6) Genetic Variant

[Mirta Dozar]

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A genetic variant database contains information about genetic differences (also called genetic variants). Researchers submit data to these databases, which collect, organize, and publicly document the evidence supporting links between a human genetic variant and a disease or condition. These databases may make assertions about genetic variants, which are informed assessments of the correlation (or lack thereof) between a disease or condition and a genetic variant based on the current state of knowledge. Better understanding the relationships between genotypes (the genetic code of an organism) and diseases or conditions can aid in the diagnosis and treatment of individuals with genetic conditions.

FDA recognition of a database indicates that the FDA believes the data and assertions contained in the database can be considered valid scientific evidence. This program will allow sponsors to use the assertions within FDA-recognized databases to support the clinical validity of their tests.

Database administrators who wish to seek recognition for their databases should follow the recommendations outlined in the final guidance.

Participation in the FDA database recognition process is voluntary and participation does not subject the database to FDA oversight, beyond what is needed to retain the recognition. There are no user fees associated with the FDA Database Recognition program.

A request for recognition can be for the entire genetic variant database or for a subset of the database as decided by the database administrator. Submissions should demonstrate that the recommendations in the final guidance have been followed, or should explain why an alternative approach was taken.

1. Prior to submitting an application for database recognition, database administrators should contact FDA staff at OIRPM...@fda.hhs.gov to determine how to address their recognition request. Database administrators should then submit an application as an eCopy. The eCopy should be in the form of a DVD, CD, or flash drive and should be sent to the Document Mail Center at the following address:

A gene variant is a permanent change in the DNA sequence that makes up a gene. This type of genetic change used to be known as a gene mutation, but because changes in DNA do not always cause disease, it is thought that gene variant is a more accurate term. Variants can affect one or more DNA building blocks (nucleotides) in a gene.

Genetic research is a component of precision medicine, an emerging approach that considers individual variability in genes, environment, and lifestyle. Precision medicine will enable researchers and doctors to predict more accurately which treatment and prevention strategies will work in particular groups of people.

Some people learn their APOE status through consumer genetic testing. These products are available for a fee and provide some information around the results and what they mean. While at-home genetic tests are convenient, people considering them may also benefit from talking with a doctor or genetic counselor to better understand this type of test and their test results.

Research shows the rates of dementia vary among different racial and ethnic groups. While the concepts of race and ethnicity are socially defined, these social definitions offer researchers another way of looking at risk factors that may affect certain groups. These risk factors can include external influences, such as the environment, education, and income levels, as well as biological factors like genetics.

Tests are available to see if someone has inherited a harmful variant in BRCA1 and BRCA2. However, testing is not currently recommended for the general public. Instead, expert groups recommend that testing be focused on those who have a higher likelihood of carrying a harmful BRCA1 or BRCA2 variant, such as those who have a family history of certain cancers. Testing can be appropriate for both people without cancer as well as people who have been diagnosed with cancer. If someone knows they have a mutation in one of these genes, they can take steps to reduce their risk or detect cancer early. And if they have cancer, the information about their mutation may be important for selecting treatment.

Before testing is done, a person will usually have a risk assessment, in which they meet with a genetic counselor or other health care provider to review factors such as which of their relatives had cancer, what cancers they had, and at what ages they were diagnosed. If this assessment suggests that someone has an increased risk of carrying a harmful BRCA1 or BRCA2 gene variant, their genetic counselor can discuss the benefits and harms of testing with them and order the appropriate genetic test, if the individual decides to have genetic testing (22).

The United States Preventive Services Task Force recommends risk assessment for women who have a personal or family history of breast, ovarian, fallopian tube, or peritoneal cancer or whose ancestry is associated with having harmful BRCA1 and BRCA2 variants, as well as follow-up genetic counseling as appropriate.

The National Comprehensive Cancer Network (NCCN) has criteria for genetic testing of BRCA1 and BRCA2 as well as for several other genes (including CDH1, PALB2, PTEN, and TP53) that are associated with increased risk of breast and/or ovarian cancer (23). NCCN recommends risk assessment for people who have a blood relative with a known or likely harmful variant in any of these genes; who have certain personal and/or family histories of cancer (cancer diagnosed at a younger age, certain types of cancer, people with two or more cancer diagnoses, or families with multiple cases of cancer); or who have certain inherited cancer predisposition disorders, such as Cowden syndrome, Peutz-Jeghers syndrome, Li-Fraumeni syndrome, or Fanconi anemia.

The American Society of Clinical Oncology recommends that all women diagnosed with epithelial ovarian cancer be offered genetic testing for inherited variants in BRCA1, BRCA2, and other ovarian cancer susceptibility genes, regardless of the clinical features of their disease or their family history (24).

Professional societies do not recommend that children under age 18 undergo genetic testing for BRCA1 and BRCA2 variants. This is because there are no risk-reduction strategies that are specifically meant for children, and children are very unlikely to develop a cancer related to an inherited BRCA variant.

Testing for inherited BRCA1 and BRCA2 variants may be done using a blood sample or a saliva sample. That is because blood cells and cells that are present in saliva, like every cell in the body, contain the BRCA1 and BRCA2 genes. Sometimes people with cancer find out that they have a BRCA1 or BRCA2 mutation when their tumor is tested to see if they are a candidate for treatment with a particular targeted therapy. Because harmful BRCA variants reported in the tumor may be of somatic or germline origin, someone with such a variant in their tumor should consider having a germline genetic (blood) test to determine if the variant was inherited.

When a family history suggests the possibility that someone without cancer may have inherited a harmful variant in BRCA1 or BRCA2, it is best for a family member who has already been diagnosed with cancer to be tested, if such a person is alive and willing to get tested. If such testing reveals a known harmful variant, then testing the individual for that variant will provide a clear indication of whether they also carry it. If all family members with cancer are deceased or are unwilling or unable to have genetic testing, testing family members who have not been diagnosed with cancer may still be of value and provide good information.

People considering BRCA1 and BRCA2 variant testing may want to confirm their insurance coverage for genetic counseling and testing. Genetic counselors can often help answer questions about insurance coverage for genetic testing.

Negative result. A negative test result can have several meanings, depending on the personal and family medical history of the person who is tested and whether or not a harmful mutation has already been identified in the family. If a close blood relative of the tested person is known to carry a harmful BRCA1 or BRCA2 variant, a negative test result is clear: it means the tested person did not inherit the harmful variant that is present in the family and cannot pass it to their children. A person with such a test result, called a true negative, has a risk of cancer that is similar to that of someone in the general population. However, there are other factors besides genetic factors that may increase the risk of cancer, such as radiation exposures at an early age, and those factors should be considered in assessing their risk of cancer.

As more research is conducted and more people are tested for BRCA1 and BRCA2 variants, scientists will learn more about uncertain changes and cancer risk. Clinicians and scientists are actively working to share information on these mutations so that they can be reclassified as either clearly harmful or clearly not harmful (26, 27).

Genetic counseling can help a person understand what a VUS in BRCA1 or BRCA2 may mean in terms of their cancer risk. Until the interpretation of the variant is clarified, management of risk should be based on family history and other risk factors. However, it is important that a person who has a VUS test result regularly obtains updated information from the testing provider in case that VUS is reclassified as a harmful or likely harmful variant. Testing providers have different policies about notifying a tested person of a change in the interpretation of a VUS test result. Some will contact the tested person directly, whereas others place the responsibility on the tested person to check back in on a regular basis to learn of updates to the interpretation of their VUS test result.

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