A Validated Functional Analysis of Partner and Localizer of BRCA2 Missense Variants for Use in Clinical Variant Interpretation.

Clinical genetic testing readily detects germline genetic variants. Yet, the rarity of individual variants limits the evidence available for variant classification, leading to many variants of uncertain significance (VUS). VUS cannot guide clinical decisions, complicating counseling and management.

Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.

Background: The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This includes the strong evidence codes PS3 and BS3 for "well-established" functional assays demonstrating a variant has abnormal or normal gene/protein function, respectively. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes are a contributor to variant interpretation discordance between laboratories.

Recommendations for the collection and use of multiplexed functional data for clinical variant interpretation.

Variants of uncertain significance represent a massive challenge to medical genetics. Multiplexed functional assays, in which the functional effects of thousands of genomic variants are assessed simultaneously, are increasingly generating data that can be used as additional evidence for or against variant pathogenicity. Such assays have the potential to resolve variants of uncertain significance, thereby increasing the clinical utility of genomic testing.

Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels.

Background: The 2015 American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that "well-established" functional studies can be used as evidence in variant classification. These guidelines articulated key attributes of functional data, including that assays should reflect the biological environment and be analytically sound; however, details of how to evaluate these attributes were left to expert judgment. The Clinical Genome Resource (ClinGen) designates Variant Curation Expert Panels (VCEPs) in specific disease areas to make gene-centric specifications to the ACMG/AMP guidelines, including more specific definitions of appropriate functional assays.

Quantifying the potential of functional evidence to reclassify variants of uncertain significance in the categorical and Bayesian interpretation frameworks.

Additional variant interpretation tools are required to effectively harness genomic sequencing for clinical applications. The American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) published guidelines for clinical sequence variant interpretation, incorporating different types of data that lend varying levels of support towards a benign or pathogenic interpretation. Variants of uncertain significance (VUS) are those with either contradictory or insufficient evidence, and their uncertainty complicates patient counseling and management.

Navigating the nuances of clinical sequence variant interpretation in Mendelian disease.

Understanding clinical genetic test results in the era of next-generation sequencing has become increasingly complex, necessitating clear and thorough guidelines for sequence variant interpretation. To meet this need the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for a systematic approach for sequence variant interpretation in 2015. This framework is intended to be adaptable to any Mendelian condition, promoting transparency and consistency in variant interpretation, yet its comprehensive nature yields important challenges and caveats that end users must understand.