Guided Practice Case: Leslie

Welcome to Your Patient!

Leslie, a 40-year-old mother of two, was referred for genetic testing by her gastroenterologist...

Key Symptoms: Changes in bathroom habits, bleeding and abdominal pain

She has a medical history of colonic polyps. Her family history reveals that her maternal grandmother, mother and uncle had several forms of cancers including colon, breast, and endometrium. Her gastroenterologist suspects Lynch Syndrome.

QUESTION: What do you think is wrong with Leslie?

**A Case Workup worksheet for use to keep track of your patient's information**

Researching the Referral

In this scenario, Leslie was referred to the genetics clinic because their preliminary diagnosies suggested that she might have a potentially serious genetic condition. If a known pathogenic genetic variant is found, it can validate the diagnosis and provide additional patient-specific information that might help customize her case management plan.

To learn more about a case, please click on the Referral icon above to open the form.
Read it over and fill in below what you can glean from the description and proposed preliminary diagnosis.

	Notes
Phenotype
Preliminary Diagnosis

To learn more about Lynch Syndrome, you can take a look in NCBI's MedGen Database with the search term Lynch_Syndrome[exacttitle]. In the "Disease Characteristics" section, scan the summary and consider accessing and reading the whole article. You may particularly be interested in the "Diagnosis" section through the "Establishing the Diagnosis" sub-section.

Note: GeneReviews® is a project run by the University of Washington producing expert-authored, point-of-care information with clinically relevant and medically actionable information for inherited conditions. It is an incredible review article-type of resource, and is thus featured in it's own section on relevant MedGen records - as an abstract with links to key sections.

What does the patient's genetic test report say?

In this scenario, the genetic test was selected and performed. The results have come back from the laboratory and have been sent to you for consultation.

To learn more about Leslie's genetic test results, please click on the Test Results icon above to open the form.
Read it over and fill in below what you can glean from the report with regard to any genetic variants found and anything they laboratory might be asserting about how this relates to the preliminary diagnosis.

	Notes
Genetic Variation(s)
Laboratory Assertion(s)

To find genetic tests for a condition-of-interest, you can search directly in the Genetic Testing Registry or on a MedGen disorder page on the right-hand side in the Genetic Testing Registry section - click See all.

What is currently known about the identified variant?

Genetic testing laboratories attempt to stay up to date with what is known about the genetic variants that they are assessing. However, it is sometimes valuable to quickly consult with national database of clinical variants (NCBI's ClinVar database) to learn what other organizations have asserted/interpreted for that variant, if anything. In addition to information from testing laboratories, ClinVar receives curated interpretations from authoritative sources such as ClinGen, ACMG and disorder-specific specialist panels.

To learn more about Leslie's genetic variants, search NCBI's ClinVar database with each of the variants indicated on the genetic test result:

MSH2 g.4951T>C OR MSH2 p.Glu48Ter

Look over the ClinVar records to identify variant's:

Clinical Interpretation
- Does this match what was listed on the lab report?
- Where on this record can you find out who submitted assertions and what evidence they pointed to?
HGVS (Human Genome Variation Syntax) aliases, in particular - look for the NG_ and the first NP_ accession-located variants.
- These will be helpful for mapping the variant on these structures and sequences.
dbSNP Link (and rsID) - The dbSNP database has been collecting biological genetic variant data for 25 years!
- Human population data has been added to relevant variant records from several major projects. What about your patient's variant?

	Notes on MSH2:g.4951T>C	Notes on MSH2:p.Glu48Ter
Variant Information: Asserted interpretation listed in ClinVar HGVS names from ClinVar What is the dbSNP rsID for this variant & is population data available in dbSNP?

Which of these variants warrant further investigation? Why?

What is currently known about the identified gene?

If a particular gene has been implicated in a genetic test results indicating a pathogenic variant exists in a patient, it is often helpful to understand what that gene is, what its normal function is, where it is found (cellular and tissue expression patterns), and other sources of accessible information, such as links to relevant scientific literature.

NCBI's Gene database aggregates data from many NCBI databases as well as other high-quality resources to provide information and links to help users find and understand what is currently known about a particular organism's gene.

To learn more about Leslie's the impacted gene, search NCBI's Gene database with the gene symbol indicated on the genetic test result and find the record for the human version.

Look over the Gene record that was implicated in the genetic test result and identify:

Summary
- What does this gene normally do? What else has been noted?
Expression
- In which tissues is this gene normally expressed? (Note there are several tissue sets from different project available to view. Try selecting them in the pull-down menu.)
Gene Ontology
- Where in the cell does this gene product act?
- In what processes/pathways?
- Is there more specific confirmation about what it does?

