BRCA1 description

Pathogenic variants in the BRCA1 gene are associated with hereditary breast and ovarian cancer (HBOC) syndrome, and convey a significantly increased risk of both breast and ovarian cancer. Studies have demonstrated that BRCA1 gene pathogenic variants can be associated with up to an 85% breast cancer risks and up to a 63% ovarian cancer risks. Furthermore, women with a BRCA1 pathogenic variant have an increased risk of a second breast cancer diagnosis (contralateral or ipsilateral). This risk has estimated to be up to 27% within the first 5 years of diagnosis and up to 40-50% within 20 years of initial diagnosis. Pathogenic variants in BRCA1 may also be associated with an increased risk of other types of cancer, including peritoneal, pancreatic, prostate, and male breast cancer. However, the exact level of risk is not yet known.

BRCA2 description

Pathogenic variants in the BRCA2 gene are associated with Hereditary Breast and Ovarian Cancer (HBOC) syndrome, and convey a significantly increased risk of several cancers, including breast, ovarian, pancreatic, melanoma, and prostate cancer. Studies have demonstrated that BRCA2 gene pathogenic variants can be associated with up to an 84% breast cancer risk and up to a 27% ovarian cancer risk. Furthermore, in women who have had breast cancer, having a BRCA2 pathogenic variant increases risk of a second breast cancer diagnosis (contralateral or ipsilateral). This risk has estimated to be up to 12% within the first 5 years of diagnosis and up to 40–50% within 20 years of initial diagnosis. BRCA2 pathogenic variants may also be associated with small increased risks of developing primary peritoneal, gallbladder, bile duct, and stomach cancer. However, these risks are not yet clearly defined.

Inheritance and Familial Implications

BRCA1 and BRCA2 pathogenic variants are inherited in a dominant pattern, meaning that anyone with a pathogenic variant has a 50% chance of passing it on to each of his or her children. Conversely, this also means that they have a 50% chance of not passing on the pathogenic variant to each child. Individuals who carry a BRCA1 or BRCA2 pathogenic variant do not have any control over whether or not a variant is passed on to their children. Both men and women can have pathogenic variants in BRCA1 or BRCA2 and can pass them down to their children, even though the cancer risks may be different for males and females. In addition to children, each first-degree relative (parents and full siblings) of someone with a BRCA1 or BRCA2 pathogenic variant has a 50% chance to have the same pathogenic variant.

Genetic testing is available to at-risk family members to determine if they also carry the identified BRCA1 or BRCA2 pathogenic variant. Because of the increased risks for certain cancers, identified carriers of the BRCA1 or BRCA2 should seek recommendations from their provider regarding future medical management. Those individuals found not to carry the familial BRCA1 or BRCA2 gene pathogenic variant will have risks similar to the general population.

BRCA High Risk Patient Criteria

The test is best suited for individuals with either a history of early onset breast or ovarian cancer or a strong family history of breast and/or ovarian cancer. Individuals with the following medical or family history factors should consider testing for mutations in BRCA1/2:

• Early onset breast cancer (under 50 years of age)
• Bilateral or multiple breast cancers
• Diagnosed with both breast and ovarian cancer
• Family history of breast and/or ovarian cancer
• Two or more BRCA1 or BRCA2 related cancers in a single family member
• Male breast cancer within family
• Ashkenazi Jewish ethnic background

Clinical Utility of BRCA Testing

• Guide decisions on prevention strategies (e.g. chemoprevention, prophylactic surgery)
• Increase surveillance for breast cancer
• Inform treatment decisions
• Identify family members at increased risk

Familial Studies Program

In the process of sequencing the patient’s DNA, we may identify a likely pathogenic genetic variant, or a genetic variant with uncertain pathogenicity (VUS). To help understand the significance of these types of variants, and how the patient and family members may be affected, Luminus offers a Familial Studies Program. Testing additional family members for the same variant observed in your patient, and determining the correlation between cancer history and occurrence of the variant, may provide further insight into the clinical relevance of the variant.

Below are the next-generation sequencing tests that Luminus Diagnostic offers for risk of hereditary breast cancer:

1. BRCA
2. BRCA Ashkenazi Jewish (3-Site)
3. BRCA Hispanic (8-Site)
4. Breast High Risk Panel
5. Single Site Testing

Reflex Options

1. BRCA with reflex to Breast High Risk Panel
2. BRCA Ashkenazi Jewish (3-Site) with reflex to BRCA
3. BRCA Ashkenazi Jewish (3-Site) with reflex to Breast High Risk Panel
4. BRCA Hispanic (8-Site) with reflex to BRCA
5. BRCA Hispanic (8-Site) with reflex to Breast High Risk Panel

Classification System

Luminus Diagnostics classifies variants using a 5-tier system based on the American College of Medical Genetics (ACMG) guidelines. Likely Benign and Benign variants are not reported.

Pathogenic
Mutations with known clinical significance and demonstrated to increase the risk of cancer

Likely Pathogenic
Genetic changes that have some preliminary clinical data suggesting an association with cancer but not sufficient to make a definitive determination of pathogenicity and associated cancer risk

Uncertain Pathogenicity (VUS) | Genetic changes with either conflicting data or no supporting data, thus a determination of pathogenicity cannot be made

Likely Benign
Genetic changes with strong but limited evidence to be classified as benign and are not likely to increase the risk for cancer

Benign
Genetic changes that are previously reported and have sufficient evidence to be classified as benign with no clinical relevance

TEST SPECIFICATIONS

Colorectal Tests analyze the coding and flanking regions (+/- 20 bp) of 13 genes associated with hereditary colorectal cancer (APC, BMPR1A, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53) by next-generation sequencing-based (NGS) and Sanger confirmation of reported gene variants. Additionally, site-specific analysis is performed to test for the variant defined as SNP309T>G in the MDM2 gene. Sanger fill-in is used for all genes in areas of low coverage, which is defined as a read depth of less than 25x. Gross deletions and duplications in the aforementioned 13 genes and EPCAM are identified by microarray analysis and multiplex ligation-dependent probe amplification (MLPA). Suspected deletions in exons 13-15 of PMS2 are confirmed with long range PCR to exclude the pseudogene signal.

TESTING OPTIONS

Below are the next-generation sequencing tests that Luminus Diagnostics offers for risk of hereditary colorectal cancer:

1. LynchSyndrome
2. Colorectal
3. Single Site Testing

Reflex Options

1. LynchSyndrome with reflex to Colorectal

Individuals who meet one or more of the following criteria should consider genetic testing for colorectal cancer:

• History of early onset colorectal or endometrial cancer
• History of ≥ 10 adenomas or polyps
• History of two of more associated cancers
• Two or more relatives with associated cancers, with one diagnosed <50yrs
• Three or more relatives with related cancers at any age
• Abnormal MSI and/or IHC testing

Positive for a Pathogenic or Likely Pathogenic Variant Detected

A variant was found that is known to be, or strongly thought to be, associated with an increased risk of developing certain cancer types. This does not mean the individual will develop cancer. Each pathogenic variant may convey a different specific risk of developing cancer in the individual’s lifetime. The report may specify the increased risk for the variant we identified or may give the general risks for the gene in which the variant was found.

Variant of Uncertain Significance Detected

A variant was detected, but at this time it is unclear whether the variant is associated with an increased risk of cancer or instead, is just a benign (non-harmful) change.

No Variant Detected

Although no variants known to increase the risk for cancer were found, this does not mean the individual will not develop cancer. The physician will determine the level of screening that is appropriate for the patient.