This study is about understanding the use of a genetic test (Myriad Genetics myRisk panel) that analyzes 25 genes related to different hereditary cancer conditions. The investigators hope to learn more about how this type of genetic test is used clinically. The investigators also hope to understand more about the experience of individuals and families who undergoing this test of genetic testing.

If a patient is identified as fulfilling one of the screening criteria, possible participants should be referred to the Cancer Genetics Clinic for further evaluation for possible enrollment into the study. A pre-clinic questionnaire will be sent to the patients prior to their assessment in cancer genetics clinic in order to obtain baseline information that will be used to inform changes during follow-up. Assessments performed exclusively to determine eligibility for this study will be done only after obtaining informed consent. Assessments performed for clinical indications (not exclusively to determine study eligibility) may be used for baseline values even if the studies were done before informed consent was obtained.

All screening procedures must be performed on the day of registration unless otherwise stated. The screening procedures include:

1. Medical history -Complete medical and surgical history, family history including a multi-generation family pedigree, and social history
2. Demographics - Age, gender, race, ethnicity
3. Review subject eligibility criteria
4. Physical exam including vital signs, height and weight
5. Blood draw for correlative studies
6. DNA from whole blood will be isolated

Intervention Procedure:

Approximately 15 ml of blood will be drawn at the time of enrollment (one time blood draw) and sent to Myriad Genetics and Laboratories for analysis of 25 genes using next generation sequencing. This platform will sequence 25 genes in one experimental run and the results will be sent back to the cancer genetics clinic for interpretation and disclosure.

Randomization of the patient Population:

After results are given to the patient they will be randomized into 4 groups:

• Patients identified with a mutation in a gene not commonly tested for prior to the advent of multiplex panel testing. This excludes BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MYH unless a patient tested positive for one of these 9 genes but did not meet clinical criteria for the underlying syndrome (Stanford accrual goal is 62/USC 62)
• Patients identified with a variant of unknown significance (VUS) of any gene of any nonBRCA (BRCA1 and BRCA2) or non-Lynch syndrome gene (MLH1, MSH2, MSH6, PMS2 and EPCAM).

Stanford target accrual is 50 and 50 for USC.

• Patients who test negative for all the genes tested. Target goal is 50 for Stanford/50 for USC for the study.
• All other participants who do not meet any of the above criteria or fall into one of these groups after the target goal is met for that group. Only participants who are in the 1st three groups will be asked to complete questionnaires for the duration of the study (up to 60 months after enrollment)

Follow-up Procedures:

Patients (as noted above) will be followed at 3 months, 6 months, 12 months, 24 months, 36 months, 48 months, and 60 months

• At 3 months and 6 months after disclosure of genetic testing results, follow up questionnaires will ask if participants had initiated or intend to undergo any of the following risk reducing interventions and/or treatment: (i) Cancer surveillance/screening: breast MRI, mammograms, self-breast examinations, thyroid ultrasound, dermatology exams, urinalysis, upper endoscopy, colonoscopy, endometrial biopsy, transvaginal ultrasound, or other imaging (i.e. whole body rapid MRI) (ii) Chemoprevention/Behavior Modification: Tamoxifen, Oral Contraceptives (OCP), Raloxifene, Sulindac, Abstinence from Smoking (iii) Prophylactic procedures: Mastectomy, TAHBSO, polypectomy, total and segmental colectomy (iv) Cancer Treatment: aggregated pharmacologic and radiation therapy.

Inclusion Criteria:Screening Criteria Patients meeting one of the following criteria will be eligible for screening the study.

• Any individual with multiple primary cancers

• Any individual diagnosed with cancer under age 50

• Individuals with two or more first or second-degree relatives with cancer.

• Individuals from families where at least one family member was diagnosed with cancer under age 50

• Individuals meeting a phenotypic diagnosis of specific hereditary cancer syndromes including, but not limited to:

  • Hereditary Breast and Ovarian Cancer
  • Lynch Syndrome
  • Familial or Attenuated Adenomatous Polyposis Syndrome
  • Hereditary Melanoma Syndrome
  • Hereditary Pancreatic Syndrome
  • Li Fraumeni Syndrome
  • Cowden Syndrome
  • Hereditary Diffuse Gastric Cancer
  • Peutz Jeghers Syndrome
  • Juvenile Polyposis Syndrome
  • Ataxia Telangiectasia (Louis-Bar syndrome)

Individuals with a pretest mutation probability of > 2.5% based on validated published models 15

• Mismatch Repair (MMR)pro
• Prediction model for mutL homolog 1 (MLH1), muS homolg 2 (MSH2), and mutS homolog 6 (MSH6) gene mutations (Premm 1,2,6)
• Pancreas (Panc)Pro
• Melanoma (Mela)Pro
• Breast cancer (BRCA)Pro
• Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA)
• International Breast Cancer Intervention Study (IBIS) (Tyler-Cuzick)
• Myriad II
• Phosphatase and tensin homolog (PTEN) Cleveland Clinic Score
• Clinical probability of > 2.5% where models are not available

Or one of the following:

Individuals with a phenotypic diagnosis of the following recognized cancer genetic syndromes which automatically confers a clinical chance of > 2.5%:

• Hereditary Breast and Ovarian Cancer
• Lynch Syndrome
• Familial or Attenuated Adenomatous Polyposis Syndrome
• Hereditary Melanoma Syndrome
• Hereditary Pancreatic Syndrome
• Li Fraumeni Syndrome
• Cowden Syndrome
• Hereditary Diffuse Gastric Cancer
• Peutz Jeghers Syndrome
• Juvenile Polyposis Syndrome
• Ataxia Telangiectasia (Louis-Bar syndrome) Participation will be open to patients of both sexes, all races and ethnic backgrounds, and of all ages. Subjects will include healthy individuals, cancer survivors, and patients actively being treated for cancer. Individuals at-risk for a hereditary cancer syndrome under age 18 will eligible for HCP testing if they meet the eligibility criteria with written parental consent and child assent where appropriate. Cognitively impaired adult subjects will be invited to participate through the written, informed consent of a legal representative designated on the consent form.

Exclusion Criteria:

Patients meeting one of the following criteria will be excluded the study

• Individuals with a pretest mutation probability of < 2.5% based on validated published models
• Prior genetic testing for germline cancer susceptibility
• Inability to provide written informed consent

High-risk cancer genetics populations. Both male and female participants will be recruited.