Co-segregation Analysis Likelihood ratio Leiden (CAL-Leiden)

The Co-segregation Analysis Likelihood ratio Leiden (CAL-Leiden) program calculates the likelihood ratio (LR) for pathogenicity of variants of uncertain significance (VUS) in BRCA1, BRCA2, and PALB2 genes. Further details regarding the methodology can be found in [1, 2].

Data format : CanRisk 2.0

The supported data format for this tool aligns with the file format generated by and used in CanRisk (https://www.canrisk.org/). An example pedigree example.txt has been made available for use. Ensure that the pedigree data is correctly formatted according to CanRisk 2.0 specification.

How to use

Once the pedigree data is imported, you can proceed to select your population and gene of interest. Additionally, you can choose from three different versions of the model based on the considered follow-up:

  • Complete: This is the default option. Diagnoses of all gene-related cancers within a single person are considered. For BRCA1 and BRCA2, contralateral breast cancer is also taken into account.

  • First diagnosis: The person-specific follow-up is stopped after the first gene-related cancer diagnosis.

  • First diagnosis+CBC: Select this option when the first gene-related cancer is breast cancer, and you want to also account for contralateral breast cancer (CBC). Follow-up for other gene-related cancers is stopped after the primary breast cancer diagnosis.

Clicking on “Calculate LR” will provide you with the likelihood ratio. Additionally, you have the option to generate a PDF report, which can be saved for administrative purposes.

FAQ

  • LR is 1, how is it possible?

    • If the family being tested is carrying a Variant of Uncertain Significance (VUS) in a specific gene, and the datafile has been filled in accordingly, but you choose to calculate the Likelihood Ratio (LR) for a different gene on the website, the LR will become 1. This indicates that the chance that the variant under study is a pathogenic variant is similar to the chance that it is a benign variant.

  • Is it possible to exclude subsequent cancers in the calculation?

    • CAL-Leiden automatically takes other cancers and contralateral breast cancer into account. If you wish to include only the first cancer (i.e. youngest age of onset) in the calculation, please choose Follow-up::First diagnosis.

  • The pedigree doesn’t give the likelihood ratio. What is the reason?

    • The model can easily handle pedigrees with around 60-70 members, unless the pedigrees have a complex structure. That is because of the computational burden of the method. The possibility to prune the pedigrees is discussed in the article.

References

[1] Mohammadi L, Vreeswijk MP, Oldenburg R. et al. A simple method for co-segregation analysis to evaluate the pathogenicity of unclassified variants; BRCA1 and BRCA2 as an example. BMC Cancer (2009) PMID: 19563646

[2] Moghadasi S, Monajemi R, Braspenning M.E., Vreeswijk M.P.G., Rodríguez-Girondo M. A Comprehensive and Accessible Model for Co-Segregation Analysis in BRCA1, BRCA2, and PALB2 Variant Classification [doi:10.1101/2024.09.23.614309].

Contact

For inquiries, please feel free to reach out via email at: craft@lumc.nl. Please note CAL-Leiden in your subject. Your feedback is highly appreciated.


Pedigree file:

Examples

Below are three simple pedigrees in which family members III.4 and II.2 are carrying a Variant of Uncertain Significance (VUS) in BRCA1, BRCA2, or PALB2. They are both affected at the ages of 45 and 50 years, respectively. More examples can be found in the manuscript. Both Likelihood Ratios (LR) based on the Netherlands and United Kingdom population are reported.

1) LR: NL=1.4, UK=1.43

2) LR: NL=1.51, UK=1.54

3) LR: NL=1.56, UK=1.58

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