Germline Burden Test

Overview

A gene-level statistical approach comparing the frequency of qualifying germline variants (typically (likely) pathogenic / pathogenic variants) in a case cohort against a reference population of controls. Common implementations use logistic regression or Fisher’s exact test to test whether a gene is significantly enriched for rare deleterious variants in the cases. The method is used to identify cancer-predisposition genes when case numbers are insufficient for linkage studies.

Used by

• Used in Daugs et al. to compare LP/PV frequencies in 25 HBOC-related genes across 372 pediatric cancer patients (cases) vs. gnomAD v3.1.1 non-cancer controls (n=74,023), using logistic regression and two-sided Fisher’s exact tests (p < 0.05 threshold); identified TP53, CHEK2, ATM, NF1, and NBN as significantly enriched PMID:29489754

Notes

• Results are sensitive to choice of control population; gnomAD non-cancer subsets are a common reference but may not fully exclude pre-symptomatic carriers.
• Multiple-testing burden scales with candidate gene set size; explicit correction is important.
• Statistical power is limited by small case cohorts; joint analysis across cohorts can augment power.

Sources

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