NCBI's Medical Genetics and Human Variation resources are used in both clinical and research
settings to help explore, diagnose, and treat conditions.
We'll examine these resources from the point of view of a practitioner whose fictitious
patient is a 40-year-old mother of two presenting with,
changes in bathroom habits, bleeding, and belly pain
a medical history of colonic polyps and, a family history of several forms of
cancers involving the colon, breast, and endometrium.
These features lead to a suspicion of Lynch Syndrome.
Here is a quick summary of a path the practitioner might take at NCBI to explore diagnosis and
treatment options for the patient.
We’ll examine each resource in a bit more detail after this summary.
We’ll lookup Lynch Syndrome in MedGen, NCBI's portal to medical genetics.
From MedGen we’ll link to GeneReviews, which can help to establish a diagnosis, including
recommendations for genetic tests that we find in GTR, NIH’s Genetic Testing Registry.
We’ll find a genetic test to order, then in ClinVar, a database reporting the clinical
significance of variations, we will explore a specific variant from the test results.
From ClinVar we’ll link to even more variant detail in dbSNP, our database of short nucleotide
polymorphisms.
And we now have ALFA, the Allele Frequency Aggregator, to give us population-associated
allele frequencies derived from subjects in dbGaP,
our database of Genotypes and Phenotypes, which includes subject-level studies on Lynch
Syndrome.
And finally, we’ll find potential Clinical Trials involving Lynch Syndrome.
Let’s look at these resources in more detail, starting with an entry for Lynch Syndrome
in MedGen.
This page provides many resources for disease descriptions.
We see in the Table of Contents, Professional Guidelines, Suggested Reading, Recent clinical
studies, and Recent systematic reviews.
I’ll focus on the Diagnosis section of GeneReviews, but you might also find useful the Differential
Diagnosis section.
Diagnosis is divided into Suggestive Findings, and Establishing the Diagnosis, where I’ll
start.
Here we see that a multi-gene panel including 4 mismatch repair genes, plus EPCAM, is most
likely to identify the genetic cause of the condition.
In addition, DNA methylation analysis of the MLH1 promoter region is recommended.
The practitioner can link to GTR to find genetic tests for these mismatch repair genes.
I’ll use this link for MSH6, which returns all tests that include that gene.
The practitioner narrows the list of tests by selecting CLIA Certified labs, in the United
States.
She selects, as an example, this Lynch Syndrome test, which includes deletion/duplication
analysis, recommended for the EPCAM gene, and sequence analysis of the entire coding
region, suitable for variant analysis of the 4 mismatch repair genes.
She follows the instructions to order the test from the lab.
Say your test results include the variant shown here in the MSH6 gene, p.Tyr214Ter,
a protein change from tyrosine to a stop codon at position 214 in one product of the MSH6
gene.
You can search ClinVar directly with that term, MSH6 p.Tyr214Ter.
Within the ClinVar record, you see the interpretation - pathogenic, and that this variant has been
reviewed by an Expert Panel.
You can also explore the Variant Details, including a link to the dbSNP entry,
where you can get allele frequencies from several sources, including our ALFA project,
the Allele Frequency Aggregator, which provides population frequencies for millions of variants
in dbGaP.
If you want to perform molecular analyses on Lynch Syndrome genetics, dbGaP houses studies
that provide access to molecular data, via an application.
Finally, your patient may want to participate in a clinical trial.
You can link to ClinicalTrials dot gov from our original MedGen record.
And try our ClinicalTrials Beta site.
We’ve come full circle in our Medical Genetics and Human Variation resources.
If you have questions or feedback about any of our resources, we'd love to hear from you.
Please use the Feedback button you'll find on most NCBI web pages.