GENETIC TESTING FOR HEREDITARY CANCER

Transcription

1 Oxfrd UnitedHealthcare Oxfrd Clinical Plicy GENETIC TESTING FOR HEREDITARY CANCER Plicy Number: DIAGNOSTIC T2 Effective Date: January 1, 2019 Instructins fr Use Table f Cntents Page CONDITIONS OF COVERAGE... 1 COVERAGE RATIONALE... 1 DEFINITIONS... 4 APPLICABLE CODES... 4 DESCRIPTION OF SERVICES... 5 CLINICAL EVIDENCE... 6 U.S. FOOD AND DRUG ADMINISTRATION REFERENCES POLICY HISTORY/REVISION INFORMATION INSTRUCTIONS FOR USE Related Plicy Preventive Care Services CONDITIONS OF COVERAGE Applicable Lines f Business/Prducts Benefit Type Referral Required (Des nt apply t nn-gatekeeper prducts) Authrizatin Required (Precertificatin always required fr inpatient admissin) This plicy applies t Oxfrd Cmmercial plan membership. General Benefits Package N Yes 1 Precertificatin with Medical Directr Review Required Yes 1 Applicable Site(s) f Service (If site f service is nt listed, Medical Directr review is required) Special Cnsideratins COVERAGE RATIONALE Labratry 1 Precertificatin with review by a Medical Directr r their designee is required. Genetic cunseling is strngly recmmended prir t these tests in rder t infrm persns being tested abut the advantages and limitatins f the test as applied t a unique persn. Hereditary Breast and Ovarian Cancer (BRCA1/BRCA2) Genetic testing fr BRCA1 and BRCA2 fr individuals with a persnal histry f a related cancer is prven and medically necessary in the fllwing situatins: Men with a persnal histry f Breast Cancer. Wmen with a persnal histry f Ovarian Cancer. Wmen with a persnal histry f Breast Cancer in any f the fllwing situatins: Metastatic Breast Cancer and may be a candidate fr treatment with a PARP inhibitr (e.g., laparib). Breast Cancer diagnsed at any age in an individual with at least ne clse (1st-, 2nd-, and 3rd-degree relative) bld relative wh has a BRCA1 r BRCA2 mutatin. Breast Cancer diagnsed at any age in an individual with Ashkenazi Jewish ancestry. Breast Cancer diagnsed at any age with any ne f the fllwing: At least ne Clse Bld Relative with Ovarian Cancer; r At least ne clse male bld relative with Breast Cancer; r At least ne Clse Bld Relative with Breast Cancer diagnsed at age 50 r yunger; r At least ne Clse Bld Relatives with pancreatic cancer; r Genetic Testing fr Hereditary Cancer Page 1 f 20

2 At least ne Clse Bld Relative with metastatic prstate cancer at any age; r At least tw Clse Bld Relatives with Breast Cancer, pancreatic cancer and/r prstate cancer at any age; r An unknwn r Limited Family Histry (see Definitins sectin fr further clarificatin f Limited Family Histry). Breast Cancer diagnsed at age 45 r yunger. Triple-Negative (Her2 negative, ER negative and PR negative) Breast Cancer diagnsed at age 60 r yunger. Breast Cancer diagnsed at age 50 r yunger with any f the fllwing: An additinal Breast Cancer primary (prir diagnsis r bilateral cancer); r At least ne Clse Bld Relative with Breast Cancer, pancreatic cancer, and/r prstate cancer; r An unknwn r Limited Family Histry (see Definitins sectin fr further clarificatin f Limited Family Histry). Individuals with a persnal histry f pancreatic cancer. Men with a persnal histry f prstate cancer in any f the fllwing situatins: At least ne Clse Bld Relative wh has a BRCA1 r BRCA2 mutatin. Metastatic prstate cancer diagnsed at any age. High Risk prstate cancer (Gleasn Scre at least 7) diagnsed at any age with any f the fllwing: At least ne Clse Bld Relative with Ovarian Cancer at any age; r At least ne Clse Bld Relative with Breast Cancer diagnsed at age 50 r yunger; r At least ne Clse Bld Relative with pancreatic cancer at any age; r At least ne Clse Bld Relative with metastatic prstate cancer at any age; r At least tw Clse Bld Relatives with Breast Cancer, pancreatic cancer and/r prstate cancer; r An unknwn r Limited Family Histry. Individuals with a BRCA ½ pathgenic mutatin detected in tumr tissue. Genetic testing fr BRCA1 and BRCA2 fr individuals withut a persnal histry f a related cancer is prven and medically necessary in the fllwing situatins: When there is a knwn BRCA1/BRCA2 mutatin in a Clse Bld Relative (defined as first-, secnd- r thirddegree relative). When there is at least ne f the fllwing familial risk factrs: At least ne first- r secnd-degree bld relative meeting any f the abve criteria fr individuals with a persnal histry f a related cancer; r At least ne third-degree bld relative with Breast Cancer and/r Ovarian Cancer wh has at least tw Clse Bld Relatives with Breast Cancer (at least ne with Breast Cancer at age 50 r yunger) and/r Ovarian Cancer. Genetic testing fr BRCA1 and/r BRCA2 testing is unprven and nt medically necessary fr all ther indicatins including: Screening fr Breast r Ovarian Cancer risk fr individuals nt listed in the prven indicatins abve; r Risk assessment f ther cancers; r Cnfirmatin f direct t cnsumer genetic testing withut meeting any f the prven indicatins abve. Further evidence is needed t establish the clinical utility f testing in ther ppulatins. Multi-Gene Hereditary Cancer Panel Testing Criteria Genetic testing with a multi-gene hereditary cancer panel in individuals with an indicatin fr testing fr hereditary breast and Ovarian Cancer is prven and medically necessary if all f the fllwing criteria are met: The suspected hereditary cancer syndrmes can be diagnsed by testing f ne r mre genes included in the specific hereditary cancer panel; and The results f testing will directly impact this patient s medical management; and The individual meets at least ne f the criteria in Hereditary Breast and Ovarian Cancer (BRCA1/BRCA2) (see abve sectin); and The individual has a family histry r persnal histry that is strngly suggestive f mre than ne hereditary cancer syndrme including at least ne f the fllwing: A persnal histry f at least tw different cancers (e.g., Breast Cancer and Ovarian Cancer). A persnal histry f cancer diagnsed at age 40 r yunger. A persnal histry f cancer and at least ne relative with a cancer assciated with Lynch Syndrme (i.e., brain, clrectal, endmetrial, gastric, varian, pancreatic, renal pelvis, small intestine, r ureter cancers, sebaceus adenmas, sebaceus carcinmas, and keratacanthmas). At least ne clse bld relative diagnsed with Breast Cancer, Ovarian Cancer, prstate cancer r pancreatic cancer at age 40 r yunger. At least three Clse Bld Relatives n the same side f the family diagnsed with any cancer. Genetic Testing fr Hereditary Cancer Page 2 f 20

