to: clinical and family history information, gene content of the panel, limitations of the sequencing and informatics technologies, and variant interpretation and reporting practices.”

Blue Cross Blue Shield Association. Moderate Penetrance Variants Associated With Breast Cancer in Individuals at High Breast Cancer Risk. Evidence Street, January 2017.

Individuals with HBOC risk receive genetic testing for PALB2 variant.

“The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.”

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) – Genetic/Familial High-Risk Assessment: Breast and Ovarian, version 1.2017.

Panels test genes in parallel without substantially increasing cost – and all known contributing genes are assayed at first evaluation.

“Advantages of cancer gene panels include decreased cost and improved efficiency of cancer genetic testing by decreasing the time involved, number of patient visits, and number of tests sent. A negative genetic test is more reassuring at eliminating the likelihood of inherited risk when all known genes for that phenotype have been assayed.”

The American Society of Breast Surgeons. Consensus Guideline on Hereditary Genetic Testing for Patients With and Without Breast Cancer. September 13, 2016.

Panel testing evaluates genes more efficiently and cost-effectively than sequential gene sequencing.

“Numerous recent studies have shown that panel testing can significantly increase the rate of detection of pathogenic mutations […]. […] Breast surgeons can consider panel testing for patients who qualify for hereditary breast cancer testing to more efficiently and cost-effectively evaluate genes that confer risk and affect management recommendations. […] Insurance companies are urged to incorporate these advantages of panel testing into the algorithm of allowed hereditary cancer genetic testing for patients at high risk.”

Robson ME, et al. American Society of Clinical Oncology policy statement update: Genetic and genomic testing for cancer susceptibility. J Clin Oncol 2015 Nov; 33(31):3660-67.

Several studies demonstrate the prevalence of mutations identified by panel-based testing.

“The use of germline multiplex or multigene panel testing is rapidly expanding in cancer risk assessment. Potential advantages to such testing include time and cost efficiency, decrease in testing fatigue for patients and providers, efficient use of a single specimen, and comprehensive assessment for cancer susceptibility, particularly in common cancers or individuals without identifiable syndromes. This type of testing may be particularly useful in situations where there are multiple high-penetrance genes associated with a specific cancer, the prevalence of actionable mutations in one of several genes is high, and it is difficult to predict which gene may be mutated on the basis of phenotype or family history.”

Lancaster JM, et al. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecologic Oncology 2015; 136:3–7.

Genetic predisposition for particular cancers is changing from individual genes and syndromes to multiplex testing for a number of genes.

“Evaluation of the likelihood of a patient having [one of the] gynecologic cancer predisposition syndromes enables physicians to provide individualized assessments of cancer risk, as well as the opportunity to provide tailored screening and prevention strategies such as surveillance, chemoprevention, and prophylactic surgery that may reduce the morbidity and mortality associated with these syndromes.”

http://www.nsgc.org/p/bl/et/blogaid%3D870

https://myriad.com/managed-care/myriad-myrisk/society-statements/

https://myriad.com/managed-care/myriad-myrisk/society-statements/

www.nccn.org

https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/BRCA_Testing.pdf

http://jco.ascopubs.org/content/33/31/3660.full.pdf%2Bhtml

https://www.sgo.org/wp-content/uploads/2012/11/SGO-Position-Statement-Genetics.pdf

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HEALTH ECONOMICS

The current single-syndrome testing paradigm is not efficient for many breast and ovarian cancer patients, given the overlapping clinical phenotypes of numerous genes implicated in hereditary cancer. As an example, consider a patient diagnosed with epithelial ovarian cancer who meets the NCCN criteria for BRCA1/2 testing. Assume she tests negative for BRCA1 and BRCA2 mutations, responds well to treatment for ovarian cancer, but subsequently develops colon cancer. Based on her diagnoses of both ovarian cancer and colon cancer, she meets the NCCN criteria for Lynch syndrome testing, pursues such testing to help determine

the extent of colon surgery to be performed, and is found to have a mutation in the MSH2 gene. The sequential testing of BRCA1/2 followed by Lynch syndrome testing would cost a total of approximately $6,000, in addition to the costs of treating the patient’s colon cancer. Instead, Myriad myRisk testing at the time of the patient’s initial diagnosis of ovarian cancer would have identified her MSH2 mutation and possibly prevented her colon cancer diagnosis (due to recommendations for increased surveillance), at a cost similar to the single-syndrome BRACAnalysis® test.

