New study evaluates 6,718 variants in PALB2, supporting improved variant interpretation for breast and pancreatic cancer risk assessment.
Ambry Genetics has contributed to new research using Multiplexed Assays of Variant Effect (MAVEs) to advance interpretation of genetic variants linked to hereditary cancer, with findings published in Nature Communications.
The study, led by researchers at Leiden University Medical Center in the Netherlands and supported by Ambry’s clinical data, focused on PALB2, a gene associated with hereditary breast and pancreatic cancer. Researchers evaluated 84% of all possible missense variants across 11 PALB2 exons, generating functional data for 6,718 variants.
Results showed 3,904 variants as functionally normal (58%), 2,422 as intermediate (36%), and 392 as functionally abnormal (6%) based on PARP inhibitor sensitivity, a measure of homologous recombination.
“This study represents a major step forward in our ability to interpret PALB2 variants at scale,” says Steven M Lipkin, MD, PhD, FACMG, chief medical officer at Ambry Genetics, in a release. “MAVEs are generating the type of functional evidence that will help bridge the gap between genomic data and clinical decision-making.”
Building on Previous MAVE Studies
The PALB2 findings build on Ambry’s earlier contributions to MAVE studies evaluating BRCA2 and MUTYH genes. The BRCA2 study, published in Nature, used CRISPR/Cas9 gene editing to assess nearly 7,000 variants, achieving a 91% theoretical classification rate when integrated into the ClinGen/ACMG/AMP framework.
The MUTYH study, published in The American Journal of Human Genetics, functionally tested over 10,000 variants, providing evidence to help clarify over 97% of uncertain variants in the gene associated with MUTYH-associated polyposis.
Ambry has validated and implemented eight cancer-focused MAVE studies into reporting workflows, including genes TP53, BRCA1, MSH2, BRCA2, MUTYH, RAD51C, and PTEN. PALB2 represents the newest addition to this evaluation process.
Clinical Impact and Future Applications
The company reports that MAVE-based reclassification efforts have contributed to thousands of patient variant reclassifications to date. MAVEs use ultra-high-throughput functional screens to evaluate thousands of variants simultaneously, helping address challenges in interpreting missense variants that have limited evidence.
“At Ambry, we’re committed to advancing the clinical utility of genomic data,” says Tom Schoenherr, CEO of Ambry Genetics, in a release. “Our work with researchers conducting MAVEs validates high-throughput functional analysis of genetic variants, transforming large-scale sequencing data into clinically actionable insights.”
Additional MAVE studies focused on oncology and rare disease genes are currently underway. Ambry Genetics, now a wholly owned subsidiary of Tempus AI Inc, provides clinical genomic testing services.
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