3 Genetic testing with a multi-gene cancer panel in individuals with an indicatin fr testing fr hereditary clrectal cancer is prven and medically necessary in the fllwing situatins: The suspected hereditary cancer syndrmes can be diagnsed by testing f ne r mre genes included in the specific hereditary cancer panel; and The results f testing will directly impact this individual s medical management; and The individual has a persnal r family histry with at least ne f the fllwing criteria fr Hereditary Clrectal Cancer/Lynch Syndrme Cancer r clrectal plypsis syndrme: Men with a persnal histry f clrectal cancer r wmen with a persnal histry f clrectal r endmetrial cancer diagnsed at age 50 r yunger. Men with a persnal histry f clrectal cancer r wmen with a persnal histry f clrectal r endmetrial cancer diagnsed at age 51 r later with at least ne f the fllwing criteria: A persnal histry f anther cancer assciated with Lynch Syndrme (i.e., brain, gastric, varian, pancreatic, renal pelvis, small intestine, r ureter cancers, sebaceus adenmas, sebaceus carcinmas, and keratacanthmas); r Tumr testing results shwing that their clrectal r endmetrial cancer was MSI-high r had immunhistchemical (IHC) staining shwing the absence f ne r mre mismatch repair prteins (MLH1, MSH2, MSH6 r PMS2) A persnal histry f clrectal plypsis with at least 10 adenmatus plyps, at least 2 hamartmatus plyps, r at least 5 serrated plyps. At least ne Clse Bld Relative with a diagnsis f clrectal cancer r endmetrial cancer at age 50 r yunger. At least ne Clse Bld Relative with at least tw cancers assciated with Lynch Syndrme (i.e., brain, clrectal, endmetrial, gastric, varian, pancreatic, renal pelvis, small intestine, r ureter cancers, sebaceus adenmas, sebaceus carcinmas, and keratacanthmas). Tw r mre Clse Bld Relatives with a cancer assciated with Lynch Syndrme (i.e., brain, clrectal, endmetrial, gastric, varian, pancreatic, renal pelvis, small intestine, r ureter cancers, sebaceus adenmas, sebaceus carcinmas, and keratacanthmas), with at least ne diagnsed at age 50 r yunger. Three r mre Clse Bld Relatives with a cancer assciated with Lynch Syndrme (i.e., brain, clrectal, endmetrial, gastric, varian, pancreatic, renal pelvis, small intestine, r ureter cancers, sebaceus adenmas, sebaceus carcinmas, and keratacanthmas) diagnsed at any age. At least ne Clse Bld Relative with a clinical diagnsis f Familial Adenmatus Plypsis, Attenuated Familial Adenmatus Plypsis, Juvenile Plypsis Syndrme, r Peutz-Jeghers Syndrme. A PREMM5, PREMM1,2,6, MMRpr, r MMRpredict Scre f 5% r greater fr having a Lynch syndrme gene mutatin. Genetic testing with a multi-gene hereditary cancer panel in individuals withut an indicatin fr testing fr hereditary breast and Ovarian Cancer r clrectal cancer is prven and medically necessary in the fllwing situatins: The suspected hereditary cancer syndrmes can be diagnsed by testing f ne r mre genes included in the specific hereditary cancer panel; and The results f testing will directly impact this individual s medical management; and The individual has a family histry r persnal histry that is strngly suggestive f mre than ne hereditary cancer syndrme. Genetic testing with a multi-gene hereditary cancer panel in individuals diagnsed with cancer at age 18 r yunger is prven and medically necessary. Genetic testing with a multi-gene cancer panel is prven and medically necessary in an individual wh has previusly tested negative (indeterminate) fr the high Penetrance genes that are mst likely t explain the persnal r family histry f cancer (e.g., BRCA1/2 fr Breast Cancer and Ovarian Cancer) in the fllwing situatins: The suspected hereditary cancer syndrmes can be diagnsed by testing f ne r mre genes included in the specific hereditary cancer panel; and The results f testing will directly impact this individual s medical management; and The individual s persnal and family histry remains strngly suggestive f an inherited susceptibility that can be diagnsed by testing f ne r mre genes included in the specific hereditary cancer panel including at least ne f the fllwing: A persnal histry f at least tw different cancers (e.g., Breast Cancer and Ovarian Cancer). A persnal histry f cancer diagnsed at age 40 r yunger. A persnal histry f cancer and at least ne relative with a cancer assciated with Lynch Syndrme (i.e., brain, clrectal, endmetrial, gastric, varian, pancreatic, renal pelvis, small intestine, r ureter cancers, sebaceus adenmas, sebaceus carcinmas, and keratacanthmas). Genetic Testing fr Hereditary Cancer Page 3 f 20

4 At least ne Clse Bld Relative diagnsed with Breast Cancer, Ovarian Cancer, prstate cancer r pancreatic cancer at age 40 r yunger. At least three Clse Bld Relatives n the same side f the family diagnsed with any cancer. Multi-gene hereditary cancer panels are unprven and nt medically necessary fr all ther indicatins. DEFINITIONS Please nte, fr the purpse f this plicy: Age Guidelines: Fr the statements that include Age Guidelines, a persn is cnsidered t be 45 years f age up until the day befre their 46 th birthday, and a persn is cnsidered t be 50 years f age up until the day befre their 51 st birthday. Breast Cancer: Either invasive carcinmas r nn-invasive (in situ) ductal carcinma types. (NCCN 2018a) Clse Bld Relatives: Are defined as fllws (NCCN 2017): First degree relatives include parents, siblings, and ffspring Secnd degree relatives include half-brthers/sisters, aunts/uncles, grandparents, grandchildren and nieces/nephews affected n the same side f the family Third degree relatives include first cusins, great-aunts/uncles, great-grandchildren and great grandparents affected n same side f family Funder Mutatin: A Funder Mutatin is a gene mutatin bserved with high frequency in a grup that is r was gegraphically r culturally islated, in which ne r mre f the ancestrs were a carrier f the mutant gene. This phenmenn is ften called a Funder effect (Natinal Cancer Institute website). (NCCN 2017) Gleasn Scring: Gleasn scring is a system f grading prstate cancer tissue based n hw it lks under a micrscpe. Gleasn Scres range frm 2 t 10 and indicate hw likely it is that a tumr will spread. A lw Gleasn Scre means the cancer tissue is similar t nrmal prstate tissue and the tumr is less likely t spread. A high Gleasn Scre means the cancer tissue is very different frm nrmal and the tumr is mre likely t spread. (NCI, 2018b) Limited Family Histry: Defined as having fewer than tw knwn first-degree r secnd-degree female relatives r