Figure 8: Healthcare Cost Savings Generated with Myriad myRisk

Single Syndrome + Additional Genes Panel Test with Sample Population Testing Criteria

All h

ave

NC

CN

gu

ide

lin

es

5 tests, >16 weeks wait, >$10,000 in testing 1 test + 10 day turnaround time = cost savings

BRCA1/2 Negative

+

+

+

+

PALB2 Negative

CHEK2 Negative

TP53 Negative

Lynch Syndrome Positive

Smith S, et al. Optimization of quality assurance to increase clinical utility and cost effectiveness of hereditary cancer testing. Per Med 2017; 14(3), 213-20.

Quality assurance measures provide cost savings to payers.

“As healthcare providers and patients become more aware of the importance of personal and family history risk factors for hereditary cancer syndromes, the demand for genetic testing will continue to increase. As such, working with a diagnostic laboratory that provides extensive clinical QA measures whose goal is to support the most clinically appropriate care, while simultaneously avoiding unnecessary healthcare spending, is critical to the success of personalized medicine.”

https://www.futuremedicine.com/doi/abs/10.2217/pme-2016-0091

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Aggressive prostate cancer at early age associated with BRCA1, BRCA2 and ATM.Na R, et al. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. European Urology 2017 May; 71(5): 740-7. doi: 10.1016/j.eururo.2016.11.033.

Multigene panels should be used for the assessment of cancer risk beyond the classic predisposition syndromes.Graffeo R, et al. Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care. Breast Cancer Res Treat 2016 Dec; 160(3):393-410. Epub 2016 Oct 12.

“Canonical” genetic workup fails to detect patients with other mutations.Vilar E and Stoffel EM, et al. Universal genetic testing for younger patients with colorectal cancer. JAMA Oncol 2016 Dec 15. doi:10.1001/jamaoncol.2016.5193.

Clinical utility of panel testing in BRCA negative patients.Yadav S, et al. Outcomes of retesting BRCA negative patients using multigene panels. Fam Cancer 2016 Nov 22; 16(3): 319-28. doi:10.1007/s10689-016-9956-7.

Up to 79% of women from BRCA-negative families desire multiplex genetic testing.Flores KG, et al. Factors associated with interest in gene-panel testing and risk communication preferences in women from BRCA1/2 negative families. J Genet Counsel 2016 Aug; 26(3): 480-90. doi:10.1007/s10897-016-0001-7.

70% of physicians changed management based on panel results.Ricker C, et al. Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort. Cancer Genetics 2016 April; 209(4):130-7.

RAD51C and RAD51D genes play a role in epithelial ovarian cancer (EOC).Song H, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol 2015 Sept; 33(26):2901-14.

Several genes beyond BRCA1 and BRCA2 have robust evidence associating them with breast cancer risk.Easton DF, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 2015 Jun; 372:2243-225.

Appropriate surgical intervention improves overall survival. Heemskerk-Gerritsen BA, et al. Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. Int J Cancer 2015 Feb; 136(3):668-77.

PALB2 mutation carriers have a significant increased risk of breast cancer.Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014 Oct; 371(6):497-506.

Testing beyond a negative BRCA 1/2 result leads to greater detection of pathogenic mutations. Kurian AW, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014 Jul 1; 32(19):2001-9.

Greater sensitivity prevents more cancer cases, saving healthcare dollars. Stenehjem D, et al. Economic analysis of alternative genetic tests for BRCA1 and BRCA2 mutations. Scientific poster presented at the 31st Annual Breast Cancer Conference in Miami, FL, March 2014.