	Notes
Gene Information on the NCBI Gene record: Symbol & Name Gene Summary Gene/Tissue expression information Gene Ontology information

Does what you've found above make sense based on the patient's symptoms and personal and family history?

NCBI's Literature resources (PubMed, PMC, the Bookshelf) have lots of helpful information including things similar to things like this....

An example graphic describing the function of the MSH2 protein complex in DNA damage/repair

Map the variant through the bioinformatic flow!

Now that we understand which gene may be affected by the presence of the detected variant, mapping the variant through the central dogma of molecular biology can help indicate at which point it has its strongest impact.

Note: Currently, genetic testing laboratories most often use genomic DNA for their genetic tests - identifying a variant by its position on a particular chromosome. They most often report variants found in gene regions, since currently this is where most research has been focused on to explain impacts on human biology.

Click here to review an overview of the central dogma and genetic variation.

Graphic showing the bioinformatic flow steps for variant impact

In addition to a lot of helpful aggregated information, NCBI's Gene database provides links to visualization tools which can help to identify where a variant is located in several critical biomolecules.

To learn about the molecular impact of the genetic variant, begin your search on the relevant NCBI Gene record.

Click on helpful linked resources to map the location and infer it's impact through this bioinformation flow.

Genome Data Viewer shows the chromosome zoomed into the gene region. Note that you are looking at a portion of the chromosome (the accession shown is an NC_).

- - Type in the NP_000242.1:p.Glu48Ter in the top-left text box to search for the variant location.

Click here to find a direct link to the GDV display.

Try this!

Where is the variant located in relation to the indicated gene?
Based on the location of the variant and the type - what impact do you think it might have on the gene?

RefSeqGene Graphic view shows the gene region, including some areas upstream and downstream.

- - Type in the NG_007110.2:g.5210G>T in the top-left text box to search for the variant location.

Click here to find a direct link to the RefSeqGene Graphic display.

Try this!

Where is the variant located in relation to the gene structure?
Based on the location of the variant and the type - what impact do you think it might have on the gene expression and resulting transcript?

RefSeq Protein Graphic view shows the protein sequence, including conserved domains and other regions. Look for the record labeled DNA mismatch repair protein Msh2 isoform 1 [Homo sapiens] with the accession that matches what you found in ClinVar: NP_000242.1. (Hint: likely the last one.)

- - Type in the NP_000242.1:p.Glu48Ter in the top-left text box to search for the variant location.

Click here to find direct links to the RefSeq Protein Graphic display.

Try this!

- - - Where is the variant located in relation to the protein sequence and it's annotated functional domains?
      
      Click here to see something pretty cool.
      
      Click the image to open iCn3D and interact with the structure:

Based on the location of the variant and the type - what impact do you think it might have on the protein?

	Notes
Ultimate Impacted Biomolecule based on: GDV to view the chromosome and gene region RefSeqGene Graphics view of gene region and transcript(s) RefSeq Protein Graphics view of protein and domains CDD or iCn3D to view a structure

Let's put it all together to understand what is happening in the patient!

Leslie would like to have some answers.

Click here to review some things you may want to consider when formulating the answer to her questions.

- - Which gene is impacted by the genetic variation and what does the gene product normally "do"?
    - what is it's biomolecular function?
    - what is it's impact on cellular physiology?
    - in which cells/tissues is the gene product usually expressed?
  - Based on the patient's variation(s):
    - what do you think this would do to the gene product's structure and biomolecular function?
    - what would this do to cellular physiology?
    - what tissues or organs impact be impacted?
  - Based on the proposed impacted-tissues/organs, may some of the the patient's symptoms be explained by this? (validating her experience)

What do you think is happening in your patient?

	Notes
Diagnosis
Genetic Variation(s)
Proposed Molecular Mechanism of Variant Impact
How does this relate to the phenotype?

Take-away message!

Workflow: We've practiced this same step-by-step process to learn more about a different patient's genetic variant.

Genetic disorder: Missense variants causing premature termination in the production a critical protein can dramatically compromise both the function of that gene product, but also the function of a key biochemical pathway. In this case, several DNA damage sensing complexes are compromised by the lack of a functional MSH2 protein. With a dysfunctional DNA damage and repair system is not functioning optimally, damage due to intracellular or environmental exposure to mutagens can build up over time and cause dysregulation of cellular growth mechanisms - leading to cancer.

ANSWER

Last Reviewed: August 20, 2024