female relatives surviving beynd 45 years f age n either r bth sides f the family (e.g., individual wh is adpted). (NCCN 2017) Lynch Syndrme Cancers: Clrectal, endmetrial, gastric, varian, pancreatic, ureter and renal pelvis, brain (usually gliblastma), and small intestinal cancers, and sebaceus adenmas, sebaceus carcinmas, and keratacanthmas as seen in Muire-Trre syndrme. (NCCN, 2017b) Ovarian Cancer: Includes fallpian tube cancers and primary peritneal carcinma. (NCCN, 2018) Penetrance: The prbability f a clinical cnditin develping in the presence f a specific genetic variant/mutatin. (Daly et al. 2017) Persnal and Family Histry Dcumentatin: in the frm f a pedigree drawing/diagram utilizing standardized nmenclature, shuld be in the cntempraneus medical recrds submitted with the testing request (i.e., request frm) (NCCN, 2017b). PREMM (PREdictin Mdel fr gene Mutatins): The PREMM mdel estimates the verall cumulative prbability f having an MLH1, MSH2, MSH6, PMS2, and EPCAM gene mutatin. Triple-Negative Breast Cancer: Refers t any Breast Cancer that des nt shw expressin f estrgen receptrs (ER), prgesterne receptrs (PR) r HER2/neu. (NCCN, 2017a) APPLICABLE CODES The fllwing list(s) f prcedure and/r diagnsis cdes is prvided fr reference purpses nly and may nt be all inclusive. Listing f a cde in this plicy des nt imply that the service described by the cde is a cvered r nncvered health service. Benefit cverage fr health services is determined by the member specific benefit plan dcument and applicable laws that may require cverage fr a specific service. The inclusin f a cde des nt imply any right t reimbursement r guarantee claim payment. Other Plicies may apply. Genetic Testing fr Hereditary Cancer Page 4 f 20

5 CPT Cde BRCA1 and BRCA Multi-Gene Panel Descriptin BRCA1 (BRCA1, DNA repair assciated), BRCA2 (BRCA2, DNA repair assciated) (e.g., hereditary breast and varian cancer) gene analysis; full sequence analysis and full duplicatin/deletin analysis (i.e., detectin f large gene rearrangements) BRCA1 (BRCA1, DNA repair assciated), BRCA2 (BRCA2, DNA repair assciated) (e.g., hereditary breast and varian cancer) gene analysis; full sequence analysis BRCA1 (BRCA1, DNA repair assciated), BRCA2 (BRCA2, DNA repair assciated) (e.g., hereditary breast and varian cancer) gene analysis; full duplicatin/deletin analysis (i.e., detectin f large gene rearrangements) BRCA1 (BRCA1, DNA repair assciated) (e.g., hereditary breast and varian cancer) gene analysis; full sequence analysis BRCA1 (BRCA1, DNA repair assciated) (e.g., hereditary breast and varian cancer) gene analysis; full duplicatin/deletin analysis (i.e., detectin f large gene rearrangements) BRCA2 (BRCA2, DNA repair assciated) (e.g., hereditary breast and varian cancer) gene analysis; full duplicatin/deletin analysis (i.e., detectin f large gene rearrangements) BRCA1 (BRCA1, DNA repair assciated), BRCA2 (BRCA2, DNA repair assciated) (e.g., hereditary breast and varian cancer) gene analysis; 185delAG, 5385insC, 6174delT variants BRCA1 (Breast Cancer 1) (e.g., hereditary breast and varian cancer) gene analysis; knwn familial variant BRCA2 (Breast Cancer 2) (e.g., hereditary breast and varian cancer) gene analysis; full sequence analysis BRCA2 (Breast Cancer 2) (e.g., hereditary breast and varian cancer) gene analysis; knwn familial variant Hereditary Breast Cancer-related disrders (e.g., hereditary Breast Cancer, hereditary varian cancer, hereditary endmetrial cancer); genmic sequence analysis panel, must include sequencing f at least 10 genes, always including BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, PALB2, PTEN, STK11, and TP53 Hereditary Breast Cancer-related disrders (e.g., hereditary Breast Cancer, hereditary varian cancer, hereditary endmetrial cancer); duplicatin/deletin analysis panel, must include analyses fr BRCA1, BRCA2, MLH1, MSH2, and STK11 Hereditary cln cancer disrders (e.g., Lynch syndrme, PTEN hamartma syndrme, Cwden syndrme, familial adenmatsis plypsis); genmic sequence analysis panel, must include sequencing f at least 10 genes, including APC, BMPR1A, CDH1, MLH1, MSH2, MSH6, MUTYH, PTEN, SMAD4, and STK11 Hereditary cln cancer disrders (e.g., Lynch syndrme, PTEN hamartma syndrme, Cwden syndrme, familial adenmatsis plypsis); duplicatin/deletin analysis panel, must include analysis f at least 5 genes, including MLH1, MSH2, EPCAM, SMAD4, and STK11 Hereditary neurendcrine tumr disrders (e.g., medullary thyrid carcinma, parathyrid carcinma, malignant phechrmcytma r paraganglima); genmic sequence analysis panel, must include sequencing f at least 6 genes, including MAX, SDHB, SDHC, SDHD, TMEM127, and VHL Hereditary neurendcrine tumr disrders (e.g., medullary thyrid carcinma, parathyrid carcinma, malignant phechrmcytma r paraganglima); duplicatin/deletin analysis panel, must include analyses fr SDHB, SDHC, SDHD, and VHL CPT is a registered trademark f the American Medical Assciatin DESCRIPTION OF SERVICES Genetic testing fr hereditary cancer susceptibility is used t predict an individual's risk f cancer develpment in the future. It has been estimated that 5-10% f all cancers are hereditary. (Heald et al. 2016) Genetic Testing fr Hereditary Cancer Page 5 f 20

6 Hereditary Breast and Ovarian Cancer (BRCA1/BRCA2) Breast Cancer is the secnd mst cmmn cause f cancer-related deaths amng wmen. The inherited tendency t develp Breast and Ovarian Cancer has been termed the hereditary Breast and Ovarian Cancer syndrme (HBOC). Mutatin in either f tw genes, BRCA1 and BRCA2, has been assciated with an increased risk fr Breast Cancer and Ovarian Cancer. A deleterius mutatin in either gene may be inherited frm either parent; and later an acquired mutatin f the ther allele can lead t cancer develpment. It has been estimated that inherited BRCA1 and BRCA2 mutatins accunt fr 5 t 10 percent f Breast Cancers and 10 t 15 percent f Ovarian Cancers amng white wmen in the United States. (Natinal Cancer Institute [NCI], 2015) Harmful BRCA1 mutatin may als increase a wman s risk f develping ther cancers. Men with a harmful BRCA1 mutatin als have an increased risk f Breast Cancer and, pssibly, f pancreatic cancer, testicular cancer, and earlynset prstate cancer. Hwever, male Breast Cancer, pancreatic cancer, and prstate cancer appear t be mre strngly assciated with BRCA2 gene mutatin. (Thmpsn and Eatn, 2002; NCCN, 2017) Multi-Gene Hereditary Cancer Panels Multi-gene hereditary cancer panels using next generatin sequencing technlgy are currently