Appropriate prophylactic surgery improves survival rates.Metcalfe K, et al. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. BMJ 2014 Feb; 348:g226.

Oophorectomy reduces risk of ovarian, fallopian tube, or peritoneal cancer in women with a mutation.Finch AP, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 2014 May; 32(15):1547-53.

Panel testing for multiple genes saves thousands of healthcare dollars.Walsh T, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 2011 Nov 1; 108(44):18032-7.

Risk-reducing surgery improves mortality rates.Domcheck S, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010; 304(9):967-75.

SUPPORTINGPUBLICATIONS

http://www.europeanurology.com/article/S0302-2838%2816%2930885-5/abstract/germline-mutations-in-atm-and-brca1-2-distinguish-risk-for-lethal-and-indolent-prostate-cancer-and-are-associated-with-early-age-at-death

https://link.springer.com/article/10.1007%2Fs10549-016-4003-9




http://dx.doi.org/10.1016/j.cancergen.2015.12.013

http://jco.ascopubs.org/content/33/26/2901.long

http://www.nejm.org/doi/full/10.1056/NEJMsr1501341

https://www.ncbi.nlm.nih.gov/pubmed/?term=Int+J+Cancer+2015%3B136(3)%3A668-77

http://www.nejm.org/doi/full/10.1056/NEJMoa1400382

http://www.ncbi.nlm.nih.gov/pubmed/24733792



http://www.gotoper.com/conferences/mbcc/meetings/31st-annual-miami-breast-cancer-conference/resources

http://www.bmj.com/content/348/bmj.g226

http://jamanetwork.com/journals/jama/fullarticle/186510

35CLINICAL DOSSIER

Accurate variant classification is vital to ensuring appropriate medical management.Gradishar W, et al. Clinical variant classification: A comparison of public databases and a commercial testing laboratory. Published ahead of print on April 13, 2017 as 10.1634/theoncologist.2016-0431.

Conflicting variant interpretations between commercial labs reported to PROMPT.Balmaña J, et al. Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing. J Clin Oncol 2016, 34: 4071-8. doi: 10.1200/JCO.2016.68.4316.

29% rate of discordance observed in variant interpretation.Amendola LM, et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet 2016; 98(6):1067-76.

Substantial disparity of variant classifications among databases.Vail PJ, et al. Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases. J Community Genet 2015 Oct; 6(4):351-9.

ACMG Guidelines are not a definitive variant classification program.Joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, May 2015.

Clinical classification of hereditary sequence variants in disease-related genes directly affects clinical management.Thompson BA, et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nature Genetics 2014; 46:107–115.

Myriad is the unquestioned industry leader in variant classification and reclassification. Over the past 20 years, Myriad has conducted approximately two million genetic tests for hereditary cancer. The resulting analysis and interpretation of the variant database supports the Myriad commitment to reduce variants of uncertain significance in genetic test results.

Every day new variants are evaluated and classified by the Myriad Variant Classification Program, a diverse team of more than 30 scientists who determine the clinical significance of variants. By tapping the expertise of these individuals from all applicable disciplines, myVision represents unrivaled experience and expertise in variant classification.

Myriad is the only lab with published interpretive and analytical accuracy data.15, 17, 18

myVision is our commitment to accurately interpret and identify variants to promote responsible healthcare spending and medical management • 30 PhD scientists and a team of certified genetic counselors • Classified 46,000 genetic variants •>50 variants classified each day •>40 variants re-classified each month • Testing experience led to development of proprietary tools • Positive and negative predictive value >99% for proprietary tools • >99% confidence in statistical methods

