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The Secondary Genomics Finding Service (SGFS) is a team-based clinical service provided by NHGRI to Intramural Investigators employing exome/genome sequencing to accomplish their research goals. The SGFS will annotate de-identified research exome/genome data for the presence of possible actionable secondary variants. Any secondary variants found in the research data will be clinically confirmed. The SGFS will coordinate confirmatory samples and provide genetic counseling and results disclosure to participants with secondary findings.

Principal Investigators

The SGFS can support annotation of up to 2000 exomes/genomes per year on a first-come, first-served basis with a limit of 250 per year for any one study. The SGFS is open to any Intramural Investigator.

Please review the following documents prior to applying to the SGFS.

SGFS Documents and Guidance

SGFS Guidance Memo
Start here, describes SGFS processes in detail

SGFS Application
Complete the attached application, print and send via email to SGFS staff

Suggested language for protocols and consent
Suggested language to incorporate into your protocol and/or consent form describing the process of annotation and return of secondary findings through the SGFS service. SGFS staff are available if your IRB has questions. Contact Julie Sapp at sappj@mail.nih.gov for more information.

Please Note: An IRB-approved protocol and/or consent is not required to submit an application to utilize the SGFS. We understand that Investigators may need to amend existing protocols (or incorporate this procedure into planned protocols) to allow for the return of secondary findings to participants. Investigators are encouraged to apply to utilize the SGFS while their protocols are in development or under amendment. Sequence data will not be annotated until the SGFS has been able to review the IRB-approved protocol and consent that applies to your participant population.

Supplementary Documents

NIH Intramural Working Group on Secondary Findings
Background information on the rationale behind the development and implementation of the SGFS

NIH Intramural Policy for Secondary Findings from Next-Generation Sequencing Research

Darnell et al., 2016
Publication outlining a proposal for a centralized service to facilitate annotation and return of secondary genomic findings as part of the research enterprise

Kalia et al., 2017
Recommendations from the American College of Medical Genetics for the annotation and return of actionable secondary findings in clinical sequencing. Contains the most recent list of genes annotated for secondary findings by the SGFS.

  • Principal Investigators

    The SGFS can support annotation of up to 2000 exomes/genomes per year on a first-come, first-served basis with a limit of 250 per year for any one study. The SGFS is open to any Intramural Investigator.

    Please review the following documents prior to applying to the SGFS.

    SGFS Documents and Guidance

    SGFS Guidance Memo
    Start here, describes SGFS processes in detail

    SGFS Application
    Complete the attached application, print and send via email to SGFS staff

    Suggested language for protocols and consent
    Suggested language to incorporate into your protocol and/or consent form describing the process of annotation and return of secondary findings through the SGFS service. SGFS staff are available if your IRB has questions. Contact Julie Sapp at sappj@mail.nih.gov for more information.

    Please Note: An IRB-approved protocol and/or consent is not required to submit an application to utilize the SGFS. We understand that Investigators may need to amend existing protocols (or incorporate this procedure into planned protocols) to allow for the return of secondary findings to participants. Investigators are encouraged to apply to utilize the SGFS while their protocols are in development or under amendment. Sequence data will not be annotated until the SGFS has been able to review the IRB-approved protocol and consent that applies to your participant population.

    Supplementary Documents

    NIH Intramural Working Group on Secondary Findings
    Background information on the rationale behind the development and implementation of the SGFS

    NIH Intramural Policy for Secondary Findings from Next-Generation Sequencing Research

    Darnell et al., 2016
    Publication outlining a proposal for a centralized service to facilitate annotation and return of secondary genomic findings as part of the research enterprise

    Kalia et al., 2017
    Recommendations from the American College of Medical Genetics for the annotation and return of actionable secondary findings in clinical sequencing. Contains the most recent list of genes annotated for secondary findings by the SGFS.

Clinical Research Staff and Protocol Coordinators

The SGFS will annotate new and existing exome and genome sequencing data for the presence of "actionable secondary findings." Participants with confirmed secondary findings will be offered genetic counseling to disclose these results with the SGFS genetic counselor.

The complete Guidance Memo describes the SGFS in detail.

How does it work?

We review your research sequence data to look for possible secondary findings
  • We will review your de-identified data. All findings are considered preliminary until confirmed with a second sample.
  • We will call you if we find possible secondary variants for return.

Down arrow

We need to know who the best point of contact is for us to work with.
  • We will also want to talk with someone in your group who is familiar with the participant and can give us some basic information, like the participant's name and what language they speak, etc.