available, and many different test panels are marketed cmmercially, mst f which als include large deletin/duplicatin analysis. These panels are intuitively attractive because they can rapidly test fr numerus mutatins bth within a single gene and acrss multiple genes related t increased cancer risks. It is als pssible that these multi-gene tests can, in the case f families where mre than ne hereditary cancer syndrme is suspected, be perfrmed mre cst effectively than stepwise individual gene testing. Hwever, many f these panel tests als include lw t mderate-risk genes that may result in the identificatin f gene mutatins that are f unclear clinical significance r which wuld nt clearly direct a patient s medical management recmmendatins. Identificatin f mutatins fr which the clinical management is uncertain may lead t unnecessary fllw-up testing and prcedures, all f which have their wn inherent risks. (NCCN 2017; NCCN 2018b; LaDuca et al., 2014; Rbsn et al., 2015; Kurian et al., 2014; Tung et al., 2015; Pln et al., 2011) CLINICAL EVIDENCE Genetic testing fr hereditary cancer susceptibility is used t predict an individual's risk f cancer develpment in the future. It has been estimated that 5-10% f all cancers are hereditary (Heald et al. 2016). Hereditary cancers typically have an earlier age f nset and have an autsmal dminant pattern f inheritance bservable in a family (NCCN, 2017a). A small subset f these inherited cancers, abut 15-20%, may be the result f a cmplex interactin between multiple genes. (ASCO 2018) T identify if an individual has an increased risk f having a hereditary cancer, it is imprtant t take a detailed family histry that includes first, secnd and third degree relatives that fcuses n cancer diagnses by age f nset, primary site(s), presence f bilateral disease, and current age r age at time f death. Other cnditins that can be a feature f hereditary cancers shuld be nted, as well as medical and surgical histry. The individual shuld have a thrugh physical exam perfrmed by a clinician with familiarity with hereditary cancer syndrme. When applicable, risk assessment tls shuld be utilized t help identify the risk an individual has a hereditary cancer gene (NCCN 2017). Sme examples f tls include BRCAPRO, the Breast and Ovarian Cancer Analysis f Disease Incidence and Carrier Estimatin Algrithm (BOADICEA) (NCCN 2017) and Predictin f MLH1 and MSH2 Mdel (PREMM) (NCCN 2018b). Genetic testing is recmmended generally when there is a persnal r family histry cnsistent with a hereditary cancer susceptibility, the test can be adequately interpreted, and the results can be used t diagnse r influence the medical management f the individual r at risk family members. (Rbsn et al. 2015) Table 1 lists cmmn cancers that can be hereditary, the assciated genes, and references that can be utilized t learn abut each hereditary cancer syndrme in mre detail. Hereditary Cancer Syndrme(s) Hereditary Breast and Ovarian Cancer Gene(s) BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD51C,RAD51D Ɨ, PTEN, TP53, STK11, NBN, ATM, CDH1 Assciated Cancer(s) and References Breast (Antniu et al. 2003; Chen et al. 2006; Hilgart et al 2012; Shivitz 2015, Daly et al. 2017) Ovarian (Risch et al. 2001; Chen et al. 2006; Lancaster et al 2015) Fallpian tube (Medeirs et al. 2006; Lancaster et al 2015) Primary peritneal (Casey et al. 2005; Finch et al. 2012; Lancaster et al 2015) Pancreatic (BCLC, 1999; van Asperen et al. 2005; Mersch et al 2015) Prstate (Risch et al. 2001; Thmpsn et al. 2002; van Asperen Genetic Testing fr Hereditary Cancer Page 6 f 20

7 Hereditary Cancer Syndrme(s) Familial adenmatus plypsis (FAP) Ataxia-telangiectasia PTEN hamartma tumr syndrme/cwden syndrme Hereditary nnplypsis cln cancer (HNPCC)/Lynch syndrme Peutz-Jeghers syndrme Li-Fraumeni syndrme Hereditary diffuse gastric cancer syndrme Juvenile plypsis syndrme Hereditary mixed plypsis APC ATM PTEN Gene(s) EPCAM, MLH1, MSH2, MSH6, PMS1, PMS2 STK11 (LKB1) TP53 Assciated Cancer(s) and References et al. 2005; Mersch et al 2015) Melanma (BCLC, 1999; Mersch et al 2015) Gastric/stmach (BCLC, 1999) Breast (He et al. 2016) Ovarian (Mstwska et al. 2014) Clrectal (Feng et al. 2014; Slwik et al. 2015; Leshn et al. 2016) Pancreatic (Leshn et al. 2016) Skin (Leshn et al. 2016) Thyrid (Septer et al. 2013) Breast (Marabelli et al. 2016) Sarcma (Ballinger et al. 2016) Lung (Bhwmik et al. 2015; Huang et al. 2016) Gastric (Helgasn et al. 2015) Melanma (Antnpulu et al. 2015) Pancreatic (Rberts et al. 2016) Breast (Slattery et al. 2012; Ozturk et al. 2013) Endmetrial (Eng, 2016) Gastric/digestive (Ga et al. 2013) Clrectal (Jing et al. 2014) Thyrid (Eng, 2016) Breast (Smlarz et al. 2015; Kappil et al. 2016; Stffel et al. 2015; Bland, 2018) Ovarian (Watsn et al. 2008; Bnadna et al. 2011; Auranen, 2011) Clrectal (Senter et al. 2008; Raskin et al. 2011) Hepatcellular (Khlmann and Gruber, 2014) Endmetrial/uterine (Raskin et al. 2011; Castellsagué et al. 2015; Watsn et al. 2008; Renknen-Sinisal, 2007; Auranen, 2011) Breast (Bardman et al. 1998) Ovarian (McGarrity et al. 2016) Clrectal (Slattery et al. 2010) Gastric (Giardiell et al. 1987) Pancreatic (Klein et al. 2001) Breast (Sagne et al. 2013; Mai et al. 2016) Ovarian (Schildkraut et al. 2010) Brain/CNS (Mai et al. 2016) Prstate (Brges and Ayres, 2015) Sarcma (Mai et al. 2016) Thyrid (Chen et al. 2015) CDH1 Breast (Benusigli et al. 2013; Hansfrd et al. 2015) Gastric (Hansfrd et al. 2015) BMPR1A, SMAD4 Gupta et al. (2017) POLD1, GREM1, POLE Gupta et al. (2017) BRCA1/BRCA2 The BRCA1 and BRCA2 genes are assciated with causing HBOC. This syndrme results in an increased risk fr Breast Cancer fr men and wmen, and an increased risk fr Ovarian Cancer in wmen. Other cancers have been assciated with HBOC, particularly with BRCA2 variants, including prstate, pancreatic and melanma. Management f HBOC fr thse with cancer includes bilateral masectmy due t the high risk f Breast Cancer. Treatment f varian and ther Genetic Testing fr Hereditary Cancer Page 7 f 20