myVisionVARIANT CLASSIFICATION PROGRAM

Head Laboratory Director Chief Medical Officer

† AMERICAN BOARD OF MEDICAL GENETICS* AMERICAN BOARD OF GENETIC COUNSELING

Research Scientists Statisticians

Variant Specialists Molecular Biologists

Informatics SpecialistsBiochemists

ABMG†-CertifiedLaboratory Directors

ABGC*-CertifiedGenetic Counselors

Structural Biologists

http://theoncologist.alphamedpress.org/content/early/2017/04/07/theoncologist.2016-0431.abstract%3Frelated-urls%3Dyes%26legid%3Dtheoncologist%3Btheoncologist.2016-0431v1

http://ascopubs.org/doi/full/10.1200/JCO.2016.68.4316


http://www.nature.com/ng/journal/v46/n2/full/ng.2854.html


https://link.springer.com/article/10.1007%2Fs12687-015-0220-x

36CLINICAL DOSSIER

1. Tung N, et al. Frequency of mutations in individuals with breastcancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 2015 Jan 1; 121(1):25-33.

2. Yurgelun MB, et al. Identification of a variety of mutations incancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology 2015 Sep; 149(3):604-13.

3. Langer LR. Hereditary cancer testing in patients with ovarian cancer using a 25-gene panel. JCSO 2016 July; 14:314-19.

4. Saam J, et al. Patients tested at a laboratory for hereditarycancer syndromes show an overlap for multiple syndromes in their personal and familial cancer histories. Oncology 2015; 89(5):288-93.

5. Antoniou AC, et al. Breast-cancer risk in families with mutationsin PALB2. N Engl J Med 2014 Oct; 371(6):497-506.

6. Lerner-Ellis J, et al. Genetic risk assessment and prevention:The role of genetic testing panels in breast cancer. Expert Rev Anticancer Ther 2015; 15(11):1315-26.

7. Minion LE, et al. Hereditary predisposition to ovarian cancer,looking beyond BRCA1/2. Gynecol Oncol 2015 Apr; 137(1):86-92.

8. Myriad Internal Data.

9. Hughes K, et al. Prevalence of family history of breast andovarian cancer in a single primary care practice using a self-administered questionnaire. The Breast Journal 2003; 9(1):19-25.

10. The American Society of Breast Surgeons. Consensus Guidelineon Hereditary Genetic Testing for Patients with and without Breast Cancer. September 13, 2016; www.breastsurgeons.org.

11. NCCN Clinical Practice Guidelines in Oncology (NCCNGuidelines®) – Genetic/Familial High-Risk Assessment: Breast and Ovarian, version 1.2017.

12. NCCN Clinical Practice Guidelines in Oncology (NCCNGuidelines®) – Genetic/Familial High-Risk Assessment: Colorectal. Version 1.2016.

13. McGlynn EA, McDonald KM, Cassel CK. Measurement isessential for improving diagnosis and reducing diagnostic error: A report from the Institute of Medicine. JAMA 2015; 314(23):2501-2.

14. Gallego CJ, et al. Next-generation sequencing panels for thediagnosis of colorectal cancer and polyposis syndromes: A cost-effectiveness analysis. J Clin Oncol 2015 Jun 20; 33(18):2084-91.

15. Eggington J, et al. A comprehensive laboratory-based programfor classification of variants of uncertain significance in hereditary cancer genes. Clin Genet 2014 Sep; 86(3):229-37.

16. Morris B, et al. Classification of genetic variants in genesassociated with Lynch syndrome using a clinical history weighting algorithm. BMC Genetics 2016; 17:99.

17. Pruss D, et al. Development and validation of a new algorithmfor the reclassification of genetic variants identified in the BRCA1 and BRCA2 Genes. Breast Cancer Research Treatment 2014 Aug; 147(1):19-32.

18. Judkins T, et al. Development and analytical validation of a 25gene next generation sequencing panel that includes the BRCA1 and BRCA2 genes to assess hereditary cancer risk. BMC Cancer 2015 Apr 2; 15:215.

19. Tung N, et al. Frequency of germline mutations in 25 cancersusceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol 2016 May 1; 34(13):1460-8.

20. Yorczyk A, Robinson LS, Ross TS. Use of panel tests in place ofsingle gene tests in the cancer genetics clinic. Clin Genet 2015 Sep; 88(3):278-82.