Down arrow

SGFS staff will coordinate getting a second sample from your participant
  • PLEASE REVIEW THE SECTION ON CONSENT FOR INFORMATION ABOUT HOW TO TALK WITH PARTICIPANTS ABOUT THIS POSSIBILITY
  • You will need to register your patient at the NIHCC (if he/she is not already registered) and enter an order in NHGRI Genomic Variant Confirmation (CRIS) for confirmation of research findings

Down arrow

We will confirm the preliminary finding and provide genetic counseling to your participant
  • We will send your participant a counseling letter, file the result in the NIH medical record, and complete a genetics consult

 

 

What's an actionable secondary finding and why return it?

  • Actionable secondary findings are generally unrelated to your primary research questions, but should be returned to participants
  • Currently, the American College of Medical Genetics recommends that variants in 59 genes be returned to people undergoing clinical sequencing - this is frequently referred to as the "ACMG list."
  • Secondary findings are genetic predispositions to treatable or preventable diseases that participants may not have been aware of - they have the potential to improve health outcomes for your participants and their families
  • Most participants, when asked, say that they would like to receive this kind of information.

What does genetic counseling for secondary findings look like?

A very brief outline of the results return counseling session is:

  • Disclosure of result
  • Communication of recommendations for healthcare
  • Family history and risk assessment
  • Psychosocial assessment
  • Referral to appropriate provider near the patient's home
  • A genetic counseling letter and the result will be sent to the patient and a genetics consult will be entered into CRIS.

Key points to consider when submitting an application to the SGFS

  • Don't give participants a choice about receiving secondary findings if you intend to submit your exome data to us for annotation; we assume that every patient's data we review has consented to have their exome analyzed for these variants
  • Consider characteristics about your cohort or an individual participant that might complicate the return of secondary variants and be honest about these complications when consenting participants (e.g., your cohort/participant is not English-speaking, lives outside the US, has little access to healthcare, or all three)

Confirmation of Secondary Variants

  • If a pathogenic or likely pathogenic variant is identified in one of the SGFS genes then confirmation by Sanger sequencing will be offered.
  • A new DNA sample will be required. Saliva is strongly preferred; in rare instances a blood sample or previously isolated DNA can be accepted. DNA can be collected via a saliva sample kit mailed to the patient by an SGFS staff member.
  • Direct submission of previously isolated DNA may be acceptable but submission of a saliva sample is strongly preferred.
  • Direct submission of previously isolated DNA can only be accepted for confirmation of secondary findings if:
    1. There is documentation that the new sample and the original sample were collected at a different times (i.e. independently of one another)
    2. The new sample was processed in a CLIA certified lab. DNA from any other source cannot be processed for confirmation of secondary findings

Ordering a confirmation test in CRIS

You are welcome to work with SGFS staff to obtain saliva collection kits to be mailed to participants who need to provide a confirmation sample. An ordering clinician from your team should use one of the following two CRIS orders to request confirmation testing in CRIS from a second DNA sample (see screenshot below as well):

A printout of this order must accompany sample submissions for confirmation testing. SGFS staff can help with this process.

  1. “Exome-Confirmation, Saliva, NHGRI”
  2. “Exome-Confirmation, Blood, NHGRI”
SGFS Printout

How do I explain this to our participants? What about consent?

The SGFS staff has some suggestions based our experience working with research participants who will receive secondary findings as part of their participation in an NIH research study. Suggested language to incorporate into protocols and consent forms can be found here.

In our experience, the wait between told that there is a possible secondary finding and actually getting that finding confirmed can be very anxiety provoking. To mitigate this, the SGFS staff member who will contact your participant to coordinate getting a confirmatory sample will not know the participant's possible finding and will simply state that there is a potential genetic finding that your team would like to learn more about and that this will require submission of a new sample. When consenting participants, it may be helpful to emphasize that the participant may be re-contacted in the future to provide another sample for any number of reasons, not solely to confirm a potential secondary finding.

Practical points to emphasize during consent

  • The purpose of annotating for and returning secondary findings is to improve outcomes for participants - most participants are very comfortable with this idea, even if seems like initially unwelcome information
  • Secondary variants will only be present in a small fraction of your participants
  • Not having any secondary findings present does not mean that a person has a "clean genetic bill of health" - they can still get any of the diseases associated with the genes we look at in our analysis
  • Participants who have secondary findings will receive genetic counseling about what the finding means for them and their family members and what next steps to take.
  • Clinical Research Staff and Protocol Coordinators

    The SGFS will annotate new and existing exome and genome sequencing data for the presence of "actionable secondary findings." Participants with confirmed secondary findings will be offered genetic counseling to disclose these results with the SGFS genetic counselor.