8 cancers is similar t spradic cancers. Preventative measures fr asymptmatic individuals includes prphylactic bilateral masectmy and pherectmy, chempreventin, and increased surveillance. (Petrucelli et al. 2016) Testing fr BRCA1 and BRCA2 can include targeted variants fr at risk ppulatins, such as fr thse with Ashkenazi Jewish ancestry, full gene sequencing, and duplicatin/deletin analysis. BRCA1 accunts fr abut 66% f HBOC, and sequence analysis can identify variants in abut 80% f cases fr bth BRCA1 and BRCA2. Duplicatin/deletin testing identifies variants in each gene in an additinal 10% f cases. (Petrucelli et al. 2016) The Natinal Cmprehensive Cancer Netwrk (NCCN) guidelines present evidence based specific criteria fr genetic testing fr hereditary breast and/r Ovarian Cancer syndrme caused by BRCA1/BRCA2. The guidelines address genetic risk assessment, cunseling, testing and management based n test results (NCCN 2018b). The recmmended NCCN criteria fr testing include: Thse diagnsed with Ovarian Cancer A knwn BRCA1/BRCA2 mutatin in the family Breast Cancer diagnsed at age with: An additinal breast primary A Clse Bld Relative with high-grade (Gleasn Scre >7) prstate cancer An unknwn r limited family histry Triple negative Breast Cancer diagnsed < age 60 Tw Breast Cancer primaries in an individual Breast Cancer at any age with: At least ne Clse Bld Relative with Breast Cancer diagnsed age 50 r yunger, r Ovarian Cancer r male Breast Cancer, r pancreatic cancer, r metastatic prstate cancer. At least tw Clse Bld Relatives with Breast Cancer diagnsed at any age Ashkenazi Jewish Ancestry Diagnsed with male Breast Cancer Diagnsed with metastatic prstate cancer Diagnsed with high-grade prstate cancer (Gleasn Scre>7) with: At least ne clse bld relative with Breast Cancer diagnsed age 50 r yunger, r Ovarian Cancer, r pancreatic cancer, r metastatic prstate cancer At least tw Clse Bld Relatives with Breast Cancer r prstate cancer diagnsed at any age Ashkenazi Jewish ancestry BRCA1/2 pathgenic r likely pathgenic variant detected by tumr prfilingin additin, (NCCN recmmends testing an individual in a family with a cancer diagnsis first shuld be discussed. If there are n living family members with breast r Ovarian Cancer available fr testing, cnsider testing family members affected with ther cancers assciated with BRCA1/BRCA2, such as prstate cancer (Gleasn Scre 7 r metastatic), pancreatic cancer r melanma. Due t ptential difficulting in interpreting testing results in an unaffected persn, testing f individuals withut a cancer diagnsis shuld nly be cnsidered when there is n affected family member available fr testing. (NCCN, 2017a) The U.S. Preventive Services Task Frce (Myer, 2014) recmmends that primary care prviders screen wmen wh have family members with breast, varian, tubal r peritneal cancer with ne f several screening tls designed t identify a family histry that may be assciated with an increased risk fr ptentially harmful mutatins in Breast Cancer susceptibility genes (BRCA1 r BRCA2). Tls include the Ontari Family Histry Assessment Tl, Manchester Scring System, Referral Screening Tl, Pedigree Assessment Tl, and FHS-7. Wmen with psitive screening results shuld receive genetic cunseling and, if indicated after cunseling, BRCA testing (Grade B). Screening shuld ccur at age 18, and every 5-10 years after that t assess fr family histry changes. In additin, the USPSTF recmmends against rutine genetic cunseling r BRCA testing fr wmen whse family histry is nt assciated with an increased risk fr ptentially harmful mutatins in the BRCA1 r BRCA2 genes (Grade D). Klr et al. (2017) reviewed medical claims frm fr BRCA testing and resulting interventins amng wmen ages with emplyer spnsred health care. They nted that BRCA testing increased 2.3 times in metrplitan and 3.0 times in nn-metrplitan areas during the study perid. Receipt f preventative services within 90 days f testing als varied between these regins, with the exceptin f mastectmy (6-10% f testers ver the study perid). Wmen were less likely t receive a MRI f the breast in nn-metrplitan areas (8.2% vs. 10.3%), as well as mammgraphy (11.5% vs. 13.8%). Receipt f genetic cunseling befre r after testing was mre cmmn in the metrplitan grup, but in bth grups, an increase was seen ver the study perid frm 5.3-8% in metrplitan areas and % in nn-metrplitan areas. Overtime the disparities between the tw grups was reduced, and the authrs nte that the implementatin f the USPSTF guidelines and the availability f BRCA cunseling and testing under the Affrdable Care Act in September f 2010 may have influenced the increase in test and the reductin in differences between the tw grups. The highest rate f BRCA testing in the study was wmen per 100,000 wmen aged which is cmparable t the estimated prevalence f BRCA mutatins in the general US ppulatin. Genetic Testing fr Hereditary Cancer Page 8 f 20

9 Of 211 Ashkenazi Jewish Breast Cancer prbands with a family histry f pancreatic cancer, Stadler et al. (2011) fund that 30 (14.2%) harbred a BRCA mutatin. Furteen (47%) f the mutatins were in BRCA1 and 16 (53%) were in BRCA2. Patients diagnsed with Breast Cancer at age 50 years were fund t have a higher BRCA1/2 mutatin prevalence than prbands with Breast Cancer wh were diagnsed at age > 50 years (21.1% vs 6.9%). In patients with a first-, secnd-, r third-degree relative with pancreatic cancer, mutatin prevalence was 15.4%, 15.3% and 8.6%, respectively. The authrs fund that BRCA1 and BRCA2 mutatins are bserved with nearly equal distributin in Ashkenazi Jewish breast-pancreas cancer families, suggesting that bth genes are assciated with pancreatic cancer risk. Ferrne et al. (2009) lked at the prevalence f BRCA1 and BRCA2 in an unselected grup f Jewish patients and cmpared patients with resected BRCA mutatin-assciated pancreatic adencarcinma (PAC) t PAC patients withut mutatins. Of the 187 Jewish patients wh underwent resectin fr PAC, tissue was available fr 145 patients. Funder mutatins fr BRCA1 and BRCA2 were identified in 5.5% f patients (tw with BRCA1 [1.3%] and six with BRCA2 [4.1%]). A previus cancer was reprted by 24% (35 f 145) f patients with the mst cmmn sites being Breast Cancer (9 f 35; 74%) and prstate cancer (8 f 35; 23%). Several studies have shwn that BRCA1 Breast Cancer is mre likely t be characterized as triple-negative. Studies have reprted BRCA1 mutatins in 9-28% f patients with triple-negative Breast Cancer. In additin, it appears that amng patients with triple-negative disease, BRCA mutatin carriers were diagnsed at a yunger age cmpared with nn-carriers. (NCCN 2017) The triple-negative Breast Cancer phentype, which carries an adverse prgnsis, accunts fr 80% t 90% f BRCA1-assciated Breast Cancers. A study f 54 wmen with triple-negative Breast Cancer aged 40 years r yunger, wh were nt cnsidered candidates fr BRCA testing because f the lack f a strng family histry, shwed five with BRCA1 mutatins and ne with