21. Cragun D, et al. Panel-based testing for inherited colorectalcancer: A descriptive study of clinical testing performed by aUS laboratory. Clin Genet 2014 Dec; 86(6):510-20.

22. Desmond A, et al. Clinical actionability of multigene paneltesting for hereditary breast and ovarian cancer risk assessment. JAMA Oncol 2015; 1(7):943-51.

23. Easton DF, et al. Gene-panel sequencing and the prediction ofbreast-cancer risk. N Engl J Med 2015 Jun; 372:2243-57.

24. Howarth DR, et al. Initial results of multigene panel testing forhereditary breast and ovarian cancer and Lynch syndrome. AmSurg 2015 Oct; 81(10):941-4.

25. Ricker C, et al. Increased yield of actionable mutations usingmulti-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort. Cancer Genetics 2016 April; 209(4):130-7.

26. Tung N, et al. Counselling framework for moderate-penetrancecancer-susceptibility mutations. Nat Rev Clin Oncol 2016 Sep; 13(9):581-8.

27. Walsh T, et al. Mutations in 12 genes for inherited ovarian,fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 2011 Nov 1; 108(44):18032-7.

28. Saam J, et al. Hereditary cancer-associated mutations inwomen diagnosed with two primary cancers: an opportunity to identify hereditary cancer syndromes after the first cancer diagnosis. Oncology 2015; 88(4):226-33.

29. Rosenthal ET, et al. Outcomes of clinical testing for 76,000patients utilizing a panel of 25 genes associated with increased risk for breast, ovarian, colorectal, endometrial, gastric, pancreatic, melanoma and prostate cancers. Scientific poster presented at the American Society for Clinical Oncology Annual Meeting in Chicago, IL, June 2015.

30. Langer LR, et al. 25-Gene panel testing and integrated riskmanagement tool impacts medical management in hereditary cancer syndrome evaluation. Scientific poster presented at the American Society for Clinical Oncology Annual Meeting in Chicago, IL, June 2014.

31. Domcheck S, et al. Association of risk-reducing surgery inBRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010; 304(9):967-75.

32. Jarvinen-Heikki J, et al. Controlled 15-year trial on screeningfor colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000; 118(5):829-34.

33. Langer LR, et al. Impact of 25-gene panel testing and

integrated risk management tool on medical management in hereditary cancer syndrome evaluation. J Clin Oncol 2014; 32(15_suppl) (May 20 Supplement): 1553.

34. Kurian AW, et al. Safety of multiplex gene testing for inheritedcancer risk: Interim analysis of a clinical trial. Scientific poster presented at the American Society for Clinical Oncology Annual Meeting in Chicago, IL, June 2016.

REFERENCES

37CLINICAL DOSSIER

35. Yurgelun MB, et al. Cancer susceptibility gene mutations inindividuals with colorectal cancer. J of Clin Onc2017 Apr 1;35(10):1086-1095.

36. Coffee B, et al. Detection of somatic variants in peripheralblood lymphocytes using a next generation sequencing multigene pan cancer panel. Cancer Genetics 2017; 211:5-8.

37. Pearlman R, et al. Prevalence and spectrum of germlinecancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol 2016 Dec. doi:10.1001/jamaoncol.2016.5194.

38. Buys SS, et al. A study of over 35,000 women with breastcancer tested with a 25-gene panel of hereditary cancer genes. Cancer 2017. 123(10): 1721-30. doi:10.1002/cncr.30498.

39. Giri VN, Obeid E, Gross L, et al. Inherited mutations in menundergoing multigene panel testing for prostate cancer: emerging implications for personalized prostate cancer genetic evaluation [published online May 4, 2017]. JCO Prec Oncol. doi: 10.1200/PO.16.00039.

40. Rosenthal ET, et al. Increased identification of candidatesfor high-risk breast cancer screening through expanded genetic testing. J Am Coll Radiol 2017; 14:561-8. doi:10.1016/j.jacr.2016.10.003.

