A Comprehensive and Accessible Model for Co-Segregation Analysis in BRCA1, BRCA2 , and PALB2 Variant Classification

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Variants of uncertain significance (VUS) are genetic variations with unclear clinical implications, often complicating clinical management in genetic testing. The analysis of co-segregation of the variant with the disease in families has been shown to be a powerful tool for the classification of these variants. We present CAL-Leiden (Co-segregation Analysis via Likelihood ratio analysis-Leiden), a comprehensive co-segregation model facilitating the classification of variants in BRCA1, BRCA2 and PALB2 genes, which can be used as an important component of the ACMG/AMP classification guideline. CAL-Leiden includes an expanded range of cancer types, including pancreatic cancer, in addition to breast and ovarian cancer. It also considers contralateral breast cancer. The model integrates population incidence rates from the Netherlands and the United Kingdom, along with penetrance data from the latest literature. A web-based platform has been developed, making the model accessible and practical for use in diagnostic labs: https://bioexp.net/cosegregation/ . We demonstrate the functionality of the tool with multiple pedigrees and compare its performance with alternative approaches. These features in CAL-Leiden collectively contribute to a more comprehensive and accurate assessment of variant pathogenicity, helping lab specialists in classification of the variants of uncertain significance.

Authors 5

1. Setareh Moghadasi Aachen Department of Clinical Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Genetics, Leiden University Medical Center, the Netherlands

2. Ramin Monajemi Aachen Department of Biomedical Data Sciences

   Leiden University Medical Center

   Affiliation as printed

   Department of Biomedical Data Sciences, Leiden University Medical Center, the Netherlands

3. Merel E. Braspenning Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, the Netherlands

4. Maaike P.G. Vreeswijk Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, the Netherlands

5. Mar Rodríguez‐Girondo corresponding Aachen Department of Biomedical Data Sciences

   Leiden University Medical Center

   Affiliation as printed

   Department of Biomedical Data Sciences, Leiden University Medical Center, the Netherlands