Franklin's PMS2 biomarker reports copy number (CN) findings for the PMS2 gene. The biomarker displays information on PMS2 homologous region, i.e. exons 11–15, as calculated by Franklin's Rainbow homology model - a proprietary machine learning model. This model resolves CN at the exon level due to the high sequence homology of PMS2 with its pseudogene PMS2CL in exons 11–15.
How Franklin Calculates the PMS2 Biomarker
For each of the homologous exons (11–15), Franklin's Rainbow homology model estimates three CN values:
Total CN - the combined CN across PMS2 and PMS2CL for that exon.
PMS2 CN - the CN attributed specifically to PMS2.
PMS2CL CN - the CN attributed specifically to PMS2CL.
The individual PMS2 and PMS2CL estimates are derived from paralogous sequence variants (PSVs) - positions where PMS2 and PMS2CL differ - which allow the model to assign reads to one gene or the other and split the total CN between them.
Note: The scope of the biomarker is limited to the PMS2 homologous region, i.e. exons 11-15. CNVs detected outside this region are handled through Franklin's standard CNV detection.
Because of the ambiguous alignment of reads in exons 11–15 of PMS2, the Rainbow homology model estimates first the total CN of both genes. The total CN is predicted from the total depth of reads that map to either gene (including reads with mapping quality of zero (MQ0). The model is trained on a cohort of normals, similarly to Franklin’s general Rainbow CNV model. Since the reads are cumulative for both genes, the expected total CN for each exon is 4.
The predicted total CN is then split by the Rainbow homology model in order to predict the CN at any PSV in both genes separately. Treating the CNs at each PSV as evidence for the CN of the exon, the model selects the most likely CN as a whole, weighting each evidence by the quality of the prediction.
Note: The total CN is a more reliable value than the individual CN of each gene. A confidence level for the total CN value is calculated and provided on the biomarker tile (see below).
Biomarker Statuses
The PMS2 biomarker tile is displayed in the Additional Information section of the Workbench, having one of the following statuses:
Status | What it means |
Abnormal | An abnormal CN was detected in the PMS2 homologous region. An abnormal CN means that the total CN is not 4 for any of the scoped exons. |
Normal | No abnormal CN was detected in the PMS2 homologous region. A normal CN means that the total CN is 4 for each of the scoped exons. |
Call failed | The PMS2 calculation could not produce a reliable result for the sample. |
Not tested | The PMS2 calculation was not performed for the sample. |
Reading the Per-Exon Table
Expanding a Normal or Abnormal tile shows a table with one row per exon.
Table Columns
Column | Description |
Exon | The PMS2 exon number (11–15). |
Total CN | The combined CN across PMS2 and PMS2CL for the exon. When the total CN could not be determined, "No call" will be displayed instead of a number. |
Total CN Confidence | Franklin's confidence in the Total CN value, on the same four-level scale as Franklin's CNV confidence: High, Medium, Low, or Failed. The confidence is based on a Gaussian mixture log-likelihood of the model predictors. It estimates the likelihood of existence of a variant in this specific exon. |
PMS2 CN | The CN attributed to PMS2 for the exon. When the PMS2 CN could not be determined, "No call" will be displayed instead of a number. |
PMS2CL CN | The CN attributed to PMS2CL for the exon. When the PMS2CL CN could not be determined, "No call" will be displayed instead of a number. |
Number of supporting PSV | PSV evidence for the CN, split into a PMS2 sub-row and a PMS2CL sub-row and grouped by the CN each PSV points to. For example, "PMS2 → CN=2: 1 | CN=3: 3 | No call: 1" means a PMS2 CN of 2 is supported by one PSV, a PMS2 CN of 3 is supported by three PSVs, and one PSV in PMS2 could not be called. Higher counts indicate stronger evidence. |
Highlighted Exons
As mentioned, the expected Total CN for an exon across PMS2 and PMS2CL is 4. When an exon's Total CN is any value other than 4 (and not a "No call"), that value is shown in red and the entire row is displayed in bold. This allows you to quickly identify exons that contain a CN abnormality.
Reporting the PMS2 Biomarker
You can add/remove the PMS2 biomarker to/from the report using the biomarker tile menu. A report indication is shown on the tile once it has been added.
Note: An Abnormal biomarker is included in the report by default. A Normal biomarker is not included by default.
The level of detail included in the report is configurable. A report can be configured to include the biomarker status, together with either only the abnormal (highlighted) rows of the per-exon table, or the entire per-exon table.