Ambry's Contributions to MAVEs Support Thousands of Patient Reclassifications and Expand to New Genes

New study published in Nature Communications builds on Ambry's contributions to MAVE research to deepen understanding of PALB2 and its role in hereditary cancer predisposition.

Ambry Genetics, a leader in clinical genomic testing, and now a wholly owned subsidiary of Tempus AI, Inc. (NASDAQ:TEM), today announced its contribution to new research leveraging Multiplexed Assays of Variant Effect (MAVEs) studies to advance interpretation of hereditary cancer-linked genetic variants, published in Nature Communications. Led by researchers at Leiden University Medical Center in the Netherlands and supported by Ambry's extensive clinical data, this study revealed previously unfounded missense pathogenicity in PALB2.

PALB2 is one of the most clinically important genes associated with hereditary breast and pancreatic cancer. However, many PALB2 missense variants have remained difficult to interpret due to limited evidence and lack of support for missense variation as a mechanism of disease. This newly published study helps address these challenges by using MAVEs — ultra-high-throughput functional screens that evaluate thousands of variants— to reveal how variants influence clinically relevant functions.

Researchers assayed 84% of all possible missense variants across 11 PALB2 exons, generating functional data for 6,718 variants. The results reflected 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. These findings pave the way for improved variant interpretation, clinical management, and personalized treatment strategies for individuals carrying PALB2 variants.

"This study represents a major step forward in our ability to interpret PALB2 variants at scale," said Steven M. Lipkin, MD, PhD, FACMG, Chief Medical Officer at Ambry Genetics. "MAVEs are generating the type of functional evidence that will help bridge the gap between genomic data and clinical decision-making. This research is a crucial part of our broader mission to advance precision medicine, reduce the rate of variants of uncertain significance, and improve outcomes for individuals at risk for hereditary cancer."

The PALB2 findings build on Ambry's earlier contributions to MAVEs to evaluating BRCA2 and MUTYH led by teams at the Mayo Clinic and the University of Michigan, respectively. The results of these functional studies were published in Nature and The American Journal of Human Genetics.¹²

The Nature study used CRISPR/Cas9 gene editing to functionally assess nearly 7,000 BRCA2 variants. Findings were integrated into the ClinGen/ACMG/AMP framework, resulting in a 91% theoretical classification rate—marking a major step forward in the future of hereditary cancer and demonstrating the potential of these studies to resolve VUS and improve clinical decision-making. ²

The American Journal of Human Genetics study used a MAVE to functionally test nearly every possible mutation in MUTYH, over 10,000 variants in total. The results provided evidence to help theoretically clarify over 97% of uncertain variants in MUTYH, a gene associated with MUTYH-associated polyposis (MAP), an autosomal recessive hereditary condition linked to colorectal cancer.¹

"At Ambry, we're committed to advancing the clinical utility of genomic data. Our work with researchers conducting MAVEs validates high-throughput functional analysis of genetic variants, transforming large-scale sequencing data into clinically actionable insights that support more precise risk assessment and patient care," said Tom Schoenherr, CEO of Ambry Genetics.

Ambry has validated and implemented eight cancer-focused MAVE studies into reporting workflows, including comprehensive reclassification efforts for the following genes: TP53, BRCA1, MSH2, BRCA2, MUTYH, RAD51C, PTEN. PALB2 is the newest gene to undergo comprehensive MAVE-based evaluation, contributing to thousands of patient variant reclassifications to date. Additional MAVE studies focused on oncology and rare disease genes are already underway. Large-scale reclassification efforts, such as those supported by MAVEs, are increasingly recognized as a powerful tool in clinical genomics, supporting more confident variant classifications and accelerating diagnoses.

About Ambry Genetics ®

Ambry Genetics, a wholly owned subsidiary of Tempus, translates scientific research into clinically actionable test results based upon a deep understanding of the human genome and the biology behind genetic disease. It is a leader in genetic testing and aims to improve health by understanding the relationship between genetics and disease. Over its 25-year history, Ambry has remained committed to empowering patients to make informed healthcare decisions based on their genetic data.

About TEMPUS®

Tempus is a technology company advancing precision medicine through the practical application of artificial intelligence in healthcare. With one of the world's largest libraries of multimodal data, and an operating system to make that data accessible and useful, Tempus provides AI-enabled precision medicine solutions to physicians to deliver personalized patient care and in parallel facilitates discovery, development and delivery of optimal therapeutics. The goal is for each patient to benefit from the treatment of others who came before by providing physicians with tools that learn as the company gathers more data. For more information, visit tempus.com.

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