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Updated: Aug 18, 2025
07:15
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
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KMT2A-D pathogenicity, prevalence, and variation according to a population database.
Jenna K Larson1, DeVon N Hunter-Schlichting2,3, Erin L Crowgey4
1Deparatment of Genetic Counseling, University of Minnesota, Minneapolis, Minnesota, USA.
Cancer Medicine
|December 8, 2022
Summary
Pathogenic germline variants in KMT2A-D genes are more common in the general population than previously thought. These findings suggest incomplete penetrance for many variants, potentially impacting cancer predisposition.
Area of Science:
- Genetics
- Epigenetics
- Cancer Genomics
Background:
- The KMT2 gene family comprises crucial epigenetic regulators involved in gene expression.
- KMT2A-D genes are frequently altered in various cancers, with known roles in infant leukemia and other leukemias.
- The prevalence and penetrance of non-synonymous variations in these genes were previously unknown.
Purpose of the Study:
- To determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in KMT2A-D genes within a cancer-free adult population.
- To compare variant interpretation using manual genomic analysis versus an automated ACMG pipeline.
Main Methods:
- Utilized the Genome Aggregation Database (gnomAD) for variant data from cancer-free adults.
- Employed both manual genomic variant interpretation and an automated ACMG pipeline for variant classification.
- Focused on KMT2A, KMT2B, KMT2C, and KMT2D gene variants.
Main Results:
- The manual interpretation method identified significantly more P/LP variants (n=660) than the ACMG pipeline (n=89).
- Higher P/LP prevalence (1:112) and allele frequency (4.46E-03) were observed with the manual method compared to ACMG (1:832, 6.01E-04).
- Identified ancestry-exclusive variants and a higher frequency in males; many variants are linked to juvenile conditions.
Conclusions:
- Germline variation in KMT2A-D genes is more prevalent in cancer-free adults than anticipated.
- The findings suggest incomplete penetrance for many KMT2A-D variants.
- Further research is warranted to explore the genetic predisposition role of these variants in infant leukemia and pediatric cancers.
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