41. The American College of Obstetricians and GynecologistsACOG practice bulletin: Hereditary breast and ovarian cancer syndrome. Clinical management guidelines for obstetrician–gynecologists, Number 182, September 2017.

42. National Society of Genetic Counselors (NSGC), March 2017.

43. BlueCross BlueShield Association. Moderate PenetranceVariants Associated With Breast Cancer in Individuals at High Breast Cancer Risk. Evidence Street, Current Review Date: January 2017.

44. Robson ME, et al. American Society of ClinicalOncologypolicy statement update: Genetic and genomic testing for cancer susceptibility. J Clin Oncol 2015 Nov; 33(31):3660-67.

45. Lancaster JM, et al. Society of Gynecologic Oncologystatement on risk assessment for inherited gynecologic cancer predispositions. Gynecologic Oncology 2015; 136:3–7.

46. Smith S, et al. Optimization of quality assurance to increaseclinical utility and cost effectiveness of hereditary cancer testing. Per Med 2017; 14(3), 213-20.

47. Na R, et al. Germline mutations in ATM and BRCA1/2 distinguishrisk for lethal and indolent prostate cancer and are associated with early age at death. European Urology 2017 May; 71(5):740-7. doi: 10.1016/j.eururo.2016.11.033.

48. Graffeo R, et al. Time to incorporate germline multigene paneltesting into breast and ovarian cancer patient care. Breast Cancer Res Treat 2016 Dec; 160(3):393-410. Epub 2016 Oct 12.

49. Vilar E and Stoffel EM, et al. Universal genetic testing foryounger patients with colorectal cancer. JAMA Oncol 2016 Dec 15. doi:10.1001/jamaoncol.2016.5193.

50. Yadav S, et al. Outcomes of retesting BRCA negative patientsusing multigene panels. Fam Cancer 2016 Nov 22; 16(3): 319-28. doi:10.1007/s10689-016-9956-7.

51. Flores KG, et al. Factors associated with interest in genepanel testing and risk communication preferences in women from BRCA1/2 negative families. J Genet Counsel 2016 Aug; 26(3): 480-90. doi:10.1007/s10897-016-0001-7.

52. Song H, et al. Contribution of germline mutations in theRAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol 2015 Sept; 33(26):2901-14.

53. Heemskerk-Gerritsen BA, et al. Improved overall survival aftercontralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. Int J Cancer 2015 Feb; 136(3):668-77.

54. Kurian AW, et al. Clinical evaluation of a multiple-genesequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014 Jul 1; 32(19):2001-9.

55. Stenehjem D, et al. Economic analysis of alternative genetictests for BRCA1 and BRCA2 mutations. Scientific poster presented at the 31st Annual Breast Cancer Conference in Miami, FL, March 2014.

56. Metcalfe K, et al. Contralateral mastectomy and survivalafter breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. BMJ 2014 Feb; 348:g226.

57. Finch AP, et al. Impact of oophorectomy on cancer incidenceand mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 2014 May; 32(15):1547-53.

58. Gradishar W, et al. Clinical variant classification: A comparisonof public databases and a commercial testing laboratory. Published ahead of print on April 13, 2017 as 10.1634/theoncologist.2016-0431.

59. Balmaña J, et al. Conflicting interpretation of genetic variantsand cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing. J Clin Oncol 2016, 34: 4071-8. doi: 10.1200/JCO.2016.68.4316.

60. Amendola LM, et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet 2016; 98(6):1067-76.

61. Vail PJ, et al. Comparison of locus-specific databases for BRCA1and BRCA2 variants reveals disparity in variant classification within and among databases. J Community Genet 2015 Oct; 6(4):351-9.

62. Richards, et at. Standards and guidelines for the interpretationof sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 2015 May; 17(5):405-24.

63. Thompson BA, et al. Application of a 5-tiered scheme forstandardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nature Genetics 2014; 46:107–115.

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