a BRCA2 mutatin (11% mutatin prevalence). (Natinal Cancer Institute 2018a; Yung et al. 2009) In a chrt f triple negative Breast Cancer patients, Gnzalez-Angul et al. (2011) fund a 19.5% incidence f BRCA mutatins. Median age was 51 years (27-83 years). The authrs recmmend that genetic testing be discussed with patients with triple negative Breast Cancer. Almst 10% f wmen with Breast Cancer wh are yunger than age 50 have BRCA mutatins. Mst f the BRCApsitive wmen d nt have persnal r family histries f breast r Ovarian Cancer and are nt f Ashkenazi Jewish ancestry. Using a simulatin mdel, Kwn et al. (2010) evaluated six ppulatins f wmen yunger than 50 with Breast Cancer, lking at csts and health benefits. The results led the authrs t cnclude that testing wmen with triple negative Breast Cancers wh were yunger than 50 years fr BRCA mutatins shuld be adpted int current guidelines fr genetic testing. The prevalence f BRCA1/2 LRs was investigated in 48,456 patients with diverse clinical histries and ancestries that were referred fr clinical mlecular testing fr suspicin f hereditary breast and Ovarian Cancer. Prevalence data was analyzed fr patients frm different risk and ethnic grups. Patients were designated as high-risk (n=25,535) if their clinical histry predicted a high prir prbability. Fr these patients, large rearrangement (LR) testing was perfrmed autmatically in cnjunctin with sequencing. Elective patients (n=22,921) did nt meet the high-risk criteria, but underwent LR testing if BRCA1/2 sequencing indicated n knwn mutatins. Overall BRCA1/2 mutatin prevalence amng high-risk patients was 23.8% versus 8.2% fr the elective grup. The mutatin prfile fr highrisk patients was 90.1% sequencing mutatins versus 9.9% LRs, and fr elective patients, 94.1% sequencing versus 5.9% LRs. The authrs nted that this difference may reflect the bias in high-risk patients t carry mutatins in BRCA1, which has a higher penetrance and frequency f LRs cmpared with BRCA2. Significant differences in the prevalence and types f LRs were fund in patients f different ancestries. LR mutatins were significantly mre cmmn in Latin American/Caribbean patients. (Judkins et al., 2012) A study (Walsh 2006) fund that the nly genetic test cmmercially available in the United States t determine risk fr develpment f hereditary Breast Cancer failed t detect BRCA1 and BRCA2 mutatins in apprximately 12% f Breast Cancer patients (n=300) wh were members f a family with at least fur cases f Breast Cancer and/r Ovarian Cancer. In this study, researchers retested participants fr carrier status f genetic mutatins knwn t influence risk fr develpment f Breast Cancer using a mlecular methd nt currently cleared fr market in the United States knwn as multiplex ligatin-dependent prbe amplificatin (MLPA). Prir t enrllment, all participants had received a negative result frm the Breast Cancer genetic test (Myriad Genetics Inc.) used rutinely in the United States. The results f MLPA analysis indicated that 17% f study participants were, in fact, carriers f Breast Cancer-relevant genetic mutatin, with 12% fund t have alteratins f BRCA1 r BRCA2. Inherited alteratins f BRCA1 were mre frequent amng participants wh were diagnsed with Breast Cancer prir t 40 years f age (16%) than amng thse wh were lder when diagnsed (6.5%). The clinical implicatins f these Genetic Testing fr Hereditary Cancer Page 9 f 20

10 findings cannt be generalized t ther ppulatins, but results strngly suggest that imprved methds fr determining Breast Cancer risk are needed fr individuals with strng family histries f breast and/r Ovarian Cancer. Unger et al. (2000) assessed the frequency f genmic rearrangements in BRCA1 was in 42 American families with breast and Ovarian Cancer wh were seeking genetic testing and wh were subsequently fund t be negative fr BRCA1 and BRCA2 cding-regin mutatins. The exn 13 duplicatin was detected in ne family, and fur families had ther genmic rearrangements. A ttal f 5 (11. 9%) f the 42 families with breast/ovarian Cancer wh did nt have BRCA1 and BRCA2 cding-regin mutatins had mutatins in BRCA1 that were missed by cnfrmatin-sensitive gel electrphresis r sequencing. Fur f five families with BRCA1 genmic rearrangements included at least ne individual with bth breast and Ovarian Cancer; therefre, fur (30.8%) f 13 families with a case f multiple primary breast and Ovarian Cancer had a genmic rearrangement in BRCA1. Families with genmic rearrangements had prir prbabilities f having a BRCA1 mutatin, ranging frm 33% t 97% (mean 70%). In cntrast, in families withut rearrangements, prir prbabilities f having a BRCA1 mutatin ranged frm 7% t 92% (mean 37%). Prfessinal Scieties American Cllege f Obstetricians and Gyneclgists (ACOG) In a 2009 practice bulletin (reaffirmed 2015), the ACOG recmmended criteria fr genetic risk assessment f hereditary breast and Ovarian Cancer syndrme (HBOC). These recmmendatins cnclude: BRCA psitive wmen shuld be ffered salping-phrectmy by age 40 r when childbearing is cmpleted. Fr a risk reducing bilateral salping-phrectmy, all tissue frm the varies and fallpian tubes shuld be remved. Thrugh visualizatin f the peritneal surfaces with pelvic washings shuld be perfrmed. Cmplete, serial sectining f the varies and fallpian tubes is necessary, with micrscpic examinatin fr ccult cancer. Genetic risk assessment is recmmended fr patients with a greater than an apprximate 20-25% chance f having an inherited predispsitin t Breast Cancer and Ovarian Cancer. This includes wmen with the fllwing: A clse relative (mther, sister, daughter, grandmther, granddaughter, aunt r niece) with a knwn BRCA mutatin Persnal histry f bth breast and Ovarian Cancer Ovarian Cancer and a clse relative with Ovarian Cancer r premenpausal Breast Cancer r bth Ovarian Cancer and Ashkenazi Jewish ancestry Breast Cancer by age 40 years and Ashkenazi Jewish ancestry Breast Cancer by age 50 years and a clse relative with Ovarian Cancer r male Breast Cancer Additinally, in a 2017 Cmmittee Opinin (ACOG 2017), ACOG recmmends that wmen with a strng family histry f varian, breast, r cln cancer may have a BRCA mutatin r Lynch Syndrme, and shuld be referred fr frmal genetic cunseling t assess their cancer risk, and if apprpriate, be ffered testing. American Sciety f Clinical Onclgy (ASCO) An ASCO plicy statement recmmends that genetic testing fr cancer susceptibility be perfrmed when the fllwing three criteria are met: the individual being tested has a persnal r family histry