    The complete Guidance Memo describes the SGFS in detail.

    How does it work?

    We review your research sequence data to look for possible secondary findings
    • We will review your de-identified data. All findings are considered preliminary until confirmed with a second sample.
    • We will call you if we find possible secondary variants for return.

    Down arrow

    We need to know who the best point of contact is for us to work with.
    • We will also want to talk with someone in your group who is familiar with the participant and can give us some basic information, like the participant's name and what language they speak, etc.

    Down arrow

    SGFS staff will coordinate getting a second sample from your participant
    • PLEASE REVIEW THE SECTION ON CONSENT FOR INFORMATION ABOUT HOW TO TALK WITH PARTICIPANTS ABOUT THIS POSSIBILITY
    • You will need to register your patient at the NIHCC (if he/she is not already registered) and enter an order in NHGRI Genomic Variant Confirmation (CRIS) for confirmation of research findings

    Down arrow

    We will confirm the preliminary finding and provide genetic counseling to your participant
    • We will send your participant a counseling letter, file the result in the NIH medical record, and complete a genetics consult

     

     

    What's an actionable secondary finding and why return it?

    • Actionable secondary findings are generally unrelated to your primary research questions, but should be returned to participants
    • Currently, the American College of Medical Genetics recommends that variants in 59 genes be returned to people undergoing clinical sequencing - this is frequently referred to as the "ACMG list."
    • Secondary findings are genetic predispositions to treatable or preventable diseases that participants may not have been aware of - they have the potential to improve health outcomes for your participants and their families
    • Most participants, when asked, say that they would like to receive this kind of information.

    What does genetic counseling for secondary findings look like?

    A very brief outline of the results return counseling session is:

    • Disclosure of result
    • Communication of recommendations for healthcare
    • Family history and risk assessment
    • Psychosocial assessment
    • Referral to appropriate provider near the patient's home
    • A genetic counseling letter and the result will be sent to the patient and a genetics consult will be entered into CRIS.

    Key points to consider when submitting an application to the SGFS

    • Don't give participants a choice about receiving secondary findings if you intend to submit your exome data to us for annotation; we assume that every patient's data we review has consented to have their exome analyzed for these variants
    • Consider characteristics about your cohort or an individual participant that might complicate the return of secondary variants and be honest about these complications when consenting participants (e.g., your cohort/participant is not English-speaking, lives outside the US, has little access to healthcare, or all three)

    Confirmation of Secondary Variants

    • If a pathogenic or likely pathogenic variant is identified in one of the SGFS genes then confirmation by Sanger sequencing will be offered.
    • A new DNA sample will be required. Saliva is strongly preferred; in rare instances a blood sample or previously isolated DNA can be accepted. DNA can be collected via a saliva sample kit mailed to the patient by an SGFS staff member.
    • Direct submission of previously isolated DNA may be acceptable but submission of a saliva sample is strongly preferred.
    • Direct submission of previously isolated DNA can only be accepted for confirmation of secondary findings if:
      1. There is documentation that the new sample and the original sample were collected at a different times (i.e. independently of one another)
      2. The new sample was processed in a CLIA certified lab. DNA from any other source cannot be processed for confirmation of secondary findings

    Ordering a confirmation test in CRIS

    You are welcome to work with SGFS staff to obtain saliva collection kits to be mailed to participants who need to provide a confirmation sample. An ordering clinician from your team should use one of the following two CRIS orders to request confirmation testing in CRIS from a second DNA sample (see screenshot below as well):

    A printout of this order must accompany sample submissions for confirmation testing. SGFS staff can help with this process.

    1. “Exome-Confirmation, Saliva, NHGRI”
    2. “Exome-Confirmation, Blood, NHGRI”
    SGFS Printout

    How do I explain this to our participants? What about consent?

    The SGFS staff has some suggestions based our experience working with research participants who will receive secondary findings as part of their participation in an NIH research study. Suggested language to incorporate into protocols and consent forms can be found here.

    In our experience, the wait between told that there is a possible secondary finding and actually getting that finding confirmed can be very anxiety provoking. To mitigate this, the SGFS staff member who will contact your participant to coordinate getting a confirmatory sample will not know the participant's possible finding and will simply state that there is a potential genetic finding that your team would like to learn more about and that this will require submission of a new sample. When consenting participants, it may be helpful to emphasize that the participant may be re-contacted in the future to provide another sample for any number of reasons, not solely to confirm a potential secondary finding.