suggestive f genetic cancer susceptibility; the test can be adequately interpreted; and the test results have accepted clinical utility. (Rbsn et al., 2015) Natinal Sciety f Genetic Cunselrs (NSGC) The NSGC recmmends that genetic testing be perfrmed in the cntext f an infrmed decisin-making prcess. (Berliner et al., 2013) The prcess f cancer risk assessment and genetic cunseling fr hereditary breast and Ovarian Cancer syndrme requires many steps, including the fllwing: Gathering persnal medical and family histry data Psychscial assessment Discussin f cancer and mutatin risk and hw persnalized risk estimates are derived Facilitatin f the infrmed cnsent prcess thrugh discussin f the risks, benefits, limitatins, and likelihd f identifying a mutatin with genetic susceptibility testing Results disclsure (if applicable) Discussin f medical management ptins Review f issues related t genetic discriminatin Multi-Gene Hereditary Cancer Panels Multi-gene hereditary cancer panels can be used t investigate varius cancers thrugh the use f evaluating multiple genes simultaneusly. In sme situatins, the use f a multi-gene panel test may result in a cst and time efficient apprach. This is mst useful where multiple high-penetrance genes with actinable results are pssible because it is difficult t predict which gene is mst likely t be mutated based n persnal r family medical histry. (Rbsn et al. 2015) Genetic Testing fr Hereditary Cancer Page 10 f 20

11 In a study by Gardner et al. (2018), 630 individuals were tested with a 27-gene inherited cancer panel and 84% had a family histry f cancer. Of these individuals, 65 were determined t have variants classified as pathgenic r likely pathgenic acrss 14 genes (10.3%). Only 42% f these variants ccurred in classic HBOC r Lynch Syndrmeassciated genes, while 58% were bserved in high r mderate t lw risk genes n the panel. The researchers cncluded that there is utility t using multi-gene panels ver single gene testing particularly in thse with an inherited predispsitin t cancer. Daly et al. (2017) prvided an verview t NCCN breast and varian cancer susceptibility screening guideline updates, and Gupta et al. (2017) published insights regarding the NCCN 2017 updated fr susceptibility screening fr clrectal cancer syndrmes, specifically arund multigene cancer panels. They cmmented that multigene testing shuld fcus n clinically actinable genes, and avid the inclusin f lw t mderate risk genes that lack evidence regarding risk management strategies. After review f available evidence, Daly et al. (2017) identified the knwn high and mderate penetrance genes with available guidelines r recmmendatins n risk surveillance and/r management, which included fr breast and varian cancer, BRCA1/2, TP53, and PTEN (high penetrance) and ATM, BRIP1, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and STK11 (mderate penetrance). Gupta et al. (2017) nted that high r mderate penetrance genes with published guidelines r recmmendatins fr risk management/surveillance included APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53, POLD1, GREM1, and POLE. Bth authrs nted that these lists are nt an endrsement by NCCN f specific genes r panels, but was prvided fr educatinal purpses t aid clinicians in selecting an apprpriate panel fr their patients. Crawfrd et al (2017) tested 300 wmen wh previusly tested negative fr BRCA1/2. All f the subjects met additinal criteria including: a persnal histry f bilateral Breast Cancer; r a persnal histry f Breast Cancer and a first r secnd degree relative with varian cancer; r a persnal histry f varian, fallpian tube, r peritneal carcinma. The testing determined that 9% f wmen had pathgenic mutatins and 8% had mutatins in genes ther than BRCA1/BRCA2. The researchers cncluded that individuals with additinal criteria may be candidates fr additinal multi-gene panel testing which has imprtant implicatins fr family testing. An analysis f 252,223 individuals by a 25-gene pan-cancer panel was perfrmed by Rsenthal et al. (2017). Of these individuals, the majrity (92.8%) met testing criteria fr Hereditary Breast and Ovarian Cancer (HBOC) and/r Lynch syndrme (LS). Pathgenic variants were identified in 6.7% f the tested individuals with BRCA1/2 (42.2%), ther Breast Cancer (BR) genes (32.9%), and the LS genes (13.2%). Hwever, half f the pathgenic variants in individuals wh met nly HBOC criteria were in nn-brca1/2 genes. Likewise, in individuals wh met LS criteria, half f the pathgenic variants identified were in nn-ls genes. These researchers suggest that a pan-cancer panel may prvide imprved identificatin f pathgenic variants ver single-syndrme testing. Lincln et al. (2015) tested 1105 individuals using a 29-gene next-generatin sequencing panel. The 1105 cases included 1062 clinical cases (735 patients prspectively accrued fllwing NCCN guidelines fr HBOC, 118 patients with knwn familial mutatins, 209 patients retrspectively cllected with high-risk criteria). Of the 1062 clinical cases, 975 had previusly received BRCA1/2 testing and the results shwed a cncrdance f 99.8%. Overall, 260 variants were determined. The 735 prspective patients had 66 patients (9.0%) with a BRCA1 r BRCA2 variant. Twenty-six patients (3.9%) were BRCA-negative, but had variants in ther genes with knwn assciated t breast/varian cancer r thse assciated with Lynch syndrme. Mst cmmn nn-brca findings were ATM (five cases), PALB2 (five cases), CHEK2 (three cases), and the Lynch syndrme genes (eight cases). Anther 2.7% f these BRCA-negative patients were carriers f MUTYH. The high-risk patients (n=2009) were determined t have BRCA1 r BRCA2 in 40% f the patients and f the BRCA-negative individuals, 6.1% were psitive f anther variant. The researchers fund that variants f uncertain significance (VUS) increased as the number f genes was tested. Of the 1062 clinical cases, 41.0% had at least ne VUS and f thse 11.4% had tw r mre. Additinally, 68% f the VUS detected were rare, missense variants that were nt identified in the 1000Genmes Prject. They cncluded that NGS testing f panels can ffer results that may be missed by traditinal testing, but the issue with understanding and addressing VUS remains a challenge. Zhang et al. (2015) studied the prevalence f cancer pre-dispsitin germline mutatins in children and adlescents with cancer in 1,120 patients under the age f 20. Whle exmes were sequenced in 456 patients and whle genmes were sequenced in 595, r bth in 69. Results were analyzed in 565 genes, including 60 that are assciated with autsmal dminant cancer syndrmes. Genetic variant pathgenicity was determined by a team f experts wh relied n peer reviewed literature, cancer and lcus specific databases, cmputatinal predictins, and secnd hits identified in the participant tumr genme. This same variant calling apprach was used t analyze data n 966 cntrls frm the 1000 Genmes Prjects wh were nt knwn t have cancer, and data frm 733 children frm an autism study. Overall, germline mutatins were fund in 95 children with cancer (8.5%), as cmpared t nly 1.1% f 1000 Genme Prject and 0.6% f autism study cntrls. The mutatins were mst cmmnly fund in TP53, APC, BRCA2, NF1, PMS2, RB1 and RUNX3. Eighteen patients als have variants in tumr suppressr genes. Of the 58 Genetic Testing fr Hereditary Cancer Page 11 f 20