    Practical points to emphasize during consent

    • The purpose of annotating for and returning secondary findings is to improve outcomes for participants - most participants are very comfortable with this idea, even if seems like initially unwelcome information
    • Secondary variants will only be present in a small fraction of your participants
    • Not having any secondary findings present does not mean that a person has a "clean genetic bill of health" - they can still get any of the diseases associated with the genes we look at in our analysis
    • Participants who have secondary findings will receive genetic counseling about what the finding means for them and their family members and what next steps to take.

Laboratory and Bioinformatics Staff

The SGFS will annotate your existing research exome/genome sequence data for the presence of possible actionable secondary variants in a list of genes that the SGFS will develop, curate, and update. The current list is based on the genes and variant types specified by the most recent ACMG clinical ES/GS secondary findings report Kalia et al., 2017. This list will be re-evaluated and updated at least annually by the SGFS with notification of any changes in the list to currently participating PIs and all IRP IRBs.

Sequence Data Submission

Please ensure that your data do not include any participant identifiers. Please note files must be submitted in variant call (.vcf) format and should be restricted to the coding/splice regions of the genes included in the ACMG list of genes for return of secondary variants. See below for additional details:

VCF (Variant Call Format) file requirements

  1. VCF file
    1. If there is only one sample, a single VCF file for the patient is acceptable.
    2. If there are more than one sample, a single multi-sample VCF for all samples to be analyzed is acceptable. Please do not send individual VCF files.
  2. Bioinformatics pipeline
    1. We strongly recommend the VCF file to be generated using the GATK best practices pipeline
    2. For other pipelines, please check recommended QC filter to exclude low quality variants.
  3. Reference genome
    1. GRCh37, hg19 or other variation of reference human genome GRCh37/hg19 (eg. b37) is acceptable.
    2. Please note that hg38 is not accepted and will not be processed.

Pre-processing a VCF file

  1. VCF file must be restricted to ACMG 59 genes. Coordinates are provided as a BED file ACMG_59_isplice2_esplice2.bed. Please check the compatibility of chromosome notations (i.e. “chr1” vs “1”) when using the BED file for subsetting the VCF file.
  2. Filter the VCF file to only include high quality (“PASS”) variants. If GATK pipeline was not used, please filter variants to only include high quality variants suggested by the method used.

Mode of Transferring files

  1. For NIH investigators, please use NIH Secure Email to send the VCF file to henoke.shiferaw@nih.gov. 
  2. For non-NIH investigators, Globus is available to any investigator sending files to NIH (No license required). A Globus endpoint will be shared where the file can be transferred to.
Confirmation of Secondary Variants
  • If a pathogenic or likely pathogenic variant is identified in one of the SGFS genes then confirmation by Sanger sequencing will be offered. More information about this process can be found here.
  • A new DNA sample will be required which can be collected via a saliva sample kit mailed to the patient or a blood draw performed at the NIH Clinical Center.
  • Direct submission of previously isolated DNA may be acceptable but submission of a saliva sample is strongly preferred.
  • Direct submission of previously isolated DNA can only be accepted for confirmation of secondary findings if:
    1. There is documentation that the new sample and the original sample were collected at different times (i.e. independently of one another).
    2. The new sample was processed in a CLIA certified lab. DNA from any other source cannot be processed for confirmation of secondary findings.

SGFS Guidance Memo
Start here, describes SGFS processes in detail

SGFS Application
Complete the attached application, print and send to SGFS staff

  • Laboratory and Bioinformatics Staff

    The SGFS will annotate your existing research exome/genome sequence data for the presence of possible actionable secondary variants in a list of genes that the SGFS will develop, curate, and update. The current list is based on the genes and variant types specified by the most recent ACMG clinical ES/GS secondary findings report Kalia et al., 2017. This list will be re-evaluated and updated at least annually by the SGFS with notification of any changes in the list to currently participating PIs and all IRP IRBs.

    Sequence Data Submission

    Please ensure that your data do not include any participant identifiers. Please note files must be submitted in variant call (.vcf) format and should be restricted to the coding/splice regions of the genes included in the ACMG list of genes for return of secondary variants. See below for additional details:

    VCF (Variant Call Format) file requirements

    1. VCF file
      1. If there is only one sample, a single VCF file for the patient is acceptable.
      2. If there are more than one sample, a single multi-sample VCF for all samples to be analyzed is acceptable. Please do not send individual VCF files.
    2. Bioinformatics pipeline
      1. We strongly recommend the VCF file to be generated using the GATK best practices pipeline
      2. For other pipelines, please check recommended QC filter to exclude low quality variants.
    3. Reference genome
      1. GRCh37, hg19 or other variation of reference human genome GRCh37/hg19 (eg. b37) is acceptable.
      2. Please note that hg38 is not accepted and will not be processed.

    Pre-processing a VCF file

    1. VCF file must be restricted to ACMG 59 genes. Coordinates are provided as a BED file ACMG_59_isplice2_esplice2.bed. Please check the compatibility of chromosome notations (i.e. “chr1” vs “1”) when using the BED file for subsetting the VCF file.
    2. Filter the VCF file to only include high quality (“PASS”) variants. If GATK pipeline was not used, please filter variants to only include high quality variants suggested by the method used.

    Mode of Transferring files

    1. For NIH investigators, please use NIH Secure Email to send the VCF file to henoke.shiferaw@nih.gov. 
    2. For non-NIH investigators, Globus is available to any investigator sending files to NIH (No license required). A Globus endpoint will be shared where the file can be transferred to.
    Confirmation of Secondary Variants
    • If a pathogenic or likely pathogenic variant is identified in one of the SGFS genes then confirmation by Sanger sequencing will be offered. More information about this process can be found here.
    • A new DNA sample will be required which can be collected via a saliva sample kit mailed to the patient or a blood draw performed at the NIH Clinical Center.
    • Direct submission of previously isolated DNA may be acceptable but submission of a saliva sample is strongly preferred.
    • Direct submission of previously isolated DNA can only be accepted for confirmation of secondary findings if:
      1. There is documentation that the new sample and the original sample were collected at different times (i.e. independently of one another).
      2. The new sample was processed in a CLIA certified lab. DNA from any other source cannot be processed for confirmation of secondary findings.

    SGFS Guidance Memo
    Start here, describes SGFS processes in detail

    SGFS Application
    Complete the attached application, print and send to SGFS staff

Resources

SGFS Guidance Memo
Start here, describes SGFS processes in detail

SGFS Application
Complete the attached application and send to SGFS staff

SGFS Workflow

Suggested Language for Protocols and Consent
Suggested language to incorporate into your protocol and/or consent form describing the process of annotation and return of secondary findings through the SGFS service. SGFS staff are available if your IRB has questions - contact Julie Sapp at sappj@mail.nih.gov for more information

Genes Currently Annotated by SGFS for Secondary Findings

NIH Intramural Working Group on Secondary Findings
Background information on the rationale behind the development and implementation of the SGFS

NIH Intramural Policy for Secondary Findings from Next-Generation Sequencing Research

Darnell et al., 2016
Publication outlining a proposal for a centralized service to facilitate annotation and return of secondary genomic findings as part of the research enterprise

Kalia et al., 2017
Recommendations from the American College of Medical Genetics for the annotation and return of actionable secondary findings in clinical sequencing; contains the "ACMG 59 gene list"

Still have questions?

SGFS staff hold monthly office hours to answer questions and offer guidance. See schedule below for upcoming days, times and locations.

Date Time  Location
August 21, 2019 12:00 P.M. FAES Room 6 (10/B1C208)
September 10, 2019 11:00 A.M. FAES Room 7 (10/B1C206)
October 7, 2019 10:00 A.M. FAES Room 6 (10/B1C208)
November 20, 2019 2:00 P.M. FAES Room 7 (10/B1C206)

Additional dates/times will be added quarterly.

  • Still have questions?

    SGFS staff hold monthly office hours to answer questions and offer guidance. See schedule below for upcoming days, times and locations.

    Date Time  Location
    August 21, 2019 12:00 P.M. FAES Room 6 (10/B1C208)
    September 10, 2019 11:00 A.M. FAES Room 7 (10/B1C206)
    October 7, 2019 10:00 A.M. FAES Room 6 (10/B1C208)
    November 20, 2019 2:00 P.M. FAES Room 7 (10/B1C206)

    Additional dates/times will be added quarterly.

Staff

Service Head

Leslie G. Biesecker, M.D.
Leslie G. Biesecker, M.D.
  • Chief & Senior Investigator
  • Medical Genomics and Metabolic Genetics Branch

Annotation Support

Kate Driscoll
Kate Driscoll, Ph.D.
  • Research Fellow
  • Clinical Genomics Section
Jennifer Johnston
Jennifer Johnston, Ph.D.
  • Staff Scientist
  • Clinical Genomics Section

Genetic Counselor

Julie C. Sapp
Julie C. Sapp
  • Genetic Counselor
  • Clinical Genomics Section

Research Assistant

Anna Buser
Anna Buser
  • Research Assistant
  • Clinical Genomics Section

Last updated: August 5, 2019