12 patients wh had family histry infrmatin available and a mutatin in a predispsing dminant cancer gene, 40% had a significant family histry f cancer. Parsns et. Al (2016) cnducted a study t determine the prevalence f smatic and germline mutatins in children with slid tumrs. Frm August 2012 thrugh June 2014, children with newly diagnsed and previusly untreated central nervus system (CNS) and nn-cns slid tumrs were prspectively enrlled in the study at a large academic children s hspital. Bld and tumr samples underwent whle exme sequencing (WES) in a certified clinical labratry with genetic results categrized by clinical relevance. A ttal f 150 children participated, with a mean age f 7 years, with 80 bys and 70 girls. Tumr samples were available fr WES in 121 patients. In this grup, smatic mutatins with established clinical utility were fund in 4 patients, and mutatins with pssible clinical utility were fund in 29. CTNNB1 had the mst mutatins, fllwed by KIT, TSC2, BRAF, KRAS, and NRAS. Diagnstic germline mutatins related t the child s clinical presentatin was fund in 150 patients and included 13 dminant mutatins in knwn cancer susceptibility genes, including TP53, VHL, and BRCA1. One recessive liver disrder with liver cancer was identified in TJP2 and ne renal cancer, CLCN5. Incidental findings were fund in 8 patients. Nearly all patients (98%) had variants f unknwn significance in knwn cancer genes, drug respnse genes, and genes knwn t be assciated with recessive disrders. Bhlah and Bunchman (2017) published a review f the literature regarding neurendcrine tumrs phechrmcytma (PCC) and paraganglima (PGL) in which they demnstrated that the generally accepted cncept f 10% f cancers are inherited may nt apply t PCC and PGL. They nted that the Eurpean-American- Phechrmcytma-Paraganglima-Registry (EAPPR) has released data that 80% f individuals in their registry had a germline mutatin, and smaller series f reprts gave a germline mutatin prevalence f 30-40%. Genes that are invlved in PCC and PGL include genes respnsible fr knwn neurendcrine syndrmes such as vn Hippel Lindau (VHL), multiple endcrine neplasia type II (RET) and neurfibrmatsis I (NF1), as well as mitchndrial related genes. These include the subunits fr succinate dehydrgenase, SDHA, SDHB, SDHC, SDHD and SDHAF2, and the TMEM, HIPF2A and MAX genes. Variants in these genes can cause rare autsmal dminant PGL-PCC syndrmes with varying penetrance. A retrspective study by Babic et al. (2017) analyzed pediatric phechrmcytmas and paraganglimas t determine the rle f genetic testing. Of 55 patients, 44 (80%) had a germline mutatin with the majrity fund t have either VHL (38%) r SDHB (25%) mutatin. The authrs cncluded that the majrity f pediatric patients with phechrmcytmas and paraganglimas likely have detectable germline mutatins and thus, genetic testing may be helpful t guide treatment. Giri et al. (2018) reprted n a cnsensus cnference fr prstate cancer where the gal was t determine the apprpriate genetic testing rutes. Seventy-ne experts participated in the panel and determined that testing f HOXB13 fr suspected hereditary prstate cancer was cnsidered t have high grade evidence. Similarly, BRCA1/2 mutatins being linked t prstate cancer als prvided high grade evidence. The evidence the panel reviewed fr DNA mismatch repair genes fr suspected Lynch syndrme t prstate cancer risk was cnsidered mderate grade. Bth ATM and NBN mutatins were cnsidered t be emerging but nt quite mderate grade. Other genes n many panels were determined t have lw r insufficient data t determine the prstate cancer risk. The authrs cnclude that additinal research is needed t develp mre apprpriate definitins fr hereditary prstate cancer genetic testing. Pilie et al (2017) used a multigene panel t sequence germline DNA frm 102 men with prstate cancer and at least ne additinal primary cancer wh als met ne f three additinal criteria. The researchers identified ver 3500 variants including deleterius r likely pathgenic germline mutatins in 11 f the 102 men (10.8%) f men. Eight f the men had germline variants in 1 f 6 cancer predispsitin genes including BRCA2 (three cases), ATM (tw cases), and ne case in MLH1. The researchers cncluded that men with prstate cancer and at least 1 additinal primary cancer may have a germline deleterius mutatin. In Octber f 2016, the American Assciatin f Cancer Research (AACR) held the Childhd Cancer Predispsitin Wrkshp. Internatinal experts in care f children with a hereditary risk f cancer met t define surveillance strategies and management f children with cancer predispsitin syndrmes. Several cnsensus publicatins resulted. Achatz, et al. (2017) fcused n inherited plypsis gastrintestinal syndrme cancers f childhd, and published cnsensus guidelines established by their expert panel frm the wrkshp, which included recmmendatins n genetic testing strategies. They nted that children at risk fr an inherited plypsis syndrme are typically identified in tw ways; thrugh family histry, because a clse family member has been diagnsed and secnd, because the child has symptms. In the first clinical scenari, the expert panel recmmends first testing the affected bld relative in rder t ensure that highly accurate and actinable results are available fr the family. Genetic testing in the child shuld be nly fr the familial pathgenic variant, and nt take place until 1 year befre the age at which the first surveillance actin wuld ccur. This allws time fr crdinatin f genetic cunseling and testing. In the secnd scenari, when the child presents with symptms, genetic testing shuld be targeted fr the gene mst likely t be Genetic Testing fr Hereditary Cancer Page 12 f 20